Exercise Ameliorates Neurocognitive Impairments in a Translational Model of Pediatric Radiotherapy

Abstract

Background

While CRT is an effective treatment, healthy areas surrounding irradiation sites are negatively affected. Frontal lobe functions involving attention, processing speed and inhibition control are impaired. These deficits appear months to years after CRT and impair quality-of-life. Exercise has been shown to rejuvenate the brain and aid in recovery post-injury through its effects on neurogenesis and cognition.

Methods

We developed a juvenile rodent CRT model that reproduces neurocognitive deficits. Next, we utilized the model to test whether exercise ameliorates these deficits. Fischer rats (31-days old) were irradiated with a fractionated dose of 4Gy x 5 days, trained and tested at 6, 9, and 12 months post-CRT using 5-Choice Serial Reaction Time Task. After testing, fixed rat brains were imaged using diffusion tensor imaging and immunohistochemistry.

Results

CRT caused early and lasting impairments in task acquisition, accuracy, and latency to correct response, and also caused stunting of growth, changes in brain volume and diffusion. Exercising after irradiation improved acquisition, behavioral control, processing speed, mitigated the stunting of brain size, and increased brain fiber numbers compared to sedentary CRT values. Further, exercise partially restored global connectome organization including assortativity and characteristic path length, and while it did not improve the specific regional connections that were lowered by CRT, it appeared to remodel these connections by increasing connectivity between alternate regional pairs.

Conclusions

Our data strongly suggests that exercise may be useful in combination with interventions aimed at improving cognitive outcome following pediatric CRT.