Effects of Exercise Training on Neurotrophic Factors and Subsequent Neuroprotection in Persons with Multiple Sclerosis—A Systematic Review and Meta-Analysis

Abstract

Background: Evidence indicates that exercise holds the potential to counteract neurodegeneration experienced by persons with multiple sclerosis (pwMS), which is in part believed to be mediated through increases in neurotrophic factors. There is a need to summarize the existing evidence on exercise-induced effects on neurotrophic factors alongside neuroprotection in pwMS. Aim: To (1) systematically review the evidence on acute (one session) and/or chronic (several sessions) exercise-induced changes in neurotrophic factors in pwMS and (2) investigate the potential translational link between exercise-induced changes in neurotrophic factors and neuroprotection. Methods: Five databases (Medline, Scopus, Web of Science, Embase, Sport Discus) were searched for randomized controlled trials (RCT) examining the effects of exercise (all modalities included) on neurotrophic factors as well as measures of neuroprotection if reported. The quality of the study designs and the exercise interventions were assessed by use of the validated tool TESTEX. Results: From N = 337 identified studies, N = 14 RCTs were included. While only N = 2 of the identified studies reported on the acute changes in neurotrophic factors, all N = 14 RCTs reported on the chronic effects, with N = 9 studies revealing between-group differences in favor of exercise. This was most prominent for brain-derived neurotrophic factor (BDNF), with between-group differences in favor of exercise being observed in N = 6 out of N = 12 studies. Meta-analyses were applicable for three out of 10 different identified neurotrophic factors and revealed that exercise can improve the chronic levels of BDNF (delta changes; N = 9, ES = 0.78 (0.27; 1.28), p = 0.003, heterogeneity between studies) and potentially also ciliary neurotrophic factor (CNTF) (N = 3, ES = 0.24 (−0.07; 0.54), p = 0.13, no heterogeneity between studies) but not nerve growth factor (NGF) (N = 4, ES = 0.28 (−0.55; 1.11), p = 0.51, heterogeneity between studies). Indicators of neuroprotection (e.g., with direct measures of brain structure assessed by MRI) were assessed in N = 3 of the identified studies only, with N = 2 partly supporting and thus indicating a potential translational link between increases in neurotrophic factors and neuroprotection. Conclusion: The present study reveals that exercise can elicit improvements in chronic levels of BDNF in pwMS, whereas the effects of exercise on chronic levels of other neurotrophic factors and on acute levels of neurotrophic factors in general, along with a potential translational link (i.e., with exercise-induced improvements in neurotropic factors being associated with or even mediating neuroprotection), are sparse and inconclusive. There is a need for more high-quality studies that assess neurotrophic factors (applying comparable methods of blood handling and analysis) concomitantly with neuroprotective outcome measures. Review Registration: PROSPERO (ID: CRD42020177353).

The impact of aerobic and resistance training intensity on markers of neuroplasticity in health and disease

“…Cross-sectionally, cardiorespiratory fitness is associated with regional brain volume, gray and white matter integrity especially in the entorhinal cortex and hippocampus in humans and animals, implying AT-induced neurogenesis (Burzynska et al, 2015;Tsai et al, 2018). It is assumed that high-more so than low-intensity AT-generated lactate stimulates the proliferation of neurons and glia cells and brain-derived neurotrophic factor production (Diechmann et al, 2021;Ruiz-Gonzalez et al, 2021). However, recent evidence seems to question the neurogenesis mechanism at least in humans (Gogniat et al, 2021;Hvid et al, 2021;Nano and Bhaduri, 2022).…”

“…The included studies did not specifically address which direction would exercise intensity tilt the balance between the favorable antioxidant effects of AT and unfavorable reactive oxygen species-generation with respect to NP (Flockhart et al, 2021;Radak et al, 2013). While the prevailing view is that RT acts primarily through insulin-like growth factor-1 mechanisms and promotes NP in an exercise intensity-dependent manner (Amiri et al, 2021;de Alcantara Borba et al, 2020;Jiang et al, 2020), there is also strong recent evidence suggesting that levels of circulatory brain-derived neurotrophic factor change independent of exercise type, intensity, duration, age, and health history (Babaei and Azari, 2021;Diechmann et al, 2021;Ruiz-Gonzalez et al, 2021). However, the results, including those with RT in particular, are highly inconsistent: some studies across the intensity spectrum reported no changes, increases, or even reductions in insulin-like growth factor levels (Chow et al, 2021;Coelho-Junior et al, 2020;Moreno-Cabanas et al, 2022;Olesen et al, 2021) (Table 2).…”

“…The number of studies or the percent of heterogeneity did not drive the somewhat higher effect size for high-intensity training effects in NEU (N s = 12, I 2 = 71 %) than HOA (N s =14, I 2 = 49 %). While there have been reviews examining the effects of fitness, acute and chronic bouts of exercise on markers of NP in PwMS, PwPD, and PwST, none did metaanalytically examine interactions among exercise type, exercise intensity, NP domains, and populations (Ada et al, 2006;Calautti and Baron, 2003;Cruickshank et al, 2015;Diechmann et al, 2021;Dorsch et al, 2018;Ferreira et al, 2021;Gamborg et al, 2022;Hvid et al, 2021;Jorgensen et al, 2017;Lin et al, 2021;Ploughman et al, 2015;Ramazzina et al, 2017;Roeder et al, 2015;Ruiz-Gonzalez et al, 2021;Salter et al, 2016;Sandroff et al, 2020;Tablerion et al, 2020;Tillman et al, 2015;Wonsetler and Bowden, 2017). Our results in NEU agree with the general conclusions of these reviews that high-intensity AT is a feasible rehabilitation option for each of the three patient groups with the caveat that potential intensity-related side effects rarely assessed or reported (see limitation 4 in Section 4.4).…”

“…On the other hand, the prescription of exercise for healthy adults across the lifespan and rehabilitative exercise for patients has undergone a major paradigm shift to intensities often used by athletes (Boyne et al, 2019;Cancela et al, 2020;Conradsson et al, 2015;Constans et al, 2021;Crozier et al, 2018;Dempsey et al, 2022;Diechmann et al, 2021;Frazzitta et al, 2014;Gamborg et al, 2022;Hejazi, 2017;Hsu et al, 2021;Hu et al, 2021;Hugues et al, 2021;Johansson et al, 2020;Kolmos et al, 2016;Landers et al, 2019;Langeskov-Christensen et al, 2021;Luo et al, 2019;Martland et al, 2020;Morberg et al, 2014;Okamoto et al, 2021;Orban et al, 2019;Renteria et al, 2020;Rosenfeldt et al, 2021;Steen Krawcyk et al, 2019;Tang et al, 2016;Taylor et al, 2022;Tollar et al, 2021;Tollár et al, 2018Tollár et al, , 2020Zimmer et al, 2018). For example, PwMS, PwPD, and PwST exercised at 80 % of the age-predicted maximum heart rate (Tollar et al, 2021;Tollár et al, 2018Tollár et al, , 2020.…”

Investigation of in-phase bilateral exercise effects on corticospinal plasticity in relapsing remitting multiple sclerosis: a multiple baseline design

“…Corticospinal plasticity is exercise-dependent (34,35) and influenced by various factors (36,37), such as aerobic exercise (22,(38)(39)(40), resistance training (22,40), as well as interlimb coordination (41,42). Previous studies that assessed corticospinal plasticity using TMS in healthy participants and in chronic stroke survivors, reported that interlimb coordination and especially inphase bilateral movement has the strongest effect on corticospinal plasticity (43)(44)(45)(46).…”