3.1 Feasibility of recruitment, attendance, and retention
Thirty-seven MS patients were contacted to determine their willingness to participate. Thirteen MS patients did not meet eligibility criteria, seven declined to participate, and seven were not contactable (see Flow Chart in Supplement 1). Out of 10 MS patients who agreed to participate, eight passed the PAR-Q, and two passed PAR-Med-X, and were thus enrolled (n=10) in the study (Table 1). Recruitment was stopped prior to reaching enrollment goal (n=11) due to slow accrual and difficulty finding patients who were willing to participate in the training program. All participants (n=10) identified themselves as having fatigue and sensitivity to heat. Ten participants (9 females), aged 29 to 74 years, with EDSS ranging from 6.0 to 7.0 completed the baseline assessments following which, two dropped out of the study (after completing 2 and 7 sessions respectively), and eight participants continued to participate in the exercise training sessions (range, 24 to 30 sessions) (Table 1). Eight participants (7 females) completed the 10-week exercise training and completed the assessments immediately after the training program. Three months after exercise training, seven participants (6 females) returned to complete the follow-up assessments.
3.1.2 Attendance rates and reasons for missed appointments
The attendance rates ranged from 80% to 100% among those who completed exercise training and the total number of missed appointments ranged from 1 to 6 per participant (Table 1). The reasons for missing appointments were feeling tired or unwell (n=15), transportation issues (n=5), having medical appointments (n=4), personal scheduling conflict (n=4), leg pain and stiffness (n=3), inclement weather (n=3), recent fall (n=2), and forgot appointment (n=1). Participants rescheduled the missed appointments and continued to participate in the exercise sessions (Table 1).
3.1.3 Baseline characteristics
On average, the participants were 53.2 years of age (+15.6) and had a body mass index of 28.2(+6.6) (Table 2). Four had confirmed diagnosis of progressive MS and six were in transition from relapsing-remitting to progressive phase (Table 2) (33). Participants used either unilateral (n=4) or bilateral (n=6) support during ambulation (Table 2). On average, self-selected walking speed was 57.8(+31.3) cm/s, and fast walking speed was 85.8(+54.4) cm/s. None of the participants required additional assistance from the physiotherapist during overground walking speed assessments.
3.2 Feasibility of intervention
3.2.1 Adverse events, safety, and dropouts
The intervention was laboratory-based in a rehabilitation hospital setting; therefore, the researchers relied on physicians-on-call for emergencies. No adverse events (MS relapse, syncope, or medical emergencies) occurred during assessments and training sessions. One participant required electrocardiograph monitoring by the physician during GXT due to a history of arrhythmia. The GXT was terminated due to high systolic blood pressure (>220 mmHg); however, the participant was admitted into the study after clearance from the physician. Participants wore a safety harness during all training sessions and no safety hazards were identified. Two participants discontinued intervention and one participant was lost to follow up (see Supplement 1).
3.2.2 Training load and tolerance
All participants were able to perform progressively intense BWST training from moderate to vigorous intensity (40-65% HRR) (49), however participants did not have significant change in resting heart rate after training (p=0.29). Eight out of 10 participants were able to walk on the treadmill at 80% of their self-selected overground walking speed from the first exercise session onwards. One participant was able to start training at 60% and another at 40% of their respective self-selected overground walking speeds. All participants, but one, were able to walk on the treadmill with 10% body weight support from the first exercise session. Three participants were able to completely wean off to 0% body weight support over ten weeks. Three participants required manual assistance to advance their lower extremity during initial treadmill training sessions, which was weaned off gradually. The total time walked, and distance covered progressively increased while the total time required to rest decreased (Figures 1A, B, C, and D). The participants were advised to take breaks in either sitting or standing position on the treadmill as required during training sessions (Figure 1D). There was an overall increase in workload performed and oxygen consumed in both unilateral and bilateral walking aid users (Figures 1E and F).
3.2.3 Subjective reporting of symptoms and physiological response to exercise
All participants were able to tolerate the cool room training with the air-conditioning set at 16°C. Two participants reported having mild symptoms, such as pins and needles sensations, that were fleeting for a few seconds or minutes during training sessions. Two participants reported having weak legs while walking on the treadmill. One participant complained of shoulder ache after bearing body weight through arms and requested greater body weight support. One participant had leg pain that resulted in the termination of one of the training sessions. None of the participants reported exacerbation of MS symptoms, such as the occurrence of motor weakness, ataxia of a limb, or any other MS symptoms, that lasted more than 24 hours after training sessions (54, 55). Tympanic temperature, heart rate, and fatigue increased with exercise, while mean arterial pressure remained stable (Figure 2A, B, C, and D).
3.3 Secondary outcomes
184.108.40.206 Fast walking speed
We tested fast walking speed using two methods, (1) T25FW test (in seconds) and (2) on an instrumented walkway (cm/s). In terms of the T25FW test, following ten weeks of training, participants walked 1.4 times faster, but values returned to pre levels at follow up (Table 3). Four out of 8 participants made a clinically meaningful change (>20%) after training (Figure 3A) (56-58).
In regards to fast walking speed measured on the instrumented walkway (cm/s), speed increased by 15.5%, which was sustained at follow up compared to pre assessment (Table 3). Furthermore, gait quality (duration of stance phase (%), swing phase (%), and total double support phase (%)) during fast walking improved at post (p values, 0.025, 0.025 and 0.017 respectively), but values returned to pre levels at follow up (p values, 0.13, 0.13 and 0.13).
220.127.116.11 Self-selected walking speed
There was no significant change in self-selected walking speed (cm/s) (measured on an instrumented walkway) at both post and follow up (Table 3). However, 6 out of 8 participants made a clinically meaningful change of more than 12% beyond the benchmark accepted for walking assessments in MS (Figure 3B) (59, 60).
There was no significant change in stance and swing phases (%) while walking at self-selected speed (p values, 0.09 and 0.09 respectively), however total double support phase (%) was significantly reduced at post compared to pre (p=0.036). Duration of the stance phase (%), swing phase (%), and total double support phase (%) while walking at self-selected speed improved significantly at follow up compared to pre (p values, 0.018, 0.018, and 0.018).
Participants rated three aspects of fatigue, (1) present level of energy (fatigue/energy/vitality sub-scale of SF-36 Health Survey), (2) severity of fatigue (FSS), and (3) impact of fatigue on everyday life (mFIS). Participants reported improved fatigue (36.4% or 14.3 point increase in energy levels on fatigue/energy/vitality sub-scale of SF-36 Health Survey) at post, which returned to pre levels at follow up (8.6 point increase from pre) (Table 3) (Figure 3D). However, 5 out of 8 participants made a minimally important improvement of 11.3 or more points at post, of whom 3 participants sustained the improvements at follow up (Figure 3D) (61).
Severity of fatigue reported on FSS (mean score) was not significantly different at post or at follow up compared to pre (Table 3). However, 4 out of 8 participants achieved a change of 1.9 or more points on mean FSS scores at post, a minimal detectable clinically meaningful change for people with MS (Figure 3E) (43).
Impact of fatigue reported on mFIS was significantly less at post, which was sustained at follow up compared to pre (Table 3). However, only 1 out of 8 participants had a clinically meaningful change beyond the accepted benchmark of 20.2 points at post, and two at follow up (Figure 3F) (43).
3.3.3 Aerobic fitness
There was no statistically significant change in maximal V̇O2 and maximal heart rate achieved during GXT at post compared to pre (Table 3) (Figure 3C). However, the participants were able to achieve a greater workload during GXT at both post and follow up compared to pre values (Table 3). The oxygen uptake efficiency slope, a measure of the cardiorespiratory reserve, significantly increased at post, which was sustained during follow up (Table 3) (62, 63).
In terms of indicators of achievement of a maximal GXT, four out of 10 participants achieved two or more criteria for test termination at pre, 3 out of 8 at post, and 3 out of 7 at follow up (46, 47). The maximal respiratory exchange ratio ranged from 0.84 to 1.28 (1.07+0.15) at pre, 0.93 to 1.24 (1.07+0.12) at post, and 0.90 to 1.21 (1.07+0.11) at follow up, in which five out of 10 participants achieved respiratory exchange ratio more than 1.1 at pre, 4 out of 8 at post, and 3 out of 7 at follow up. The maximal age-predicted heart rate achieved by participants ranged from 68.1% to 101.4% (88.1+11.9%) at pre, 68.1% to 104.1% (88.8+12.2%) at post, and 69.1% to 114.2% (91.6+16.9%) at follow up, in which five out of 10 participants achieved more than 90% of their age-predicted maximal heart rate at pre, 4 out of 8 at post, and 4 out of 7 at follow up. Borg’s rating of perceived exertion reported at the end of GXT ranged from 6.0 to 10.0 (9.2+1.5) at pre, 7.0 to 10.0 (9.5+1.1) at post, and 7.0 to 10.0 (9.6+1.1) at follow up, in which eight out of 10 participants rated more than 8.0 on Borg’s rate of perceived exertion at pre, 7 out of 8 at post, and 6 out 7 at follow up. All participants reported performing GXT to their maximal volitional exhaustion at all testing time points, except for two participants who reported that they could have pushed themselves more during GXT performed at post-training.
3.3.4 Quality of life
There was a clinically meaningful improvement in the quality of life in all SF-36 domains (i.e., more than a 3-point increase in all SF-36 domains separately at post compared to pre), except social functioning (1.8 point increase) (Tables 3 and 4) (64, 65). Physical functioning significantly improved at both post and follow up compared to pre (Table 4). Perception about overall health (compared to last year) and bodily pain significantly improved at post, but not at follow up (Table 4). Although not statistically significant, we noted clinically meaningful (>3-point increase) improvements reported at post on the SF-36 subscales - role limitations due to physical health, role limitations due to emotional problems, mental health/emotional well-being, and general health perceptions. We also noted clinically meaningful (>3-point increase) improvements sustained until follow up compared to pre, in bodily pain, general health perceptions, and health compared to last year.
3.3.5 Blood biomarkers
We were unable to draw blood samples from three participants on 6 out of 52 occasions. All serum BDNF levels were within the detectable ranges. Serum IL-6 levels were not detectable in seven participants on 22 out of 46 occasions.
In terms of serum BDNF, there were no significant differences in resting and exercise-induced levels (After minus Before GXT) measured at pre (Figure 4A), post (Figure 4B), and at follow up (Figure 4C) (p values, 0.22 and 1.0 respectively) (Table 5). There was a significant decrease in serum BDNF after GXT compared to before GXT levels, both at pre (Figure 4A) and follow up (Figure 4C) (p values, 0.036 and 0.028 respectively), but not at post-training (p=0.31) (Figure 4B).
In terms of serum IL-6, there were no significant differences in resting and exercise-induced levels (After minus Before GXT) measured at pre (Figure 4D), post (Figure 4E), and at follow up (Figure 4F) (p values, 0.28 and 0.37) (Table 5). There was no significant change in serum IL-6 after GXT compared to before GXT levels, at pre (Figure 4D), post (Figure 4E), and follow up (Figure 4F) (p values, 0.59, 0.90, and 1.0 respectively).
3.3.6 Relationship between outcomes
The improvement in fast walking speed was associated with reduced fatigue measured using physical subcomponent score of mFIS (Spearman’s rank correlation coefficient, rs=-0.847, p=0.008) (Figure 5A). The improvement in fatigue measured using total mFIS score was related to higher maximal respiratory exchange ratio achieved during GXT (rs=-0.810, p=0.015) (Figure 5B). The improvement in maximal respiratory exchange ratio achieved during GXT was associated with an increase in resting serum BDNF (rs=0.786, p=0.036) (Figure 5C). The improvement in fitness measured using maximal V̇O2 was associated with a decrease in resting serum IL-6 (rs=-0.757, p=0.049) (Figure 5D). However, after correcting for multiple correlations (0.05/7=0.007) (52, 53), none of the relationships were statistically significant.