Multiple sclerosis (MS) is a neuroinflammatory-mediated disease that affects both white and gray matter, leading to physical, sensory, and cognitive impairments.1 In progressive MS, chronic brain lesions and neurodegeneration are thought to limit capacity for neuroplasticity and research suggests that a gradual loss of plasticity explains disability progression.1 Exercise is one of several lifestyle interventions (eg, abstaining from smoking, absence of cardiovascular comorbidities) purported to provide neuroprotection in MS,2–5 possibly by affecting the brain directly.6 In healthy people and people with stroke, a single bout of aerobic exercise (AE) is known to enhance cerebral blood flow, elevate serum levels of neurotrophic factors such as brain-derived neurotrophic factor,7,8 and upregulate neuroprotective hormones and neurotransmitters, processes that promote neuroplasticity.9–13 For this reason, there is an emerging field of research examining whether acute AE can “prime” the brain to synergistically enhance the benefits of other rehabilitation therapies among clinical populations, such as people with stroke.7,14–17 Using transcranial magnetic stimulation (TMS), a noninvasive tool that assesses mechanisms of corticospinal excitability (CSE),18 several studies in healthy individuals have proposed that the main factors responsible for enhancing neuroplasticity associated with improved brain function post-AE are the transient increases in glutamatergic-mediated intracortical excitation and decreases in γ-aminobutyric acid (GABA)–mediated intracortical inhibition.12,14,19,20 Using TMS, Nepveu et al15 showed that among people with chronic stroke, reduced GABAergic-mediated intracortical inhibition in the affected hemisphere after a single AE session paired with a motor learning task was a potential mechanism that facilitated superior motor learning in the affected hand. Whether acute AE promotes similar neuroplasticity-associated CSE changes among people who have substantial MS-related motor disability, such as in progressive MS, is not known.
It is reasonable to think that people who have higher levels of fitness could respond differently to acute AE.21 TMS studies have shown that adherence to exercise in the longer term increases baseline levels of brain excitability, allowing fitter individuals to benefit more robustly from neuroplasticity-inducing interventions22 including acute AE.23 Likewise, among people with MS, Chaves et al6 reported an association between lower levels of fitness and increased GABAergic-mediated intracortical inhibition measured with a longer cortical silent period (CSP), a TMS biomarker of diminished neuroplasticity.24,25 Similarly, a longer CSP has been linked to greater neurological impairments in people with stroke,26,27 Huntington disease,28 and MS.29 In general, most people with MS do not engage in regular physical activity;4,6,30,31 therefore, it is important to understand whether lower fitness levels and sedentarism may be hindering the potential benefits of strategies aimed at improving brain function. The aim of this pilot study was, first, to investigate whether a single bout of AE could induce neuroplasticity in people who had severe walking disability due to progressive MS and, second, to determine whether levels of fitness would be associated with CSE changes post-AE. On the basis of previous research, we hypothesized that lower levels of fitness could be a factor limiting AE-induced changes in brain excitability.
Ten people with progressive MS (9 females, and 1 male) aged 53.20 ± 15.6 years (mean ± SD), recruited consecutively through referrals from a neurologist and physical therapists and through posters at a tertiary rehabilitation center, participated in the study. Participants met the following inclusion criteria: (1) confirmed diagnosis of progressive MS by a neurologist; (2) aged 18 years or older; (3) free of relapses in the previous 3 months; (4) walking with bilateral (eg, ambulatory assistive device [canes or walker]) support; (5) disability level quantified using the Expanded Disability Status Scale (EDSS) score of 6.0 or more (0.5-unit increment; 0 = normal neurological examination, 10 = death due to MS); (6) able to participate in physical exercise as per PAR-Q screening form32; and (7) able to undergo TMS and dual-energy x-ray absorptiometry (DEXA) as per safety standardized forms.33,34 All participants provided written consent. All procedures were approved by the local health research ethics board (Memorial University of Newfoundland, #2018.088). Participants' descriptive data are reported in Table 1. Demographic data were collected, including age (years), sex, MS type (secondary progressive or primary progressive), and disease duration (years).
Table 1 -
||MS Severity (EDSS Score 0-10)
||Mean ± SD
||53.20 ± 15.6
||17.60 ± 10.2
||6.3 ± 0.3
Abbreviations: AAD, ambulatory assistive devices; DD, disease duration; EDSS, Expanded Disability Status Scale; MS, multiple sclerosis; PPMS, primary progressive MS; SPMS, secondary progressive MS.
Participants were evaluated in 3 sessions that were 7 to 10 days apart. In session 1, whole-body lean mass (kg) and fat percentage (%) were assessed using DEXA. In session 2, cardiorespiratory fitness (maximal capacity of volume of oxygen uptake [O2max]) was assessed in a graded maximal exercise test. In session 3, CSE was assessed with TMS, performed before and after body weight–supported treadmill AE. Figure 1 illustrates a schematic overview of the experimental design.
Body Composition and Cardiorespiratory Fitness
Levels of physical fitness were determined by quantifying cardiorespiratory fitness and body fat %, both of which are biomarkers of sedentarism, and their poor levels have been proposed to contribute to development and progression of MS.4–6,35,36 Whole-body DEXA (Discovery-A densitometer; Hologic Inc, Bedford, Massachusetts) was used to assess participants' total body weight (kg), amount of muscle (ie, lean) mass (kg), and body fat %.37 Specialized trained technicians performed equipment calibration before the assessments as per the manufacturer's guidelines.33 Data analysis was performed using the system's built-in software (v.12.6.1:3; Hologic Inc).
Levels of cardiorespiratory fitness were determined by the O2max during a graded exercise test using a total body recumbent stepper (NuStep, Ann Arbor, Michigan).38 The stepper permits subjects to use all four limbs in a seated position and has been shown to be acceptable for people with MS who have mobility limitations.39,40 With participants maintaining a speed of 80 strides per minute, the resistance level (1-10; beginning at level 3) was increased by 1 unit every 2 minutes. If exhaustion was not reached until completion of resistance level 10 (maximal NuStep resistance), then workload was augmented by increasing the speed (strides per minute) by 10 every 2 minutes. During the test, an indirect calorimetry system (Moxus; AEI Technologies, Kempele, Finland) was used to measure volume of oxygen uptake (O2), volume of carbon dioxide production (CO2), and heart rate (HR) (H10; Polar Electro Inc, Bethpage, New York). The criteria for terminating the test were as follows: (i) volitional exhaustion; (ii) no increase in O2 or HR despite increases in workload; and (iii) inability to maintain required workload. The breath-by-breath collected data were smoothed using a 15-second moving average. Proper achievement of O2max was investigated on the basis of the following: (i) respiratory exchange ratio (CO2/O2) 1.1 or more; and/or (ii) HRmax ± 10 beats per minute (bpm) of predicted maximum HR calculated as follows: 206.9 − (0.67 × Age) or 164 − (0.7 × Age) if prescribed β-blockers.41 From the smoothed data, the highest absolute O2 was divided by the participant's total body weight (TBW) (kg) to obtain the participant's relative O2max (mL·min−1·kg−1TBW), which was used for descriptive analysis of the participant's fitness. In addition, the absolute O2max was divided by the amount of muscle/fat free mass (ie, lean mass [LM] in kg) to provide a more accurate estimate of cardiorespiratory fitness, especially in populations with higher body fat % (mL·min−1·kg−1LM).42
Transcranial Magnetic Stimulation
With the participant seated, motor evoked potentials (MEPs) were elicited using monophasic TMS pulses (BiStim 2002; Magstim Co, Whitland, United Kingdom), with a maximum field strength of 2.6 Tesla connected to a double 70-mm figure-of-eight coil (Magstim Co). Throughout the experiment, the TMS coil was maintained tangentially to the scalp, with the handle pointing backward and laterally at an angle of 45° from the midline perpendicular to the central sulcus to deliver posterior-anterior directed pulses in the primary motor cortex area.43 To measure electromyographic (EMG) activity and collect the MEPs, foam surface electrodes (Kendall 200; Coviden, Mansfield, Massachusetts) were placed on the belly of the hand first dorsal interosseous muscle and the ground and reference electrodes were placed on the styloid process and the interphalangeal joint of the index finger, respectively. A neuronavigation device (BrainSight; Rogue Research Inc, Montreal, Quebec, Canada) guided the coil position and collected the MEPs with its built-in EMG system. This system uses a 2500-V/V amplification and collects with a sampling rate of 3 kHz and a gain of 600 V/V with a bandwidth of 16 to 550 Hz. The Montreal Neurological Institute brain template was rendered into the BrainSight software and used as a 3-dimensional stereotaxic template.44,45 Since MS can affect either (or both) of the brain hemispheres indiscriminately,46 MEPs were assessed bilaterally; stronger (less affected) and weaker (more affected) hands46 were determined by EMG recordings of the first dorsal interosseous muscle with the participant performing maximal voluntary contraction of the pincer grip. Three to 6 trials were conducted (10-15 seconds apart; the number of trials was restricted if the TMS device reached maximum heat capacity), and the EMG values were recorded and averaged for each hand. A priori analysis showed no differences pre- or post-AE on EMG values across the maximal voluntary contraction trials on each hand (t < 2.37, P > 0.099). None of the participants reported fatigue throughout the TMS assessment pre- or post-AE. Therefore, fatigability was likely not an issue when identifying stronger and weaker hand or when assessing CSE.
TMS suprathreshold stimulations were delivered at different locations over the primary motor area, and the site with the highest averaged peak-to-peak MEP first dorsal interosseous EMG amplitude was taken as the hotspot. The hotspot was assessed pre- and post-AE because of its susceptibility to change in location as a result of acute interventions (eg, exercise)47 and its high variability, especially in older adults.48 Resting and active motor thresholds (RMT and AMT, respectively) were determined as the minimum amount of TMS intensity (maximal stimulator output percentage [MSO%] 0-100) necessary to elicit MEPs with a peak-to-peak amplitude of 50 μV or more during muscle relaxation and 200 μV or more during 10% of pincer grip maximal voluntary contraction, respectively, in at least 50% of the trials.18 Recruitment curves (RECs) were assessed with the participant performing 10% of the pincer grip maximal voluntary contraction. Three to 6 stimulations, 3 to 5 seconds apart, at stimulus intensities of 105%, 115%, 125%, 135%, 145%, and 155% of AMT, were performed in the randomized order. The averaged peak-to-peak MEP amplitudes and the CSP length at each TMS intensity (105%-155% of AMT) were recorded.18
The absolute MEP amplitudes were calculating by normalizing each acquired MEP value by the MEP with the largest peak-to-peak amplitude (μV) recorded during the REC assessment prior to the exercise (ie, % of the largest baseline MEP).49 For the excitatory REC, normalized MEP amplitudes were plotted against the TMS intensities and the slope and R squared (R2) of this linear relationship were calculated, which represent neuronal recruitment gain and accuracy of the structurally available descending axonal tracts.50 Likewise, the inhibitory REC slope and R2 were calculated by plotting the CSP length against the TMS intensities.51 For calculation of overall corticospinal excitation50 and inhibition,52 the area under the curve was calculated for both excitatory and inhibitory RECs using the trapezoid rule ΔX × (Y1+Y2)/2, whereby X is the MSO% used (ie, X-axis values, 105%-155% of AMT) and Y1 and Y2 are the recorded CSP lengths (ms) or the absolute MEP amplitudes (mV).50 The length of the CSP was taken as the time (ms) between the MEP onset, time point where the MEP exceeded ±2 SD from the EMG background activity, until the EMG activity returned to ±2 SD of the mean EMG background activity.18
The intervention consisted of 40 minutes of AE walking on a treadmill (model T652m; SportsArt Fitness Co, Mukilteo, WA, USA), with a harness supporting 10% of the participant's body weight. This AE dosage (type, length, and intensity) was based on a previous review investigating the optimal AE dosage to promote neuroplasticity in people with MS.8 Body weight–supported treadmill training has been used largely to restore walking ability in populations experiencing walking impairments due to stroke,53 spinal cord injury,54 and progressive MS.8,55 The level of body weight support was kept to a minimum (10%), sufficient to reduce risk of fall while not affecting the work performed.56 During the AE, intensity was monitored using HR (Polar H10 Heart Rate monitor). During the first 5 minutes, the speed (starting at 80% of self-selected speed) and/or incline of the treadmill (ie, grade; starting at 1%) were progressively increased until approximately 60% of heart rate reserve (HRR) was achieved: for example, intensity target = 60% × [(HRmax – HRrest) + HRrest]. Speed and incline were adjusted as necessary in order to maintain the intensity target throughout the AE. If breaks (resting) were required, the treadmill was halted and resumed only when the participant reported that he or she was ready to continue. The total time exercising was calculated by subtracting minutes resting from 40 minutes. A 5-minute cooldown, in which the treadmill speed and incline were gradually decreased, was provided for participants who completed the 35-minute protocol (total AE session time = 40 minutes). For those who could not complete the 40-minute AE (eg, walked for a total of 7.7-30 minutes; see Table 2), the session was terminated after the last walking bout.
Table 2 -
Participants' Physical Fitness
Profile and Aerobic Exercise
||Body Composition (DEXA)
||Cardiorespiratory Fitness (Graded Maximal Exercise Test)
||AE Session: Duration: 40 min, Intensity Target: 40%-65% of HRR
||Body weight, kg
||Body lean mass, kg
||O2max, mL·min−1· kg−1
||O2max, mL·min−1· kg−1
||RER at O2max (CO2/O2)
||Achieved % of Predicted HRmax
||Achieved % of Target AE Intensitya
||Total Time Exercisingb (min)
||Total Workload Performed,c kcal/session
|Mean ± SD
||164.31 ± 8.3
||77.59 ± 19.0
||43.10 ± 10.5
||40.69 ± 4.4
||29.83 ± 10.0
||16.54 ± 5.3
||1.02 ± 0.2
||146 ± 21
||85.98 ± 10.9
||92.14 ± 4.2
||26.60 ± 13.38
||78.95 ± 58.3
Abbreviations: AE, aerobic exercise
; bpm, beats per minute; DEXA, dual-energy x-ray absorptiometry; HR, heart rate; HRR, heart rate reserve (HRR = HRmax
); LM, lean mass; RER, respiratory equivalent ratio; TBW, total body weight;
, volume of carbon dioxide production;
, volume of oxygen uptake;
aAE intensity target: [Intensity60% × (HRmax – HRrest) + HRmax]; % of predicted HRmax = 206.9 – (Age × 0.67).
bRest time is subtracted from the total exercise duration (40 minutes).
AE total workload performed = 3.5 mL·min−1
× 0.1) + (Inclinegrade
× 1.8). The averaged
) was transformed into metabolic equivalents, and the kcal/min was estimated using the following equation: kcal/min = (Metabolic equivalents × 3.5 × Total body weight in kilograms)/200. The total amount of kcal spent was calculated by multiplying the kcal/min by the total time in minutes the participant spent exercising (kcal/session).
dParticipant 8 declined to undergo DEXA.
) was calculated by diving this participant's
) by the LM (kg) of sample mean (43.10 kg).
The total amount of workload performed during the AE session was estimated using standardized prediction equations.57 First, the O2 (mL·min−1·kg−1) uptake during the AE was calculated using the following equation: O2 (mL·min−·kg−1) = [(Resting component (3.5 mL·min−1·kg−1) + Horizontal component (speed (m/min) × 0.1 mL·kg−1·m−1) + Vertical component (1.8 mL·kg−1·m−1 × speed (m·min−1) × Inclinefractional grade)],57 with changes in speed and incline throughout the AE were taken into consideration. The averaged O2 (mL·min−1·kg−1) was transformed into metabolic equivalents, and the kilocalorie (kcal)/min was calculated using the following equation: kcal/min = (Metabolic equivalents × 3.5 × total body weight in kg)/200.57 Finally, the total amount of workload performed was expressed as kcal/session, calculated by multiplying the kcal/min by the total time in minutes the participant exercised (ie, total minutes walking).
Participants' Characteristics and Their Associations With Baseline CSE and AE-Induced CSE Changes
Exploratory relationships between fitness (mL·min−1· kg−1LM and body fat %) with baseline CSE (TMS variables RMT, AMT, excitatory and inhibitory REC values [MEP amplitudes105%-155% AMT, CSP lengths105%-155% AMT, slope, R2, and area under the curve]) and AE-induced CSE changes [TMS variables % changes = (Post-exercise – Pre-exercise)/Pre-exercise] were investigated in order to elucidate possible impact of fitness on baseline CSE and CSE responses to AE, respectively. Also, to examine the impact of the amount of exercise performed on CSE changes, relationships between the total workload performed during the AE (kcal/session) and % changes of TMS variables were investigated. Normally and non-normally distributed data were investigated with Pearson's (r) or Spearman's (ρ) coefficients, respectively.58 In addition, hierarchical regression analyses were performed to further test whether significant relationships (P < 0.05) were still present when controlling for age. We limited the inclusion of controlling variables to 1 due to the small sample size: age was the variable selected because of its known impact on both the independent (O2max, body fat %, kcal/session)41 and the dependent (TMS) variables.59 Separate regressions were performed for each independent variable (O2max, body fat %, and kcal/session), which were added in the first block, with the independent controlling variable age (years) added in the second block. Significant contribution (ΔR2, Fdf = rejection region, P value) of each independent variable to the final model explaining variance on the CSE responses (dependent variables, CSE % changes) to exercise was investigated. Acceptable collinearity between the predictors was identified using tolerance levels (>0.1) and the variance inflation factor (<5.0). Outliers (±3 SD and Cook's distance >1.0),60 if present, were removed from the regressions to avoid influence of this data point in the results.
Effects of AE on CSE
A priori, we used a 2-way repeated-measures analysis of variance (ANOVA), 2 × 2: Time (Pre × Post) and Group (Stronger × Weaker hands), for RMT, AMT, MEP latencies, and area under the curve of REC, and a 3-way repeated-measures ANOVA, 2 × 2 × 6: Time (Pre × Post), Group (Stronger × Weaker), and Intensity (105%-155%), for each normalized MEP amplitude (excitatory REC) and CSP lengths (inhibitory REC).61 Normality was assessed using the Shapiro-Wilk test. Since the majority of the data did not pass the assumptions of distribution, pre- and post-exercise differences between-hands (stronger Pre vs weaker Pre, and stronger Post vs weaker Post) and within-hands (weaker Pre vs weaker Post, and stronger Pre vs stronger Post) changes from exercise were assessed with separate parametric or nonparametric paired t tests. CSE (a)symmetry index (ratio = CSE weaker/CSE stronger hand) differences between pre- and post-AE were also investigated using paired t tests.15 When performing nonparametric t tests, Wilcoxon or sign paired t tests were used depending on the distribution of differences between the 2 related variables being compared (ie, symmetrical: Wilcoxon, and asymmetrical: Sign).58 Nonparametric and parametric paired t-tests statistics were reported as z-score and tdf, respectively (eg, tdf= or z = rejection region value, P value). Sensitivity analyses62 were performed whenever outliers (±3 SD) were present, and both results, with and without outliers, were reported (see Table 4). This approach was employed because of a small sample size to clarify possible impact of outliers in the results and avoid misleading conclusions.62
All comparison (t tests) and relationship analysis significance were set at an α level of less than 0.05 and not Bonferroni adjusted because (i) they were exploratory, (ii) were a priori planned, and (iii) were planned to serve as hypothesis for future investigation.63 Data are reported as mean ± SD. Data were analyzed on SPSS v.24 (IBM Corporation, Armonk, New York). Graphs were created with GraphPad Software v.6 (La Jolla, California).
All participants performed the graded maximal exercise test. Participants 4 and 7 met both predetermined criteria for achieving O2max, participants 8, 9, and 10 met at least one, and participants 1, 2, 3, 5, and 6 could not meet either of the criteria (RER ≥ 1.1 and/or HRmax within 10% of the predicted). Using normative percentile values of cardiorespiratory fitness (O2max = mL·min−1·kg−1TBW) normalized by age and sex,41 participants 4, 7, and 9 were ranked as having very poor fitness (<15%) and the remaining 7 participants had fitness levels that were below the 1% of normative values (ie, worse than very poor fitness). Using normative percentile values of body fat % normalized by age and sex,41 participant 7 had poor (<30%), participant 3, 4, 5, and 10 had very poor (<5%), and participant 1, 2, and 6 had body composition values below the 1% of normative values (worse than very poor). Participant 8 declined to undergo DEXA scan. All fitness and body composition values of the individuals are reported in Table 2.
Participants 4, 7, 9, and 10 were able to complete the full exercise session at the intended duration and intensity (40 minutes at 60% of HRR). The remaining 6 participants (ie, participants 1, 2, 3, 5, 6, and 8) could not exercise for the intended duration (range, 7.7-30 minutes), and of these, 3 (participants 1, 2, and 5) could also not maintain the intensity target while exercising (HR was below 40% of HRR). Participants who exercised for longer duration and at higher intensity had greater workload performed during exercise (kcal/session). Figure 2 reports the participants' individual data for intensity achieved (%HRR) and time exercising (minutes), as well as the total workload performed by the end of the AE session (kcal/session).
Physical Fitness, Not Workload Performed, Was Associated With Greater AE-Induced CSE Changes
Having higher cardiorespiratory fitness (mL·min−1· kg−1LM) was associated with greater exercise-induced RMT reductions in the hemisphere corresponding to the stronger hand (r = −0.745, P = 0.021; Figure 2A). Furthermore, having lower body fat % was associated with greater increases in normalized MEP145% AMT post-exercise in the weaker hand (r = −0.722, P = 0.044; Figure 2B) and greater reductions in intracortical inhibition (shortened CSP105% AMT) in the stronger hand (r = 0.692, P = 0.039; Figure 2C). Total workload performed during the AE (kcal/session) was not associated with any CSE change from AE. When testing these associations during the regression analyses controlling for age, in the stronger hand, higher cardiorespiratory fitness significantly contributed to the model explaining greater reductions in RMT (ΔR2 = +0.458, P = 0.046) and lower body fat % significantly contributed to the model explaining greater shortening of CSP105% AMT (ΔR2 = +0.568, P = 0.030). In the weaker hand, older age significantly predicted increases in normalized MEP145% AMT (increased CSE) (R2 = 0.697, P = 0.010), with lower body fat % contributing (ΔR2 = +0.162, P = 0.062) to the final model (R2 = 0.859, P = 0.007). Table 3 summarizes the regression analysis results.
Table 3 -
Predictors of Corticospinal Excitability Change Post–Aerobic Exercise
||Block 1: Controlling Variable – Age
||Block 2: Variables of Interest – Physical Fitness (O2max and Body Fat %)
||Final Model (Age + Variable of Interest)
|Outcome Variable (% Change)
||Body fat %
||Body fat %
Abbreviations: AMT, active motor threshold; CSP, cortical silent period; LM, lean mass; MEP, motor evoked potential; RMT, resting motor threshold; % Change, [(Post-exercise – Pre-exercise)/Pre-exercise];
, maximal volume of oxygen uptake (mL·min−1
); Sig., P
change (amount of contribution of variable of interest to the final model).
aSignificantly contributed to the final model (P < 0.05).
bContributed to the significant final model.
cFinal model significantly predicted the outcome variable (P < 0.01).
Exercise-Induced CSE Changes Were Limited to the Stronger Hand
In the stronger hand, CSP lengths were shorter post-exercise than pre-exercise, effect that was noted at 115% of AMT (t9 = 2.71, P = 0.024; Figure 3A). Normalized MEP amplitudes were slightly higher post-exercise than pre-exercise in 5 of 6 TMS intensities tested on the stronger hand. This effect was most evident at 125% of AMT (t9 = −2.45, P = 0.037; Figure 3C). There were no pre/post-AE differences noted in the weaker hand for CSP lengths or normalized MEP amplitudes (Figures 3B and 3D, respectively).
Effects of AE on CSE Asymmetry
Before AE, AMT was higher (lower CSE) in the hemisphere corresponding to the weaker hand than in the stronger hand (t9 = −2.56, P = 0.031). Also, excitatory neuronal recruitment slope and accuracy (R2) were lower in the weaker hand than in the stronger hand (t7 = 3.36, P = 0.012, and t6 = 2.49, P = 0.047, respectively; Figure 4). Compared with the stronger hand, the weaker hand presented with an earlier neuronal recruitment saturation (ie, plateauing), noted by an earlier approach of MEP amplitudes to the largest MEP value (ie, 100%) at lower MSO% intensities, indicating limited ability of the contralateral hemisphere to recruit further neurons with increased stimulation intensities (eg, MEP125% AMT: t7 = −2.70, P = 0.031). After AE, these baseline differences between weaker and stronger hands did not exist (P > 0.05). For the AMT, this difference did not exist after AE because of participants 2 and 8, in whom a great asymmetry at baseline could not be reassessed, likely reducing the AMT asymmetry group effect. Nonetheless, because participants 2 and 8 could not be evaluated for REC either pre-AE or post-AE (too high AMT to perform REC) in the weaker side, the reduced asymmetry between hands for REC values (slope and R2) was likely a true group effect (Figure 4). Although the difference within the weaker hand (Pre × Post) was not significant (P > 0.05), there were observable improvements in recruitment gain (slope) and accuracy (R2) in the weaker hand post-AE (Figure 4). There were no pre/post-AE differences for the (a)symmetry indexes (P > 0.05).
RMT could not be collected in participant 2 in either of the hands pre- or post-exercise because of very low CSE at rest (eg, >100% of MSO). All participants had recordable AMT in both hands before exercise. Before exercise, REC could not be recorded on the weaker side of participants 2 and 8 because participants' AMTs reached 100% of the MSO and higher stimulus intensities based on AMT could not be applied and because TMS overheated during the assessment, respectively. Prior to exercise, 155% of AMT could not be obtained in the weaker side of participant 5 during the REC because the required intensity surpassed the limits of the stimulator (ie AMT155% = 104 >100% MSO). After exercise, AMT could not be measured in the weaker side of participants 2 and 8 because of lowered CSE (ie, MEPs of ≥200 μV were not detected during contraction) as well, procedures based on this measure (eg, REC) could not be recorded. RMT and AMT amplitudes did not differ within or between the stronger and weaker hands at pre- or post-exercise (t < 1.73, P > 0.123), indicating that the same relative TMS intensities between hands and across participants were provided throughout the TMS assessments. All TMS data are provided in Table 4.
Table 4 -
Between- and Within-Hands CSE differences—Sensitivity Analysis
||Pre vs Post
||Pre vs Post
||43 ± 12
||54 ± 23
||45 ± 15
||53 ± 24
||36 ± 13
||49 ± 26
||34 ± 13
||37 ± 13
||31.67 ± 22.3
||44.78 ± 21.1
||28.85 ± 19.2
||36.49 ± 19.35
||40. 17 ± 28.04
||62.12 ± 32.19
||46.17 ± 27.8
||59.65 ± 25.1
||47.09 ± 20.9
||70.70 ± 25.5
||68.58 ± 30.3
||62.48 ± 28.3
||74.52 ± 18.77
||78.61 ± 20.8
||66.12 ± 20.1
||77.72 ± 37.7
||79.50 ± 22.2
||79.67 ± 22.5
||91.18 ± 46.6
||89.52 ± 33.8
||99.79 ± 0.6
||91.18 ± 8.8
||115.66 ± 52.2
||107.71 ± 33.9
|eREC slope (gain)
||1.49 ± 0.4
||0.79 ± 0.6
||1.45 ± 1.1
||1.24 ± 1.0
||0.82 ± 0.1
0.86 ± 0.1c
|0.49 ± 0.4
0.48 ± 0.4c
|0.76 ± 0.3
0.87 ± 0.1d
|0.71 ± 0.3
0.69 ± 0.3d
|eREC AUC (overall excitation)
||48.00 ± 41.7
||36.12 ± 20.8
||46.55 ± 31.3
||36.70 ± 22.3
||83.73 ± 44.9
67.20 ± 34.29c
|90.81 ± 71.2
68.12 ± 33.2c
|65.07 ± 28.2
61.05 ± 31.2c
|88.26 ± 68.8
65.81 ± 28.7c
||102.58 ± 47.3
86.81 ± 44.2c
|111.15 ± 68.4
88.92 ± 29.2c
|84.50 ± 40.1
72.56 ± 38.0c
|100.99 ± 60.4
81.36 ± 25.6c
||121.75 ± 52.8
98.92 ± 35.6c
|128.68 ± 57.7
110.57 ± 28.6c
|102.98 ± 40.0
90.95 ± 40.1c
|125.31 ± 79.9
100.42 ± 40.8c
||134.53 ± 51.8
116.95 ± 43.0c
|142.58 ± 64.6
124.09 ± 40.9c
|124.09 ± 54.1
112.12 ± 61.2c
|133.03 ± 60.3
115.97 ± 39.1c
||143.79 ± 62.5
120.72 ± 44.4c
|155.33 ± 79.7
130.95 ± 43.2c
|139.93 ± 49.0
122.51 ± 48.1c
|151.27 ± 71.3
129.60 ± 39.3c
||159.45 ± 62.0
146.67 ± 37.7e
|143.73 ± 41.1
157.86 ± 18.7e
|165.22 ± 65.5
160.77 ± 58.9e
|163.82 ± 72.7
178.91 ± 63.5e
|iREC slope (gain)
||1.36 ± 0.6
||1.49 ± 0.6
||1.79 ± 1.2
||1.53 ± 0.7
||0.84 ± 0.2
||0.85 ± 0.1
||0.79 ± 0.3
||0.80 ± 0.2
|iREC AUC (overall inhibition)
||54.88 ± 19.4
||62.57 ± 24.3
||51.29 ± 19.8
||59.81 ± 24.3
Abbreviations: AE, aerobic exercise; AMT, active motor threshold; AUC, area under the curve (calculated for both excitatory and inhibitory RECs using the trapezoid rule ΔX × (Y1 + Y2)/2, whereby X is the MSO% used (ie, X-axis values, 105%-155% of AMT) and Y1 and Y2 are the recorded CSP lengths (ms) or the absolute MEP amplitudes (mV); CSE, corticospinal excitability; CSP, cortical silent period; eREC, excitatory recruitment curve; eREC slope, normalized MEP (% of the largest baseline MEP amplitude) by TMS intensity105%-155% AMT; iREC, inhibitory recruitment curve; iREC slope, CSP timems by TMS intensity105%-155% AMT; MEP, motor evoked potential; MSO%, maximal stimulator output percentage; RMT, resting motor threshold; TMS, transcranial magnetic stimulation.
aDifference is significant at the unadjusted α (adjusted α for eREC and iREC [MEP amplitudes and CSP] <0.008); outliers (±3 SD) removed during analysis.
bDifference is significant at α < 0.05.
cParticipant 5 (weaker hand CSP105%-145% AMT time (ms) (pre- and post-AE): 249.76 and 245.35, 266.75 and 238.38, 255.44 and 299.54, 272.03 and 252.41, 325.93 and 302.92; stronger hand's eREC R2 (pre-exercise): 0.51.
dParticipant 1, stronger hand's eREC R2 (post-exercise): <0.01.
eParticipant 10 (weaker hand's CSP155% AMT time (ms) (pre and post): 58.22 ms.
This is the first study to investigate the effects of acute AE on neuroplasticity-like mechanisms measured in the upper limb among people with progressive MS. Previous research has proposed that CSE changes following a bout of AE when measured in the nonexercised upper limb are likely mediated by neuroplasticity-related mechanisms10,12,15,20,64 rather than peripheral exercise-induced fatigue.65 In this preliminary pilot study, we showed that capacity for AE-induced improvements in brain excitability still exists in this group of people with progressive MS, who, because of significant central nervous system damage, require bilateral ambulatory assistive devices (eg, canes, walker) in order to walk. Regardless of whether they were able to complete the entire 40-minute bout of exercise, changes in brain excitability were noted. These benefits were observed only in the hemisphere corresponding to the stronger hand, suggesting that there may be somewhat reduced flexibility in the hemisphere corresponding to the weaker side of the body. Furthermore, when controlling for age, responsivity to exercise was greater in those participants with higher levels of cardiorespiratory fitness and lower body fat. Our results support that improving fitness and participation in AE is an important therapeutic target among people with progressive MS because AE likely has beneficial effects directly on the brain.
Effects of AE on Intracortical Inhibition
Intracortical inhibition occurs when the main inhibitory neurotransmitter GABA binds to its ionotropic GABAA or metabotropic GABAB receptor, producing a short- or long-lasting type of inhibition, respectively.66 In the adult brain, the balance between brain excitation and inhibition ensures proper brain functioning.67 Excessive GABAA and GABAB receptor activities, however, are considered pathological25,66 because they diminish neuroplasticity-like mechanisms that are necessary for learning and memory consolidation.24,25,66,68 Measured with longer CSP, excessive GABAergic-mediated intracortical inhibition corresponds to a greater lesion load, poorer recovery, and worse symptom progression in diseases affecting the brain such as stroke,26,27 Huntington disease,28 and MS.29,69 For this reason, treatment strategies aiming at reducing GABAergic-mediated intracortical inhibition are purported to improve neuroplasticity, protect brain functions, and prime recovery in aging and in diseases of neurodegenerative conditions,66,68 including MS.70
In this sample of people with progressive MS, we noted that CSP tested at lower, but not higher, TMS intensities was reduced immediately following a single session of AE. GABAA and GABAB receptor activities are sensitive to stimulus intensity, with lower TMS stimulation intensities producing shorter CSPs predominantly mediated by GABAA receptors.18,51 Our results showing AE-induced shortening of CSP only when tested at lower TMS intensities suggest the predominant involvement of GABAA receptors. This finding aligns with those previously described in healthy populations exposed to acute AE,10,12,64,71 supporting that the benefit of AE on reducing GABAA-mediated brain inhibition is preserved in people with progressive MS. It is important to note that this benefit was detected only in the hemisphere corresponding to the stronger hand. Compared with the weaker side at baseline, the hemisphere corresponding to the stronger hand had higher CSE (lower AMT) and superior excitatory neuronal recruitment gain (slope) and accuracy (R2). Because lower REC parameters are indicative of corticospinal tract damage and predictors of poor recovery following stroke,50,72,73 our results suggest that a more intact and efficient cortical representation and excitatory network of contralateral descending neurons could explain the retained and higher capacity for neuroplasticity in the hemisphere corresponding to the stronger side. We have previously shown that lower CSE in the hemisphere corresponding to weaker side among people with MS corresponds to a more advanced disease stage and poorer physical and cognitive performance.46
In comparison with GABAA, the effects of acute exercise on GABAB-mediated intracortical inhibition have not been as elucidated.10 In these participants with progressive MS, reductions in CSP tested at higher TMS stimulation intensities were not noticed, suggesting that acute AE likely did not reduce GABAB-receptor activity. In healthy volunteers, CSP investigated with higher TMS stimulation intensities is reduced following long-term exercise training.74,75 Accordingly, we have recently reported that CSPs derived from higher TMS stimulation intensities were longer in people with MS with lower fitness levels.6 This suggests that GABAB-mediated intracortical inhibition is fitness associated in healthy people and in people with MS. Because excessive activity of both GABAA and GABAB receptors diminishes neuroplasticity, rehabilitation strategies should not only rely on acute AE but, more importantly, also focus on implementing long-term exercise training to improve physical fitness of people with MS.
Effects of AE on Intracortical Excitation
Higher amplitude of the MEP is a key indicator of elevated brain excitability18 and improved neuroplasticity-like mechanisms.22 Increases in MEPs following exercise have been attributed to increased release of catecholamines, such as norepinephrine, a key mediator of increased sympathetic nervous system activity to prepare the brain and body during exercise (eg, flight-or-fight response) and to enhance neuroplasticity.10 We report here that, only measured in the stronger hand, MEP amplitudes were higher post-AE in 5 of 6 intensities tested during the REC. Statistical significance was reached at approximately the midpoint of the REC (ie, 125% of AMT), previously shown to correspond to the “inflection point” of the REC,50 which represents the point of steep recruitment of higher threshold motoneuronal pools lying deep within the corticospinal tract. It is interesting to note that the approximate midpoint in the REC is also sensitive to and negatively affected by passive heat stress among people with MS.76
Previous studies investigating the effects of acute AE on CSE have shown benefits among young (∼20-30 years old) healthy individuals with high levels of fitness (∼50 mL·min−1·kg−1).10,20,64,77,78 It is noteworthy that only a modest volume of AE (moderate intensity, 7.7-40 minutes) performed by these older, disabled, and deconditioned participants with progressive MS was able to induce similar observable CSE improvements. Our findings support that people with MS, even those with more advanced disease, should be prescribed AE.
Effects of AE on CSE in Progressive MS—The Role of Fitness
Previous research has confirmed that the effects of AE on brain excitability appear to be intensity dependent, with higher exercise intensities inducing greater increases in brain excitability associated with higher levels of neurotrophins such as brain-derived neurotrophic factor,79 excitatory neurotransmitters (eg, dopamine, norepinephrine), and lactate78 and increases in cerebral blood flow.9,10 On the basis of this evidence, we expected that higher total workload would be associated with superior CSE gains, with participants performing 40 minutes of exercise benefiting more than those who performed only 7 minutes of exercise. However, this was not the case; total workload performed (kcal/session) was not associated with AE-induced changes in any TMS variable tested. Importantly, higher fitness tested at baseline was associated with greater CSE gains. Specifically, higher cardiorespiratory fitness (mL·min−1·kg−1LM) was associated with increases in CSE (measured with reductions in RMT) in the hemisphere corresponding to the stronger hand. Coco et al78 showed that reduction in RMT after a single session of exhaustive AE was associated with increased levels of lactate. However, the study investigated highly fit, lean, and young individuals, fitness profiles differing from that of our participants. Whether the fitness-dependent changes in CSE could be related to elevated lactate levels in people with MS is worthy of future research. Furthermore, we found that lower body fat % was associated with greater CSP reductions (less intracortical inhibition) in the hemisphere corresponding to the stronger side and elevated MEP amplitudes (higher CSE) in the hemisphere corresponding to the weaker hand. Recent evidence has demonstrated the link between disability, poor cardiorespiratory fitness, and higher body fat % in people with MS.35 We suggest that lower cardiorespiratory fitness and higher body fat % may also diminish AE-induced neuroplasticity-like mechanisms in people with MS.
Effects of AE on Reducing CSE Asymmetry
CSE asymmetry is a hallmark of stroke, whereby the lesioned hemisphere has a much lower excitability,80 with its magnitude related to lesion size predicting worse symptoms and disability.81 For that reason, reducing CSE asymmetry with advanced brain stimulation techniques has been a desirable goal during rehabilitation interventions in stroke.15,80 In participants with MS, we have recently demonstrated that CSE asymmetry also predicts disease and symptom progression, with CSE asymmetry of more advanced MS stages (EDSS score 3-6) comparable with those reported in stroke.46 In accordance with our previous results, we noted in this group of people with progressive MS, lower excitability (higher AMT) and inferior quality of excitatory neuronal activity (lower excitatory REC gain [slope] and accuracy [R2]) in the weaker hand compared with the stronger hand. It is noteworthy that only the TMS variables measuring excitation (AMT, excitatory REC) and not inhibition (CSP, inhibitory REC) were different between hemispheres. This asymmetry of excitation could be mediated by excitotoxicity due to excessive glutamatergic activity typical of early MS stages.1,46 After AE, we noted that differences between excitatory REC (slope and R2) were abolished, with slight increase in the excitatory REC parameters in the weaker side. Therefore, it is possible that AE could have transiently restored excitatory glutamatergic activity in the hemisphere corresponding to the weaker side in this sample of people with progressive MS.
This pilot study was designed to explore, in a preliminary way, the effects of acute AE on brain excitability in a group of people with progressive MS who use bilateral ambulatory assistive devices to walk. There are some important limitations to the study, most important of which is the small sample size. Because severity of MS could have a major impact on acute AE effects, we attempted to recruit a homogeneous group of people with MS with EDSS scores between 6.0 and 6.5. We did not complete a power analysis, and some of our regression analyses were underpowered. Moreover, because we performed multiple comparisons (sensitivity analysis using t tests), the unadjusted (ie, Bonferroni corrected) significances found in this study should be interpreted with care. Despite a small sample size, our findings may serve to develop hypotheses and methods for future longitudinal and interventional studies investigating associations between fitness and neuroplasticity in progressive MS.
The individuals with MS participating in this study were diagnosed with the progressive form of MS and required ambulatory assistive devices (eg, canes, walker) to walk likely due to the severely damaged corticospinal tract. In addition, their fitness scores indicated that they were severely deconditioned and only 4 of 10 participants could complete the intended 40 minutes of body weight–supported treadmill AE. Despite these physical challenges, neuroplasticity-related CSE improvements were noted after a single bout of AE. Specifically, a bout of AE resulted in enhanced excitation (increased MEP amplitude) and reduced intracortical inhibition (shortened CSP) in the hemisphere associated with the stronger hand. The hemisphere contralateral to the weaker hand was resistant to exercise-induced CSE changes, had lower baseline CSE (higher AMT), and poorer neuronal recruitment (lower excitatory REC), likely suggesting less neuroplastic potential. Nonetheless, typical CSE asymmetry expected in this group of people with progressive MS was abolished after AE, which could indicate some potential for neuroplasticity in the hemisphere corresponding to the weaker side. The benefits of AE-induced improvements in CSE were not related to intensity of the workload but rather baseline cardiorespiratory fitness and the percentage of body fat, with fitter participants with less body fat receiving greater benefits. The results of this preliminary study support that reducing levels of sedentarism, prescription of AE, and decreasing body fat may have direct benefits on the brain, improving brain plasticity in people with progressive MS-related walking disability.
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