Abstract
Introduction:
We aimed to determine the effect of regular exercise on aerobic capacity, strength values, and plasma levels of Nerve Growth Factor (NGF) and Neurotrophin-3 (NT-3) in patients with multiple sclerosis (MS) and investigate its effects on MS symptoms including cognitive impairment, fatigue, balance disorders, and quality of life (QOL).
Methods:
Forty-three relapsing-remitting MS patients with an Expanded Disability Status Scale (EDSS) score of 4 or less participated in the study. Participants were divided into three groups: aerobic group, strength group, and control group. The patients in the exercise groups had exercise programs three days a week for three months. Aerobic capacity (maximum VO2 value), strength measurements, and balance tests were done, and NGF and NT-3 plasma levels were analyzed in all participants at the beginning and end of the study. Multiple Sclerosis Quality of Life-54 (MSQoL-54), fatigue impact scale, Pittsburgh Sleep Quality Index (PSQI) and, to evaluate cognitive functions, BICAMS scale were applied.
Results:
Aerobic exercise and strength exercise groups had significant increases in VO2 max, back and leg strength values, and NGF and NT-3 plasma levels (p<0.01). Cognitive functions, fatigue, sleep quality, and QOL significantly improved in the exercise groups (p<0.01). The balance values were also significantly improved in the aerobic group (p<0.01), and althoughimprovement although improvement was observed in the strength group, it was not statistically significant (p>0.05).
Conclusions:
Our study provides evidence that regular exercise improves quality of life, cognitive functions, fatigue, and sleep quality in MS patients. The levels of NGF and NT-3, which are important factors in neural regeneration and remyelination, were increased post exercise. It can be suggested that exercise may have a potential effect on MS and slow down the disease process with these results.
Keywords: Cognition, exercise, multiple sclerosis, neurotrophin-3, nerve growth factor, quality of life
INTRODUCTION
Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disorder characterized by inflammation, demyelination, axonal damage, and gliosis, particularly affecting white matter, and gray matter (1). It is the most common disorder of the central nervous system (CNS) that causes neurological disability in young adults (2). Various degrees of physical and cognitive impairments are seen starting in the early period and particularly in the progressive course of the disease (2).
One of the most common complaints affecting the quality of life of MS patients is fatigue. Fatigue may develop as a result of CNS involvement, or due to depression, muscle weakness, spasticity, and sleep disturbances accompanying MS (2). Sleep disorders are more common in MS compared to the normal population, and more than 50% of MS patients have poor sleep quality (3). Balance disorders are one of the most common complaints seen in 50–80% of MS patients leading to a significant decrease in the quality of life. (4,5). As a result of all the aforementioned factors, MS patients usually adopt a sedentary life.
Physical inactivity may lead to progressive muscle atrophy in MS patients due to insufficient neural stimulation to the muscles (6). In MS patients, maximal oxygen consumption (VO2 max), which is a marker of cardiorespiratory fitness and functional performance, has been shown to decrease (7). All of these conditions may lead to worsening of MS symptoms and fatigue, which may result in a vicious cycle and cause reduced physical activity and a decrease in the quality of life.
Highlights
Exercise increases neurotrophic factors and improves physical capacity.
Neurotrophic factors are important for central nervous system health.
Because of the disease symptoms, people with MS may adopt a sedentary lifestyle.
Exercise programs should be arranged in accordance with the person and the disease.
Exercise has numerous neurobiological effects, including anatomical and physiological changes in the brains of healthy and unhealthy individuals (8). Exercise provides comprehensive alterations in cerebrovascular structures such as blood flow, nutrient delivery, angiogenesis, and regeneration of blood vessels (9). It is believed that exercise activates molecules and cellular cascades that support and maintain brain plasticity, facilitate neurogenesis, and thus may be effective in neurodegenerative processes and cognitive disorders (10). It has been shown in many studies that there is an increase in the level of neurotrophins, which play a role in the survival of neurons and the formation of new neurons during exercise (11). Neurotrophins (NT) are growth factors that provide the survival and hypertrophy of neurons, as well as neurogenesis and synaptic plasticity (12). They are synthesized by a number of cell types including peripheral nervous system neurons, peripheral tissues, and particularly in the CNS (13,14). They are divided into six subclasses: Nerve Growth Factor (NGF), Brain-derived neurotrophic factor (BDNF), Neurotrophin-3 (NT-3), Neurotrophin -4/5 (NT-4/5), Neurotrophin-6 (NT-6) and Neurotrophin-7 (NT-7) (15). Nerve growth factor is the first identified neurotrophin (15). They are necessary for the growth, maturation, regeneration of neurons, and neurotransmitter function (16). Brain-derived neurotrophic factor is an essential neurotrophin that controls cognitive state, neuroplasticity and angiogenesis, biological activities crucial to learning, and memory development (17). Neurotrophin-3 and NT-4 have an important role in the survival of neurons. It has been shown that low NT-3 levels are associated with brain atrophy (18). Although the effect of exercise on BDNF and NGF has been widely studied, there are a limited number of studies in humans investigating the relationship between NT-3 and NT4 and exercise (11).
In this study, we aimed to investigate the effect of regular exercise on aerobic capacity and strength values and to determine whether exercise contributes to the improvement of cognitive, balance, sleep quality and fatigue, and quality of life in MS patients. Our other aim was to examine the effect of exercise on NGF and NT-3 neurotrophins, which have important roles in the survival of neurons and cognitive functions.
METHODS
Study Design
A total of 53 relapsing-remitting form MS (RRMS) patients between the ages of 18 and 55 years, diagnosed with definite MS according to 2017 McDonald criteria, and followed up in Ege University MS and Demyelinating Diseases Unit, without an MS attack in the last three months, and had an Expanded Disability Status Scale (EDSS) score ≤4 that did not change with symptomatic or immunomodulatory treatments within six months were included in this prospective randomized controlled study. The procedures and possible side effects (such as exercise-related injuries and having an MS attack) were explained in detail to each participant candidate, and the Informed Consent Form was signed by the volunteers. Ege University Clinical Research Ethics Committee (date: 03 April 2019, decree no: 19-4T/43) and ClinicalTrials.gov (ClinicalTrials.gov ID: NCT04944251) approved the study protocol.
The patients who participated in the study and wished to be included in the exercise group were randomly allocated to the aerobic exercise and strength exercise groups. The patients who wanted to participate in this study for the tests and measurements to be made but did not want to exercise because of the fear that the exercise program would exacerbate MS symptoms were also included in the study as a control group. Four patients in the aerobic group and six patients in the strength group could not complete the study due to reasons such as knee pain (1), not attending exercise sessions regularly (8), and not attending control measurements (1).
Exercise procedures
The patients in the exercise groups carried out tailored exercise programs under the supervision of a faculty member of the Faculty of Sports Sciences. The temperature of the exercise room was kept at 20°C. The control patients did not participate in any exercise or physical activity program.
In the first month, the patients in the aerobic group started to exercise at a heart rate corresponding to 60% of the maximal VO2 by adjusting the pedal resistance of the exercise bike, consistent with the Karvonen formula. This was followed by exercise cycling at a heart rate corresponding to 70% of maximal VO2 in the second month, and 80% of maximal VO2 in the third month for 30 minutes three days a week (19).
The patients included in the strength exercise group performed weight training exercises involving 10 large muscle groups (leg press, chest press, leg curl, lateral pull down, leg extension, dumbbell lateral raise, calf press, upright row, sit up, quadruped arm opposite leg raise) three days a week, including one set of 12–15 repetitions in the first month, two sets of 12–15 repetitions in the second month, and three sets of 12–15 repetitions in the third month. Participants’ working weights were set as 60% of the maximum weight they could lift.
Data Collection Tools
Measures for MS symptoms
Fatigue Impact Scale (FIS), Multiple Sclerosis Quality of Life (MSQOL)-54 Instrument, Pittsburgh Sleep Quality Index (PSQI), and Brief International Cognitive Assessment for MS (BICAMS) Battery scales were applied.
Physical capacity and balance measurements
Measurement of aerobic capacity: Only one patient was able to complete the direct maximal VO2 measurement made with a gas analyzer on the test bike. Other patients could not adapt to the procedures, masks, and equipment used for direct measurement. Since the direct test completion rate is as low as 40% in the literature for MS patients, the indirect Astrand bicycle test protocol with Lode Corival bicycle ergometer was applied to all patients (20,21). For the test, the pedal resistance was set at 0.5–1 watt/kg, and the pedal rotation speed at 60 rpm/min. A chest strap (Polar T31 Coded Heart Rate Transmitter) and a heart rate monitor (Polar F5 Heart Rate Monitor Watch) were worn for heart rate monitoring. The test was continued for six minutes at a heart rate between 120/minute and 170/minute. The test was considered successful if the difference between the last two pulse rates was less than five, then the mean of these heart rates was calculated. The pedal resistance applied in the test and the mean pulse rate was marked in the Astrand nomogram, and the aerobic capacities of the patients were calculated.
Strength measurements: Strength was examined with an isometric hand and back-leg dynamometer in all patients. For hand grip strength, the patients were asked to squeeze the dynamometer with full force for about five seconds. For back strength, the patients were told to pull the chain as hard as possible and to try to extend the body without disturbing the angle of the arms. For leg strength, the patients were told to hold the chain tightly and try to bring their knees to full extension by applying force to the floor with their legs, without changing the angle of the body and arms. In all procedures, the patients rested for five minutes, and tests were performed twice. The highest value measured was taken into consideration.
Balance measurements: TecnoBody PK-252 isokinetic device was used in all patients. Static and dynamic balance tests were performed on bare feet. The static balance was tested on both legs and on one foot while the eyes were open. The dynamic balance was tested on both legs with eyes open. Each test was done twice. Each measurement took 30 seconds, and a one-minute pause was given between the measurements. The best values the patient did were taken into consideration.
Measurement of plasma NGF and NT-3 levels
Blood samples of all patients were taken into tubes with EDTA, at most two days before the start of the study, and at most two days after the end of the exercise programs. The sample was centrifuged at 2000×g for 10 minutes at room temperature. The plasma layer was removed and stored at -20°C until the time of analysis. Plasma NGF and NT-3 levels were measured with an ELISA kit (Wuhan Fine Biotech Co. Ltd.).
Statistical Analysis
Numerical data are presented as mean, standard deviation, median, minimum, and maximum, while categorical data are presented as frequencies. The data were summarized using IBM SPSS Statistics 25.0 program (IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.). The significance level was determined as p<0.05 for all analyses.
The Shapiro-Wilk test was performed separately in the groups and time points to be compared to investigate the normal distribution of the quantitative variables. Gender distributions of the groups were compared with the Pearson Chi-square test. Disease durations and ages of the groups were compared with Kruskal-Wallis test and analysis of variance (ANOVA), respectively.
The difference between pre- and post-exercise numerical variables such as the total scores of the BICAMS, MSQoL54, PSQI, and FIS scales, and the balance and strength measurements (before-after, change) were analyzed with time, group, and interaction effects under repeated measure design with Brunner-Langer model (F1-LD-F1* design). In the Brunner-Langer model, which is used as a nonparametric alternative to the repeated measure ANOVA, the interaction effect indicates whether the pre-post change is similar among groups (or it tests whether pre-post change lines of groups are parallel). If the result is found to be significant, further analyses are needed such as within-group and between-group analyses. Otherwise, group and time effects can be interpreted directly: the group effect indicates whether there is a difference between the groups at both times, and the time effect indicates whether the pre-post change was significant in both groups. The interaction effect has sometimes been analyzed in the literature against a relaxed p-value of up to 0.1, considering power.
Time-dependent changes in the total scores of BICAMS, MSQoL54, PSQI, fatigue impact scale scales, balance and strength measurements in the groups were analyzed with the nonparametric method Brunner-Langer model (F1-LD-F1 design) using R 3.5.2 software (R software, version 3.5.2, package: nparLD, R Foundation for Statistical Computing, Vienna, Austria; http://r-project.org). When the time-dependent change was not found to be similar in the groups as a result of the Brunner-Langer model (interaction <0.1), time comparison was performed separately with Brunner Langer (LD-F1 design) in each group (Bonferroni corrected) and the groups were compared at the first time point (baseline) with Kruskal Wallis test. The differences between the last measurement and the first measurement were compared between the groups using the Kruskal-Wallis test. After the Kruskal-Wallis test was found to be significant (p<0.05), pairwise comparison of the groups was performed with the Dunn test, followed by Bonferroni adjustment for p values
* F1 left side of the LD shows one independent group factor, and F1 right side of the LD shows one dependent factor (it is time here). LD stands for longitudinal design.
RESULTS
Demographic Data
Of the 16 patients in the aerobic group, 11 were females and 5 were males. The duration of the disease was 6.5±5.78 years, and the mean age was 38.12±9.11 years. There were 11 patients in the strength group, 7 females and 4 males, the duration of the disease was 8.09±6.33 years, and the mean age was 39.27±10.45 years. In the control group, there were 16 patients, 8 females and 8 males, the duration of the disease was 7.69±5.87 years, and the mean age was 37.0±9.47 years.
The median EDSS scores were 1.5 (0–4) in the aerobic exercise group, 1.5 (1–3.5) in the strength exercise group, and 1 (0–2.5) in the control group, and there was no significant change in EDSS scores at the end of the study.
There were no statistically significant differences between the study groups for genders, EDSS scores, duration of illness, or age (p=0.538, p=0.08, p=0.633, p=0.832; respectively).
Aerobic capacity (VO2 max) values (Table 1)
Table 1.
Time-dependent change in aerobic capacity and strength values
| Aerobic exercise group (n=16) | Strength exercise group (n=11) | Control group (n=16) | Brunner Langer Model (Interaction effect) | Comparison of the pre- and post-exercise difference values among the groups | ||||
|---|---|---|---|---|---|---|---|---|
| Before | After | Before | After | Before | After | |||
| Aerobic capacity (VO2 max) (mlO2/kg/min) | 31 (16–50) | 38 (27.5–60) | 30 (20–35.7) | 32 (20–38.5) | 30.6 (20–36) | 29.3 (16–36) | p<0.001¥¥ | pa<0.001§§ pb=0.88 pc=0.008§§ |
| p<0.001** | p=0.003** | p=0.002** | ||||||
| Back strength (kgf) | 36 (10–100) | 42.5 (19–110) | 23 (5–80) | 47 (20–110) | 46.5 (8–79) | 41 (10–68) | p<0.001¥¥ | pa=0.009§§ pb<0.001§§ pc=0.540 |
| p=0.002** | p<0.001** | p=0.02* | ||||||
| Leg strength (kgf) | 34 (10–95) | 52.5 (27–165) | 26 (10–75) | 60 (25–120) | 47.5 (13–83) | 54.5 (14–75) | p<0.001¥¥ | pa<0.001§§ pb<0.001§§ pc=1.000 |
| p<0.001** | p<0.001** | p=0.002** | ||||||
| Right hand grip strength (kgf) | 28 (5–75) | 32 (10–80) | 20 (5–57) | 26 (10–60) | 36 (8–60) | 37 (10–66) | p=0.486¥ | p=0.627 |
| p=0.004** | p<0.001** | p=0.012* | ||||||
| Left hand grip strength (kgf) | 24.5 (5–74) | 31.5 (8–75) | 20 (5–57) | 30 (5–70) | 37 (9–61) | 36.5 (8–66) | p=0.479¥ | p=0.612 |
| p=0.027* | p=0.002** | p=0.195 | ||||||
Values are expressed as median (minimum – maximum).
pa: Control × Aerobic, pb: Control × Strength, pc: Aerobic × Strength.
: Brunner Langer model analysis, p>0.10 indicates that there is no interaction between the independent variables.
: Brunner Langer model analysis, p<0.10 indicates an interaction between the independent variables (since the interaction was significant, additional analyses were done. Initially, the differences between pre- and post-exercise values were analyzed with Brunner Langer model analysis in each group, the differences between the first and last measurements among the groups were analyzed with the Kruskal-Wallis Test).
: p<0.05,
: p<0.01 (significant differences between pre- and post-exercise values within each group). § : p<0.05,
: p<0.01 (significant differences between pre- and post-exercise values within each group).
At the end of the study, the changes in VO2 max values were not similar in the study groups (Interaction: p<0.001). Therefore, the time-dependent changes were examined in each study group separately. VO2 max values were significantly increased in the aerobic (p<0.001) and strength exercise (p=0.003) groups but decreased in the control group (p=0.002). The comparison of before-after differences for VO2 max values revealed a significant difference between the aerobic group and the other groups (p<0.01).
Strength values (Table 1)
The changes in strength values other than hand grip strength were not similar in the groups (Interaction; back strength: p<0.001, leg strength p<0.001, right hand grip p=0.486, left hand grip p=0.479). Therefore, the time-dependent variations for back and leg strength were examined separately. At the end of the study, the values of back, leg, and hand grip strength were found to have significantly changed in all three groups (p<0.05). These values increased in aerobic and strength exercise groups.
There were significant differences between pre– and post-exercise back and leg strength values in the aerobic exercise and the control groups and between the strength and the control groups (p<0.01). They were similar in the aerobic exercise group and strength exercise group (p>0.05).
Plasma NGF levels (Table 2)
Table 2.
Time-dependent change of plasma NGF and NT-3 levels
| Aerobic exercise group (n=16) | Strength exercise group (n=11) | Control group (n=16) | Brunner Langer Model (Interaction effect) | The comparison of the pre- and post-exercise difference values among the groups | ||||
|---|---|---|---|---|---|---|---|---|
| Before | After | Before | After | Before | After | |||
| NGF (pg/mL) | 95 (32–259) | 192 (78–3177) | 58 (37–134) | 145 (44–221) | 75 (20–282) | 97 (31–491) | p=0.069¥¥ | pª=0.007§§ pb=0.961 pc=0.246 |
| p<0.001** | p=0.002** | p=0.054 | ||||||
| NT-3 (pg/mL) | 100 (22–1256) | 115 (27–3018) | 67 (19–179) | 103 (47–490) | 136 (18–511) | 117 (41–1738) | p=0.061¥¥ | p=0.594 |
| p=0.083 | p<0.001** | p=0.306 | ||||||
Values are expressed as median (minimum – maximum).
pa: Control × Aerobic, pb: Control × Strength, pc: Aerobic × Strength.
: Brunner Langer model analysis, p<0.10 indicates an interaction between the independent variables (since the interaction was significant, additional analyses were done. Initially, the differences between pre- and post-exercise values were analyzed with Brunner Langer model analysis in each group, the differences between the first and last measurements among the groups were analyzed with the Kruskal-Wallis Test).
: p<0.01 (significant differences between pre- and post-exercise values within each group).
: p<0.01 (significant differences between pre- and post-exercise values within each group).
The changes in NGF plasma levels were not similar in the study groups (Interaction: p=0.069). Therefore, the time-dependent change in each study group was examined separately. The plasma NGF levels significantly increased in aerobic exercise (p<0.001) and strength exercise groups (p=0.002). The comparison of pre- and post-exercise differences of plasma NGF levels were significant between the aerobic exercise group and the control group (p=0.007); however, this difference was not significant between the aerobic and strength exercise groups (p>0.05).
Plasma NT-3 levels (Table 2)
The changes in NT-3 plasma values were not similar in the study groups (Interaction: p=0.061). Therefore, the time-dependent variations were examined separately in the study groups. The NT-3 plasma level increased significantly in the strength exercise group (p<0.001). Although the NT-3 level increased in the aerobic exercise group, this increase was not significant (p=0.083). When the before- and after-exercise differences in NT-3 plasma levels were compared between the groups, there was not a significant difference (p=0.594).
Fatigue scores (Table 3)
Table 3.
Time-dependent changes of fatigue level, sleep quality, cognitive functions, and quality of life values
| Aerobic exercise group (n=16) | Strength exercise group (n=11) | Control group (n=16) | Brunner Langer model (Interaction effect) | The comparison of the pre- and post-exercise difference values among the groups | ||||
|---|---|---|---|---|---|---|---|---|
| Before | After | Before | After | Before | After | |||
| FIS | 67 (40–123) | 59 (40–103) | 75 (42–160) | 66 (42–104) | 71 (40–132) | 59 (42–123) | p=0.808¥ | p=0.689 |
| p=0.256 | p=0.04* | p=0.012* | ||||||
| PSQI | 6.5 (2–15) | 4.5 (2–13) | 8 (2–12) | 5 (2–11) | 5 (3–15) | 6 (2–15) | p=0.003¥¥ | pa=0.041¥ pb=0.033¥ pc=1.000 |
| p=0.006** | p=0.002** | p=0.211 | ||||||
| BVMT-R | 29 (13–34) | 32 (18–35) | 30 (13–35) | 32 (11–34) | 27 (13–34) | 30 (12–36) | p=0.062¥¥ | p=0.202 |
| p=0.005** | p=0.625 | p=0.04* | ||||||
| SDMT | 46 (29–61) | 48 (32–81) | 42 (26–70) | 52 (28–81) | 49 (18–96) | 46 (29–73) | p=0.019¥¥ | p=0.112 |
| p=0.029* | p=0.002** | p=0.897 | ||||||
| CVLT II | 62.5 (38–83) | 66.5 (39–79) | 54 (36–74) | 62 (41–75) | 53.5 (41–72) | 60 (40–83) | p=0.899¥ | p=0.840 |
| p=0.003** | p=0.007** | p<0.001** | ||||||
| MSQoL54 Mental health composite summary | 67 (29–95) | 77 (49–96) | 55 (9–88) | 69 (35–90) | 66 (24–96) | 70 (29–94) | p=0.034¥¥ | pa=0.068 pb=0.163 pc=1.000 |
| p<0.001** | p=0.004** | p=0.773 | ||||||
| MSQoL54 Physical health composite summary | 62 (33–82) | 72 (63–89) | 61 (22–86) | 70 (35–91) | 68 (38–95) | 64 (34–92) | p=0.002¥¥ | pa=0.003§§ pb=0.077 pc=1.000 |
| p<0.001** | p=0.007** | p=0.515 | ||||||
Values are expressed as median (minimum – maximum) BICAMS: The Brief International Cognitive Assessment for Multiple Sclerosis BVMT-R: Brief Visuo-spatial Memory Test Revised SDMT: Symbol Digit Modalities Test CVLT II: California Verbal Learning Test II MSQoL-54:Multiple Sclerosis Quality of Life – 54
pa=Control × Aerobic, pb=Control × Strength, pc=Aerobic × Strength
: Brunner Langer model analysis, p>0.10 indicates that there is no interaction between the independent variables
: Brunner Langer model analysis, p<0.10 indicates an interaction between the independent variables (since the interaction was significant, additional analyses were done. Initially, the differences between pre– and post-exercise values were analyzed with Brunner Langer model analysis in each group, the differences between the first and last measurements among the groups were analyzed with the Kruskal-Wallis Test)
: p<0.05,
: p<0.01 (significant differences between pre- and post-exercise values within each group) §: p<0.05,
: p<0.01(significant differences between pre- and post-exercise values within each group)
The total Fatigue Impact Scale (FIS) score and the subscales scores (physical, social, cognitive) were found to be similar and decreasing in all three groups (Interaction: p=0.808). The FIS scale total score was found to have significantly decreased in the strength exercise (p=0.04) and control groups (p=0.012), while the decrease in the aerobic exercise group was not significant (p=0.256). The fatigue scores at the beginning and end of the study showed that there was no statistically significant difference between the groups (p=0.689).
Sleep quality scores (Table 3)
The change in PSQI was not similar in the study groups (Interaction: p=0.003). The groups were analyzed separately for time-dependent changes, and it was determined that the PSQI scores decreased significantly in the aerobic exercise (p=0.006) and strength exercise groups (p=0.002), while there was no significant change in the control group (p=0.211). Before and after values were similar in aerobic and strength exercise groups (p=1.000).
Cognitive function scores (Table 3)
The changes in Brief Visuo-Spatial Memory Test (Revised BVMT-R) and Symbol Digit Modalities Test (SDMT) scores, which are the subscales of BICAMS and are used to analyze the level of cognitive function, were not found to be similar in the study groups (Interaction: BVMT-R: p=0.062, SDMT: p=0.019). Therefore, time-dependent changes were examined separately for BVMT-R and SDMT scores. We found that BVMT-R subscale scores increased significantly in aerobic exercise (p=0.005) and control groups (p=0.04). Although there was an increase in the strength exercise group, this increase was not significant (p=0.625). At the end of the study, a significant increase was found in the SDMT subscale scores in the aerobic (p=0.029) and strength exercise groups (p=0.002). The change in California Verbal Learning Test II (CVLT-2) scores was similar in the study groups (Interaction: p=0.900). The CVLT-2 subscale scores increased significantly in all three study groups (p<0.01).
Quality of life scores (Table 3)
Changes in the combined mental health (CMH) and composite physical health (CPH) scores, which are the components of the MSQoL54 scale, were not similar in the study groups (Interaction: CMH: p=0.034, CPH: p=0.002). For this reason, the time-dependent changes for CMH and CPH scores were examined separately. The mental health and physical health component scores increased significantly in the aerobic and strength exercise groups at the end of the study (p<0.01) while no statistically significant difference was observed in the control group.
The comparison of three study groups did not show any significant differences for the difference between the pre- and post-exercise mental health component scores (p>0.05). The difference between pre- and post-exercise physical health component scores was similar in the aerobic and the strength exercise groups (p=1.000), while the difference between the aerobic exercise group and the control group was statistically significant (p<0.01).
Balance Tests
Bipedal static balance scores (Table 4)
Table 4.
Time-dependent changes of the static and dynamic bipedal balance values
| Aerobic exercise group (n=16) | Strength exercise group (n=11) | Control group (n=16) | Brunner Langer model (Interaction effect) | The comparison of the pre- and post-exercise difference values among the groups | ||||
|---|---|---|---|---|---|---|---|---|
| Before | After | Before | After | Before | After | |||
| Bipedal static front-back sway (mm / sec) | 7.5 (5–25) | 7 (5–15) | 7 (5–20) | 7 (5–17) | 7.5 (4–16) | 8 (5–13) | p=0.378¥ | p=0.343 |
| p=0.507 | p=0.513 | p=0.223 | ||||||
| Bipedal static medio-lateral sway (mm / sec) | 7 (4–21) | 6 (3–15) | 6 (5–14) | 7 (5–15) | 7 (3–13) | 8 (3–13) | p=0.067¥¥ | pa=0.014§ pb=1.000 pc=0.069 |
| p=0.034* | p=0.356 | p=0.107 | ||||||
| Bipedal static ellipse area (mm2) | 330 (100–4329) | 203 (53–1579) | 263 (134–721) | 286 (120–964) | 180 (84–2548) | 342 (102–1988) | p=0.007¥¥ | pa=0.003§§ pb=0.792 pc=0.198 |
| p<0.001** | p=0.672 | p=0.128 | ||||||
| Bipedal static perimeter (mm) | 349 (220–1043) | 338 (225–692) | 337 (234–792) | 346 (268–720) | 341 (173–598) | 412 (224–677) | p=0.116¥ | pª=0.022§ pb=0.378 pc=1.000 |
| p=0.385 | p=0.555 | p=0.353 | ||||||
| Bipedal dynamic front-back sway (mm / sec) | 21 (9–47) | 16 (10–29) | 15 (10–34) | 15 (12–28) | 17 (6–27) | 17 (8–30) | p=0.068¥¥ | pa=0.004§§ pb=1.000 pc=0.260 |
| p=0.002** | p=0.806 | p=0.682 | ||||||
| Bipedal dynamic medio-lateral sway (mm / sec) | 18 (11–57) | 13 (11–37) | 14 (11–23) | 12 (10–24) | 15 (7–25) | 16 (7–23) | p=0.018¥¥ | pa=0.013§ pb=1.000 pc=0.166 |
| p=0.001** | p=0.178 | p=0.758 | ||||||
| Bipedal dynamic ellipse area (mm2) | 1369 (457–1667) | 868 (358–3578) | 1316 (402–3786) | 955 (294–2550) | 1224 (516–5726) | 1427 (576–7211) | p=0.001¥¥ | pa<0.001§§ pb=0.124 pc=0.301 |
| p<0.001** | p=0.104 | p=0.397 | ||||||
| Bipedal dynamic perimeter (mm) | 902 (472–2401) | 670 (539–1413) | 719 (544–1306) | 668 (512–1207) | 757 (322–1117) | 773 (363–1222) | p=0.007¥¥ | pa=0.005§§ pb=1.000 pc=0.139 |
| p<0.001** | p=0.401 | p=0.636 | ||||||
Values are expressed as median (minimum – maximum) pa: Control × Aerobic, pb: Control × Strength, pc: Aerobic × Strength.
: Brunner Langer model analysis, p>0.10 indicates that there is no interaction between the independent variables.
: Brunner Langer model analysis, p<0.10 indicates an interaction between the independent variables (since the interaction was significant, additional analyses were done. Initially, the differences between pre– and post-exercise values were analyzed with Brunner Langer model analysis in each group, the differences between the first and last measurements among the groups were analyzed with the Kruskal-Wallis Test).
: p<0.05,
: p<0.01 (significant differences between pre- and post-exercise values within each group).
: p<0.05,
p<0.01(significant differences between pre- and post-exercise values within each group).
The medio-lateral (ML) sway and ellipse area changes were not similar in the groups in the balance test performed on static ground on two legs (Interaction: double static ML: p=0.067; double static ellipse area: p=0.007). For this reason, the time-dependent changes in the groups were examined separately. A significant decrease was found in the ML sway (p=0.034) and ellipse area values (p<0.001) in the aerobic exercise group. In the strength exercise and control groups, however, there were no statistically significant changes (p>0.05). There were no significant changes in front-back (FB) sway and perimeter values in any of the groups (p>0.05).
A significant difference was found between the aerobic exercise group and the control group for pre– and post-exercise ML sway, ellipse area, and perimeter values of the bipedal static balance test (p=0.014, p=0.003, and p=0.022, respectively).
Bipedal dynamic balance scores (Table 4)
Changes in FB and ML sways were not similar in the groups on the bipedal dynamic balance test (Interaction; FB p=0.068, ML p=0.018). Medio-lateral sway, FB sway, ellipse area, and perimeter values were significantly decreased in the aerobic exercise group at the end of the study (p=0.001, p=0.002, p<0.001, p<0.001, respectively). However, there were no significant changes in the strength exercise and the control groups (p>0.05). There was a significant difference between the aerobic exercise and the control groups in terms of pre– and post-exercise ML sway (p=0.013), FB sway (p=0.004), ellipse area (p<0.001), and perimeter values (p=0.005).
Monopedal balance values (Table 5)
Table 5.
Time-dependent change of monopedal static balance values
| Aerobic exercise group (n=16) | Strength exercise group (n=11) | Control group (n=16) | Brunner Langer model (Interaction effect) | The comparison of the pre- and post-exercise difference values among the groups | ||||
|---|---|---|---|---|---|---|---|---|
| Before | After | Before | After | Before | After | |||
| Right leg static front-back sway (mm / sec) | 28 (19–120) | 22.5 (12–90) | 25 (18–49) | 24 (15–51) | 23.5 (12–35) | 25 (10–68) | p=0.061¥¥ | pa<0.001§§ pb=0.249 pc=0.160 |
| p<0.001** | p=0.176 | p=0.09 | ||||||
| Right leg static medio-lateral sway (mm / sec) | 33.5 (18–96) | 30.5 (14–84) | 33 (15–44) | 29 (18–45) | 31 (12–43) | 29 (13–55) | p=0.152¥ | p=0.076 |
| p=0.004** | p=0.342 | p=0.842 | ||||||
| Right leg static ellipse area (mm2) | 1069 (437–5659) | 682 (369–3549) | 915 (642–2607) | 832 (561–2360) | 180 (84–2548) | 342 (102–1988) | p=0.003¥¥ | pa=0.001§§ pb=0.088 pc=0.767 |
| p=0.015* | p=0.043* | p=0.07 | ||||||
| Right leg static perimeter (mm) | 1393.5 (913–5458) | 1215.5 (666–3958) | 1352 (890–1992) | 1163 (878–2131) | 1268 (580–1824) | 1289 (648–2437) | p=0.012¥¥ | pa=0.001§§ pb=0.574 pc=0.162 |
| p<0.001** | p=0.239 | p=0.190 | ||||||
| Left leg static front-back sway (mm / sec) | 30 (19–130) | 25 (14–89) | 33 (14–45) | 25 (15–44) | 23.5 (13–44) | 24 (14–37) | p=0.347¥ | p=0.227 |
| p=0.073 | p=0.490 | p=0.579 | ||||||
| Left leg static medio-lateral sway (mm / sec) | 35 (21–98) | 32.5 (17–103) | 33 (22–47) | 28 (20–40) | 27.5 (14–51) | 28 (15–52) | p=0.196¥ | p=0.263 |
| p=0.009** | p=0.266 | p=0.560 | ||||||
| Left leg static ellipse area (mm2) | 1384.5 (710–11886) | 842 (330–7686) | 1086 (545–2045) | 905 (507–3166) | 704.5 (246–1873) | 1133 (359–1624) | p<0.001¥¥ | pa=0.002§§ pb=0.405 pc=0.301 |
| p=0.004** | p=0.165 | p=0.005** | ||||||
| Left leg static perimeter (mm) | 1517 (925–5358) | 1263 (734–4172) | 1443 (828–2133) | 1224 (804–1689) | 1145 (636–2148) | 1256 (677–2059) | p=0.265¥ | p=0.201 |
| p=0.009** | p=0.333 | p=0.551 | ||||||
Values are expressed as median (minimum – maximum)
pa: Control × Aerobic, pb: Control × Strength, pc: Aerobic × Strength.
: Brunner Langer model analysis, p>0.10 indicates that there is no interaction between the independent variables.
: Brunner Langer model analysis, p<0.10 indicates an interaction between the independent variables (since the interaction was significant, additional analyses were done. Initially, the differences between pre– and post-exercise values were analyzed with Brunner Langer model analysis in each group, the differences between the first and last measurements among the groups were analyzed with the Kruskal-Wallis Test).
: p<0.05,
: p<0.01 (significant differences between pre- and post-exercise values within each group).
: p<0.01 (significant differences between pre- and post-exercise values within each group).
On the monopedal static balance test, FB sway, ellipse area, and perimeter on the right foot, and the ellipse area on the left foot were not similar in the groups (Right foot interaction; FB: p=0.061, ellipse area: p=0.003, perimeter: p=0.012, Left foot interaction ellipse area: p<0.001). In the aerobic exercise group, it was found that the AC oscillation, ML oscillation, ellipse area and circumference values obtained in the balance test performed on static ground on one leg decreased statistically significantly in both feet at the end of the study (p<0.01).
There was a significant decrease in only the right foot ellipse area in the strength exercise group (p=0.043), and there was a significant increase in the left foot ellipse area in the control group (p=0.005). No significant change was found in other parameters at the end of the study (p>0.05).
A statistically significant difference was found between the aerobic exercise group and the control group for the values of right foot FB sway, ellipse area, perimeter, and left foot ellipse area when the difference between the pre– and post-exercise values of the monopedal static balance test were compared (p<0.01).
DISCUSSION
In our study, we found that regular exercise increased physical fitness parameters such as strength and aerobic capacity and the plasma levels of neurotrophic factors such as NGF and NT-3, and improved sleep quality, QOL, cognitive functions, and balance parameters as well as reduced fatigue in ambulatory MS patients.
Aerobic capacity decreases as a result of a sedentary life in MS patients (7). Exercise is known to increase cardiorespiratory strength, muscle mass, muscle strength, muscle flexibility, and endurance. A study investigated aerobic capacity in MS patients and reported that there should be at least 10% increase in maximal oxygen consumption (VO2 max) in order to talk about an improvement in the aerobic capacity (20). In our study, a mean increase of 22% was observed in VO2 max in the aerobic exercise group. In addition, a mean increase of 18% was observed in back strength, and a mean increase of 54% was evident in leg strength in the aerobic exercise group. In the strength exercise group, the mean values increased by 6% for VO2 max, by 104% for back strength, and by 130% for leg strength. Although no change is expected in aerobic capacity with strength exercises, this increase may have been due to the development of peripheral components (increased diffusion of oxygen into muscle tissues, proliferation of muscle capillaries, and increased mitochondria ratio) with exercise.
Recently, a number of studies have investigated exercise-related changes in neurotrophins, which are important biomarkers in neural regeneration and re-myelination in healthy and unhealthy subjects. Generally, regular exercise increases the level of NTs (22). Although there was no significant increase in NGF levels in MS patients after eight weeks of aerobic exercise, a significant increase in NGF levels was observed in individuals with metabolic syndrome (23,24). In these studies, MS patients exercised two days a week, and other people three days a week. In our study, the participants had regular exercise three days a week for twelve weeks, in line with the recommendations of the American College of Sports Medicine (ACSM), and a significant increase was observed in plasma NGF levels in both exercise groups. The findings of this study show that regular exercise increases NGF levels in MS patients.
Neurotrophin-3 is an important neurotrophic factor for CNS development in the prenatal period. It has been shown that mice with NT-3 deficiency have neuronal loss and accompanying sensorimotor deficits in nuclei in the CNS (25). A significant increase was observed in NT-3 levels in a study examining the acute effects of exercise in overweight sedentary people without MS (BMI 25–30 kg/m2) (26). In our study, a significant increase was observed in NT-3 levels in the strength exercise group; an increase was also observed in the aerobic exercise group, but it was not significant. The reason for the insignificant increase in the aerobic group may be that a 12-week exercise program was not long enough to cause a sufficient increase in muscle mass.
It has been claimed that deficiency or impairment in NT synthesis may increase the likelihood of neurodegenerative diseases (27). Neurotrophins have also been used as therapeutic agents in the treatment of neurodegenerative disorders and nerve damage (27). We may suppose that regular exercise programs started at the early stages of MS may increase NGF and NT-3 levels and have a positive effect in slowing down the progression of MS, where neurodegeneration is seen together with neuroinflammation.
Cognitive functions were found to be better in physically active MS patients and cognitive functions improved in patients who regularly performed aerobic exercise (28,29). Neurotrophic changes have been accepted as the most popular hypothesis to explain the positive effects of exercise on cognition (8,30). Neurotrophins support glutamatergic neurons in the hippocampus and facilitate long-term potentiation (LTP), thus supporting the development of long-term memory (31). It was previously shown that aerobic exercise provides neurogenesis in the hippocampus and increases the volume of the hippocampus, and NTs support synaptic plasticity, neurogenesis, and survival of neurons (32,33). A study reported an increase in hippocampus volume and NT levels in correlation with the increase in VO2 max with exercise (34). In our study, we found improvement in cognitive function in aerobic and strength exercise groups. The mechanism of the improved cognition may be the increase in the hippocampal volume due to exercise, or the increase in the level of NT providing synaptic plasticity and neurogenesis in the hippocampus.
One of the common problems in MS patients is falls occurring as a result of the balance disorders related to the disease. Both aerobic and strength exercises have been shown to have positive effects on balance problems in MS patients (35–37). In our study, although significant improvement was observed in balance parameters in the aerobic exercise group, the improvement in the strength exercise group was not significant. Although there was a significant increase in both back and leg strength in the strength exercise group, the absence of significant changes in dynamic and static balance parameters may suggest that there may be some problems in the central integration phase of sensory and motor stimulation in MS patients. This situation can be explained by three mechanisms. The first mechanism is that although strength exercise increases NT levels, it is insufficient to affect other central components alone to improve balance; the second mechanism is the need for a longer exercise period to see the central effect; the third mechanism is that the distribution of CNS lesions differs among individuals. The balance problems in MS patients may result in falls and associated injuries; to prevent these, regular exercise, and including an aerobic component in the exercise programs, may be more effective for the development of balance.
The studies investigating the effect of exercise on sleep in MS patients have shown that sleep quality improves after aerobic exercise, and there are fewer sleep problems in physically active MS patients (38). In our study, we found significant improvements in sleep quality in the exercise groups. It is supposed that the central effects of exercise reduce pro-inflammatory cytokines and increase serotoninergic projections, and its peripheral effects are seen due to the body’s thermal regulation and the body’s need for more sleep for recovery after exercise (39–41).
The studies on the effect of exercise on fatigue reported conflicting results. In a recent meta-analysis, aerobic capacity was negatively correlated, and muscle strength was weakly correlated with fatigue (42). In one study, progressive strength training was applied to MS patients, and a significant reduction was observed in fatigue complaints (43). In our study, fatigue complaints decreased in all groups. Aerobic capacity and muscle strength decrease in MS patients (44). Multiple sclerosis patients spend more effort on activity compared to healthy people as a result of decreased aerobic capacity and muscle strength. The increase in muscle strength and aerobic capacity in the patients in the exercise groups and less effort during physical activities may have been effective in the regression of fatigue complaints. The fatigue complaints also decreased in the control group despite the lack of any increase in physical performance values. Since psychological factors can also cause secondary fatigue, the better mental state of the control patients during this period may have led to a decrease in fatigue complaints.
Multiple sclerosis negatively affects the quality of life in all aspects. Fatigue, balance problems, and cognitive impairments cause limitations in daily physical and social activities and cause the adoption of a sedentary lifestyle. As the disease progresses, the person’s self-confidence decreases. Exercise has been shown to improve the quality of life in MS patients (37,45). In our study, we found that the quality of life of MS patients improved with exercise. The improvement of the physical capacity of patients with regular exercise may have made it easier for them to perform activities that are difficult in daily life. This increment in their physical capacity may be a factor in this improvement in their quality of life.
As a result, multiple sclerosis is a chronic disease accompanied by neuroinflammation and neurodegeneration from its early stages. In addition to early immunomodulatory treatment, which is started as soon as the diagnosis is made, improving the existing symptoms and repairing the neural damage should be among the treatment strategies. In this study, an increase in plasma NGF and NT-3 levels, which are important neurotrophic factors in progression and repair, as well as improvement in balance, fatigue, sleep quality, cognition, and quality of life were observed after regular exercise. Based on the results of our study, it can be suggested that regular exercise is an easily applicable, inexpensive, and promising treatment strategy for MS.
Limitations
In our study, we aimed to investigate the change in physical capacity on sleep quality, cognition, fatigue, and quality of life levels which were assessed using scales. But we didn’t evaluate the mood of the patients. Apart from the effects of exercise, the improvement of a possible depressive state may also have affected the results we obtained from these scales. This can be a limitation of our study.
Acknowledgments:
We would like to thank Research Assistant Semiha Ozgul for her aid in statistical analysis.
Footnotes
Ethics Committee Approval: Ege University Clinical Research Ethics Committee (date: Apr 03, 2019, decree no: 19-4T/43) and ClinicalTrials.gov (ClinicalTrials.gov ID: NCT04944251) approved the study protocol.
Informed Consent: The procedures and possible side effects (such as exercise-related injuries and having an MS attack) were explained in detail to each participant candidate, and the Informed Consent Form was signed by the volunteers.
Peer-review: Externally peer-reviewed.
Author Contributions: Concept- MA, SŞ, ANY; Design- MA, SŞ, ANY, TA, RA; Supervision- MA, SŞ, ANY; Resource- MA, SŞ; Materials- MA, DT; Data Collection and/or Processing- MA, DT, SŞ; Analysis and/or Interpretation- MA, SŞ, DT, TA, RA, ANY; Literature Search- MA; Writing- MA, SŞ, ANY; Critical Reviews- MA, SŞ, ANY, DT.
Conflict of Interest: The authors declared that there is no conflict of interest.
Financial Disclosure: This research was supported by a research fund from Ege University Scientific Research Projects CoordinationUnit (project no:TTU-2019-20736) in 2020.
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