Exercises and Brain Stimulation to Preserve Function in Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.

Abstract

Background and objectives: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease leading to the loss of motor function and muscle strength. Nonpharmacologic neuromodulative therapeutic approaches such as active exercise may contribute to preserve motor functions in ALS, but this hypothesis remains debated. The present meta-analysis first aimed to evaluate the effect of active exercise on function and muscle strength preservation. Moreover, since the responsiveness to induced neuroplasticity of patients with ALS is being discussed, the second objective was to review the analogous effects of noninvasive brain stimulation (NIBS).

Methods: Following PRISMA guidelines, we systematically reviewed PubMed, CENTRAL, NIH PMC, PEDro, ScienceDirect, and Web of Science databases from the period between January 10 and July 1, 2023. Criteria limited inclusion to randomized controlled trials comparing active exercise (aerobic or resistance) with usual care or NIBS with sham. The primary outcome was assessed based on functional assessment scores reported on validated clinical scales, and the secondary outcome analysis included muscle strength and neurophysiologic changes. Methodologic quality of the selected studies was assessed using the Physiotherapy Evidence-Based (PEDro) scale. Relative risk (RR) and heterogeneity (I²) were calculated with Revman software, and evidence quality was estimated by the GRADE quality scale.

Results: Thirteen studies were included. Analysis involved 393 patients among whom 164 underwent active exercise and 155 received usual care, 41 received NIBS and 33 underwent sham stimulations. The nature of active exercise was consistent across studies but varied in frequency. NIBS parameters were consistent for stimulation sites and session frequency. Function was significantly preserved in 5 of 9 studies on active exercise and 2 of 4 NIBS trials. Meta-analysis on functional scales indicated a moderate quality of evidence for the effectiveness of active exercises (RR = 0.61 [0.18, 1.04] with I² = 69%) compared with usual care and very low quality of evidence for NIBS (RR = -1.41 [-0.44, 3.26] with I² = 89%). Only 1 NIBS study revealed neuroplastic changes in the brain.

Discussion: Active exercise likely slows functional loss in ALS, but the effects of NIBS need further investigation to support their neuroprotective effectiveness. Moreover, both interventions require further neurophysiologic investigation to elucidate ALS neuroplasticity.

Trial registration information: This review has been registered in PROSPERO (CRD42023408121).