Effects of downslope walking on Soleus H-reflexes and walking function in individuals with multiple sclerosis: A preliminary study

Abstract

BACKGROUND:

Downslope walking (DSW) is an eccentric-based exercise intervention that promotes neuroplasticity of spinal reflex circuitry by inducing depression of Soleus Hoffman (H)-reflexes in young, neurologically unimpaired adults.

OBJECTIVE:

The objective of the study was to evaluate the effects of DSW on spinal excitability (SE) and walking function (WF) in people with multiple sclerosis (PwMS).

METHODS:

Our study comprised two experiments on 12 PwMS (11 women; 45.3±11.8 years). Experiment 1 evaluated acute effects of a single 20-minute session of treadmill walking at three different walking grades on SE, 0% or level walking (LW), – 7.5% DSW, and – 15% DSW. Experiment 2 evaluated the effects of 6 sessions of DSW, at – 7.5% DSW (with second session being – 15% DSW) on SE and WF.

RESULTS:

Experiment 1 showed significantly greater acute % H-reflex depression following – 15% DSW compared to LW (p = 0.02) and – 7.5% DSW (p = 0.05). Experiment 2 demonstrated significant improvements in WF. PwMS who showed greater acute H-reflex depression during the – 15% DSW session also demonstrated greater physical activity, long-distance WF, and the ability to have greater H-reflex depression after DSW training. Significant changes were not observed in regards to SE.

CONCLUSIONS:

Though significant changes were not observed in SE after DSW training, we observed an improvement in WF which merits further investigation of DSW in PwMS.

Keywords

Treadmill training spinal excitability neuroplasticity spasticity

1 Background

Multiple Sclerosis (MS) is the most prevalent cause of neurological disability in young adults (Dutta & Trapp, 2011; Hauser & Oksenberg, 2006; Noseworthy, 1999; Noseworthy, Lucchinetti, Rodriguez, & Weinshenker, 2000). Approximately 80% of people with MS (PwMS) experience spasticity (intermittent or sustained involuntary activation of muscles, resulting from hyper-excitability of the stretch reflex in upper motor neuron lesions) (Pandyan et al., 2005; Sunnerhagen, Olver, & Francisco, 2013). Spasticity in lower limb muscles may detrimentally affect mobility and balance in PwMS (Huang, Wang, & Hwang, 2006). The Hoffman (H)-reflex is a noninvasive technique used to evaluate the efficiency of transmission in Ia afferent α-motoneurons synapses in the spinal cord (Duclay & Martin, 2005; Knikou, 2008) and elevated H-reflexes have been shown to correlate with the degree of spasticity, providing a neurophysiologic marker of spasticity in MS (Morita, Crone, Christenhuis, Petersen, & Nielsen,2001).

Downslope walking (DSW) is an eccentric-based exercise intervention that has been shown to promote neuroplasticity of the spinal reflex circuitry by inducing depression of Soleus H-reflexes in neurologically-unimpaired adults (Duclay & Martin, 2005; Hoessly, 1991; Manella, Roach, & Field-Fote, 2013; Proske & Morgan, 2001). However, whether DSW exercise induces depression of the Soleus H-reflex in PwMS is unknown. Modifying treadmill walking which has been shown to be a well-tolerated exercise intervention in PwMS (Gervasoni, Cattaneo, & Jonsdottir, 2014; Giesser, Beres-Jones, Budovitch, Herlihy, & Harkema, 2007; van den Berg et al., 2006), to include DSW may be beneficial for decreasing spasticity and improving walking function in PwMS. Compared to conventional treadmill walking, DSW has been shown to be no more metabolically demanding than walking on level ground or uphill (Hunter, Hendrix, & Dean, 2010). A recent study on PwMS demonstrated that 12 DSW training sessions (three times each week) at – 10% slope resulted in greater improvements in walking and balance outcomes compared to walking at a positive slope (10%) (Samaei, Bakhtiary, Hajihasani, Fatemi, & Motaharinezhad, 2016). However, spasticity and H-reflexes were not measured in this previous study (Samaei et al., 2016). Additionally, DSW has been shown to promote neuroplasticity in spinal circuitry in able-bodied individuals(Fang, Siemionow, Sahgal, Xiong, & Yue, 2001; Sabatier et al., 2015). Therefore, DSW may offer an efficacious exercise intervention for improving walking function through induction of spinal cord plasticity in PwMS. Based on previous studies in neurologically-intact individuals (Arnold et al., 2017) and PwMS (Samaei et al., 2016), the objective of the current study was to concurrently evaluate the effects of DSW on spinal excitability and clinical walking function.

2 Objective

Our study comprised two experiments. Experiment 1 compared the acute effects of a single 20-minute session of treadmill walking at three different walking grades (0%, – 7.5% DSW, and – 15% DSW) on spinal excitability. In a previous study with neurologically-intact individuals, DSW with a steeper slope (– 25% vs – 15%) resulted in a greater acute change in Soleus H-reflexes (Arnold et al., 2017). We aimed to determine whether the same trend of slope-dependent acute H-reflex depression occurred with PwMS. For Experiment 1, we hypothesized that DSW (– 7.5% and – 15%) would induce acute depression of the Soleus H-reflex amplitude, and a steeper slope would induce larger H-reflex depression. Experiment 2 evaluated the effects of six sessions (3 times per week) of – 7.5% DSW (2nd session being – 15% DSW) on spinal excitability and clinical walking function in PwMS. For Experiment 2, we hypothesized that multiple sessions of DSW training would decrease Soleus H-reflex amplitude and improve clinical walking function. An additional objective was to determine whether baseline spinal excitability, clinical walking function, and physical activity correlated with the magnitude of H-reflex depression induced by DSW. By evaluating the effects of a single as well as multiple DSW training sessions on spinal excitability and walking function in PwMS, our study takes a step toward elucidating the mechanisms underlying DSW as an exercise intervention for PwMS.

3 Methods

3.1 Participants

PwMS who demonstrated visible walking impairments were recruited for the study. Inclusion criteria were: age >18 years, able to walk independently at household distances, no previous downslope walking experience, and spasticity in at least one leg (evaluated using the Modified Ashworth Scale). Participants who experienced an MS relapse in the past six months, had history of cardiovascular disease, history of seizures, implanted pacemaker, unstable long bone fractures, allergies to surface electrode gel, were pregnant, or had evidence of neural lesions at or below the lumbar enlargement were excluded from the study. All participants who completed Experiment 1 also completed Experiment 2. Participants were instructed to keep spasticity medication and physical activity constant during the study period. Participants received approval from their neurologist, and provided informed consent approved by Emory University and Shepherd Center Institutional Review Boards.

3.2 Experiment 1: Acute effect of DSW on Soleus H-reflexes in people with MS

Experiment 1 used a repeated-measured design, whereby each participant completed three sessions, separated by ≥24 hours. The average inter-session interval for Experiment 1 was 4.37±2.08 days. Prior to the first session, the participant performed the two-minute walk test (2MWT) to determine the walking speed for each session. Treadmill walking speed was defined as 80% of the 2MWT speed. Session order was level walking (LW; control session), followed by two DSW sessions, one at – 7.5% (– 7.5% DSW), and another at – 15% (– 15% DSW; last session). This order was selected to help participants accommodate to DSW treadmill walking and prevent delayed onset muscle soreness following the – 15% session (Arnold et al., 2017).

3.2.1 Treadmill walking

Participants walked on a Sole Fitness F85 Folding Treadmill (Niagara Falls, ON) for 20 minutes at 80% of the speed determined from their over ground 2MWT. If participants were unable to walk at their respective 80% 2MWT speed, the speed was reduced to the participants’ tolerance. Five of the twelve participants walked at a speed less than 80% 2MWT speed (Table 1). For safety during walking, participants were harnessed to the treadmill using back and waist supports. Heart rate (HR) and rating of perceived exertion (RPE) were measured every five minutes starting at the fourth minute (Table 2). RPE was collected using the Borg scale of perceived exertion. Resting HR was collected 5-minutes prior to treadmill walking and 5-minutes after walking.

Table 1
Participant Demographics

Participant Age Gender Race EDSS 80% Treadmill Speed (mph) Treadmill Training Speed (mph)

1 51 F AA 6 0.6 0.5

2 39 F AA 2.5 2.2 2.2

3 34 M C 4.5 1.6 1.2

4 48 F AA 4.5 1.6 1.5

5 68 F AA 3.5 2.0 2.0

6 22 F C 0 2.1 2.1

7 44 F AA 4.5 0.9 0.9

8 53 F AA 4 2.0 1.7

9 53 F AA 1 1.0 1.0

10 51 F AA 4.5 1.8 1.8

11 34 F AA 5.5 1.5 1

12 47 F AA 3.5 1.6 1.6

Mean±SD 45.3±11.8 3.7±1.7 1.57±0.51 1.45±0.54

Participant	Age	Gender	Race	EDSS	80% Treadmill Speed (mph)	Treadmill Training Speed (mph)
1	51	F	AA	6	0.6	0.5
2	39	F	AA	2.5	2.2	2.2
3	34	M	C	4.5	1.6	1.2
4	48	F	AA	4.5	1.6	1.5
5	68	F	AA	3.5	2.0	2.0
6	22	F	C	0	2.1	2.1
7	44	F	AA	4.5	0.9	0.9
8	53	F	AA	4	2.0	1.7
9	53	F	AA	1	1.0	1.0
10	51	F	AA	4.5	1.8	1.8
11	34	F	AA	5.5	1.5	1
12	47	F	AA	3.5	1.6	1.6
Mean±SD	45.3±11.8			3.7±1.7	1.57±0.51	1.45±0.54

F = female; M = male; AA = African American; C = Caucasian.

Table 2

Heart Rate and Ratings of Perceived Exertion during treadmill walking. Values reported as Mean (SD)

			Treadmill Walking
		Pre	1–5 mins	6–10 mins	11–15 mins	16–20 mins	Post	Avg 1–20min
HR	LW	66.8 (10.8)	91.5 (18.8)	97.2 (19.2)	99.8 (20.2)	102.6 (22.6)	73.1 (11.1)	97.8 (19.6)
	– 7.5%	71.8 (11.6)	90.5 (15.1)	96.5 (17.4)	99.2 (18.4)	102.7 (19.2)	74.0 (9.2)	97.2 (17.3)
	– 15%	70.5 (11.4)	95.7 (16.5)	106.2 (17.6)	109.3 (18.2)	112.3 (19.3)	76.5 (10.4)	105.9 (16.7)
RPE	LW	—	10.4 (2.3)	10.5 (2.3)	10.7 (2.2)	11.3 (2.6)	—	10.7 (2.3)
	– 7.5%	—	10.4 (2.2)	10.4 (2.2)	11.0 (2.6)	11.3 (2.5)	—	10.8 (2.3)
	– 15%	—	11.6 (1.3)	11.8 (1.9)	12.2 (2.1)	12.5 (2.8)	—	12.1 (1.9)

3.2.2 Spinal excitability measurements

During each session, H-reflex data were collected before and after treadmill walking from the participant’s weaker or more affected leg (based on self-report). Data collection was scheduled at the same time of day (±2 hours) for each of the three sessions to minimize diurnal effects on H-reflexes (Lagerquist, Zehr, Baldwin, Klakowicz, & Collins, 2006). At the beginning of each session, two surface EMG sensors (11-mm diameter) (EL503 Biopac Systems Inc., Goleta, CA) 2-cm apart, were attached to skin overlying the Soleus muscle.

Soleus muscle responses were evoked by stimulating the tibial nerve in the popliteal fossa using a monopolar cathode electrode (round, 2.5 cm) with an anode (square, 5 cm) placed above the patella (Medical Products Online, Danbury, CT). Optimal electrode placement was determined by having the participant lay prone while stimulating the tibial nerve to elicit an H-reflex without an M-wave. Soleus H-reflexes were collected 10-minutes before and 7-minutes after treadmill walking. Soleus H-reflex recruitment curves were collected by delivering 40–50 stimulation pulses (1-ms pulse width) of gradually increasing intensity at pseudo-random intervals (5–8-seconds) using a constant-current stimulator (STIMSOLA, Biopac, Goleta, CA) until Mmax was achieved. Mmax was determined when three consecutive stimulations did not further increase M wave amplitudes.

During the H-reflex recruitment curve collection, the participant sat semi-reclined in a chair with the hip at 120°, knee at 30°, and ankle at 90°. Inelastic straps were used to stabilize the participant’s feet and legs. Additionally, during the recruitment curve collection, the participant maintained isometric plantarflexor background EMG activation at 20% of maximal EMG in order to minimize fatigue experienced by the subject. The participant was provided visual biofeedback regarding ongoing EMG activity. Maximum EMG activity was determined as peak EMG-RMS during three maximal 3–5-second plantarflexion contractions.

3.3 Experiment 2: Effect of 6 DSW training sessions on clinical function and spinal excitability in people with MS

After completing Experiment 1, participants completed Experiment 2 to evaluate if six DSW sessions (two sessions carried over from Experiment 1 plus additional four sessions of DSW at – 7.5% at same treadmill speed) would decrease spinal excitability and improve clinical walking function in PwMS. Unlike Experiment 1, spinal excitability measurements were not collected before and after every treadmill walking session, but was only collected during the PostTrain day. The – 7.5% DSW was chosen because not enough treadmill walking experimentation has been done in PwMS with a steeper slope and repetitive sessions of – 15% DSW may lead to delayed onset muscle soreness.

3.4 Outcome measures for Experiment 2

3.4.1 Modified Ashworth Scale

With the participant in the supine position, the hip, knee, and ankle was flexed or extended maximally over a 1-second count. A score between 0 (no increase in tone) and 4 (affected part rigid in flexion or extension) was recorded (Bohannon & Smith, 1987). The ratings were summed for all three joints for both lower limbs to achieve a total Modified Ashworth Scale (MAS) score. This procedure was completed before DSW training by an experienced physical therapist.

3.4.2 Strength (Soleus, Tibialis Anterior, & Quadriceps)

Maximal force output was obtained for three muscles: Soleus, Tibialis Anterior, and Quadriceps. The participant was instructed to plantarflex, dorsiflex, and perform knee extension three times for 3–5 seconds, and the highest force was recorded as the maximal force output for each muscle. Maximal force values for the 3 muscles were summed to create a composite strength score.

3.4.3 Modified Fatigue Impact Scale

The Modified Fatigue Impact Scale 5 Item (MFIS) is a participant-reported outcome that assesses how fatigue impacted their physical, cognitive, and psychosocial functioning during the past four weeks. The MFIS we utilized is an abbreviated version of the MFIS that has been validated in PwMS (D’Souza, 2016), with higher scores indicating greater impact of fatigue (Rietberg, Van Wegen, & Kwakkel, 2010).

3.4.4 Two Minute Walk Test

The 2 MWT measures the distance walked over a 2-minute period. Participants were instructed to pace a 50-foot hallway and walk “as much distance as they could in two minutes”.

3.4.5 25-Foot Walk Test

The 25-Foot Walk Test (25FWT) measures speed over a short distance down a hallway (Phan-Ba et al., 2011). For both the pre- and post-intervention measure, an average of two tests was used to compute gait speed.

3.4.6 Timed-Up-and-Go (TUG) Test

For the TUG, a timed measure of dynamic balance, participants were instructed to stand up from a chair, walk 3-meters, turn around, and sit back down(Cattaneo, Regola, & Meotti, 2006).

3.4.7 Physical activity measurements

During their first visit, participants were provided with a Physical Activity Monitor (wGT3X-BT, ActiGraph, Pensacola, FL). Participants were instructed to wear the activity monitor on their waist closest to the weak limb for at least 7 days. Activity data were processed using ActiLife software (ActiGraph, Pensacola, FL) and analyzed using MS Excel. Vector magnitudes (Physical Activity Counts (Vm)) were extracted for each participant over the seven-day period(Powell, Carson, Dowd, & Donnelly, 2016). Wear-time validation was processed using Choi thresholds (Choi, Liu, Matthews, & Buchowski, 2011). Physical activity counts were counted when a change in direction in either the X, Y, or Z took place as proprietarily defined by ActiGraph (all Vm scores divided by 1,000). Participants were requested to remove their physical activity monitor if a lab visit occurred during the 7-day period. Physical activity data were used for correlation analysis for Experiments 1 and 2.

3.4.8 12-Item MS walking scale

The 12-item multiple sclerosis walking scale (MSWS-12) is a self-report measure of the impact of MS on the individual’s walking ability (Hobart, Riazi, Lamping, Fitzpatrick, & Thompson, 2003). The MSWS-12 has been recommended by the 2007 consensus conference of the Consortium of Multiple Sclerosis Centers (Hutchinson et al., 2009).

3.5 Statistical analysis

For Experiment 1, a one-way repeated-measures ANOVA with post-hoc pairwise comparisons were performed to evaluate the effect of slope (0% or LW, 7.5% DSW, 15% DSW) on % depression in Soleus H-reflex amplitude from pre- to post walking. Additionally, two-way repeated measures ANOVAs were completed to evaluate the effect of slope (0% or LW, – 7.5% DSW, – 15% DSW) and time (pre, post) on HR and RPE. For Experiment 2, paired t-tests were used to compare walking function (2MWT, 25FWT, TUG) and spinal excitability after (PostTrain) versus before (PreTrain) six sessions of DSW training. Additionally, Pearson’s correlation analyses were performed to evaluate relationships between % Δ Hmax/Mmax post -15% DSW with PreTrain 2MWT, Physical Activity, and Treadmill Training Speed; % ΔHmax/Mmax PreTrain-PostTrain with Strength and % Δ Hmax/Mmax post – 15% DSW. SPSS software (version 24, IBM, New York) was used for statistical analysis and significance level was set at p < 0.05.

4 Results

Twelve adults (11 women; 45.3±11.8 years; BMI: 26.3±5.1; EDSS: 3.6±1.7) diagnosed with relapsing-remitting multiple sclerosis completed the study (Table 1).

4.1 Experiment 1: Acute effects of slope walking on Soleus H-reflexes

The one-way ANOVA evaluating the effect of treadmill slope on % depression of the H-reflex induced after treadmill walking showed a trend for an overall effect of slope (p = 0.059) (Fig. 1). Post-hoc paired t-tests detected significantly greater % H-reflex depression following – 15% DSW compared to both LW (p = 0.02) and – 7.5% DSW (p = 0.05). However, no significant difference in % H-reflex depression was detected between LW and – 7.5% DSW (p = 0.41).

Fig.1

Soleus H-reflexes decreased after a single session of – 7.5% DSW and – 15% DSW but not LW. (a) Comparison of Soleus Hmax/Mmax at pre (before) and post (immediately after) a 20-minute session of treadmill walking at LW, – 7.5% DSW, and – 15% SDSW; (b) Average % change of Soleus Hmax/Mmax for each of the three walking conditions; (c) H-reflex recruitment curve data from a representative participant showing a decrease in Soleus H-reflex amplitude for the – 15% DSW walking condition.

The 2-way ANOVA for HR showed a main effect of time (p < 0.01) and slope (p < 0.02), and no significant interaction effect (p = 0.19). Post-hoc paired comparisons showed that HR was significantly higher during the – 15% DSW session compared to the – 7.5% DSW session (p = 0.004) (Fig. 2a). The 2-way ANOVA for RPE did not display a main effect of time (p = 0.21), showed a statistical trend toward a main effect of slope (p = 0.07), and no interaction effect (p = 0.32). Post-hoc comparisons showed significantly greater RPE during – 15% DSW compared to the LW session (p = 0.03) and the – 7.5% DSW session (p = 0.02) (Fig. 2b).

Fig.2

Heart Rate and Rating for Perceived Exertion elevated during – 15% DSW. (a) Average HR for each walking epoch for each walking session - LW, – 7.5% DSW, and -15% DSW. (b) Average RPE for each epoch for each walking session. (c) Average HR for the duration of each walking session. (d) Average RPE for the duration of each walking session. Values are reported as mean (SD). HR: heart rate; RPE: rating of perceived exertion.

Correlation analyses revealed that participants who displayed greater % H-reflex depression after completing one – 15% DSW session also demonstrated greater PreTrain 2 MWT scores (Pearson r = – 0.58, p = 0.049), greater physical activity (r = – 0.61, p = 0.036), and walked at faster speeds on the treadmill (r = – 0.60, p = 0.038) (Fig. 3a– c). No significant correlations were found between % H-reflex depression induced by – 7.5% DSW or LW and clinical walking function measures, physical activity, or treadmill speed. Also, PreTrain values of Soleus Hmax/Mmax was not correlated with walking function, physical activity, or H-reflex changes observed after single session at LW, – 7.5% DSW or – 15% DSW.

Fig.3

Factors associated with Soleus H-reflex Depression after DSW. Experiment 1 showed that greater 2MWT (a) physical activity scores (b), and treadmill walking speed (c) were correlated with % H-reflex depression induced by one 20-minute session of – 15% DSW. Experiment 2 showed that greater baseline strength (d) and greater acute H-reflex depression after one session of – 15% DSW (e) correlated with greater % Soleus H-reflex depression after DSW training. ▵: Assistive device required for clinical walking measurements; •: No assistive device used during clinical walking measurements.

4.2 Experiment 2: Effects of repeated DSW training on Soleus H-reflexes and clinical function

After completing six DSW training sessions, participants demonstrated a significant increase in 2 MWT distance (26.0±38.9% change, p = 0.02) and a significant decrease in time to complete the TUG (– 11.4±14.3% change, p = 0.03) (Table 3). However, the 25FWT (p = 0.15) Soleus Hmax/Mmax ratio (p = 0.40), and MSWS-12 scores (p = 0.15) did not change significantly after DSW training.

Table 3
Clinical Walking Data before (PreTrain) and after (PostTrain) 6 sessions of DSW training. Values reported as Mean±SD.

Outcome Measure PreTrain PostTrain % Change p-value Effect size

2 MWT (ft) 346.4±112.7 412.4±117.4 26.0±38.9 0.02* 0.41

25 FWT (ft/sec) 3.27±0.94 3.55±0.92 14.2±31.6 0.15 0.22

TUG (sec) 12.7±3.8 11.0±2.9 – 11.4±14.3 0.03* 0.35

Hmax/Mmax (%) 56.6±27.3 58.8±26.9 6.43±19.3 0.4 0.06

Strength (N) 4.84±2.40 5.28±2.33 13.54±26.3 0.31 0.13

MSWS-12 (/60) 28.7±10.4 24.6±9.1 – 10.1±28.7 0.15 0.3

MAS 4.5±2.7 — — —

MFIS (/84) 38.9±14.0 — — —

Physical Activity (Vm) 28.85±15.7 — — — —

Steps (#) 3,304±2,743 — — — —

Outcome Measure	PreTrain	PostTrain	% Change	p-value	Effect size
2 MWT (ft)	346.4±112.7	412.4±117.4	26.0±38.9	0.02*	0.41
25 FWT (ft/sec)	3.27±0.94	3.55±0.92	14.2±31.6	0.15	0.22
TUG (sec)	12.7±3.8	11.0±2.9	– 11.4±14.3	0.03*	0.35
Hmax/Mmax (%)	56.6±27.3	58.8±26.9	6.43±19.3	0.4	0.06
Strength (N)	4.84±2.40	5.28±2.33	13.54±26.3	0.31	0.13
MSWS-12 (/60)	28.7±10.4	24.6±9.1	– 10.1±28.7	0.15	0.3
MAS	4.5±2.7	—	—	—
MFIS (/84)	38.9±14.0	—	—	—
Physical Activity (Vm)	28.85±15.7	—	—	—	—
Steps (#)	3,304±2,743	—	—	—	—

Correlation analysis revealed two significant correlations. PreTrain strength was associated with % change in Hmax/Mmax after DSW training (r = – 0.6, p = 0.041) (Fig. 3d). The % acute H-reflex depression observed after the – 15% DSW session was correlated with % change in Hmax/Mmax after six sessions of DSW training (r = 0.79, 0.002) (Fig. 3e).

5 Discussion

Our study findings support previous evidence suggesting the feasibility and potential efficacy of DSW as an exercise intervention for PwMS. Here, we demonstrated that DSW induces acute depression of Soleus H-reflexes in a slope-dependent manner (though some subjects display reduced Hmax/Mmax PreTrain-PostTrain, that trend is not consistent for all subjects). The – 15% slope allowed the muscle to undergo greater excursion compared to the other two slopes which contributed to the greater Soleus H-reflex depression observed. Furthermore, multiple sessions of DSW induced improvements in clinical walking function. However, contrary to our hypothesis, multiple sessions of DSW training did not induce significant modulation of spinal excitability.

Compared to LW treadmill training, walking at – 15% DSW may be a better rehabilitation exercise for PwMS because DSW induces depression of Soleus H-reflexes, which are often abnormally elevated in upper motor neuron lesions. Our findings from Experiment 1 demonstrate an acute depression of Soleus H-reflexes following a single 20-minute session of DSW PwMS. Experiment 1 results also showed that DSW at a greater slope (– 15%) induced larger magnitude of acute Soleus depression compared to the other two slope conditions. As expected from previous studies (Hunter et al., 2010), no participant complained of soreness or excessive fatigue during training, supporting the feasibility of DSW as an intervention. HR showed an overall significant difference across the 3 walking conditions, and HR was statistically greater for the -15% DSW session when compared to the – 7.5% DSW session. In addition, greater RPE was observed during the – 15% DSW compared to both LW and – 7.5% DSW. During – 15% DSW, the average HR was 105.9 and RPE was 11.7, which indicated “somewhat hard” exercise intensity (Borg, 1978). We do not think this phenomenon is occurring because of session order or cardiorespiratory intensity because none of the subjects used DSW as a form of rehabilitation therapy prior to enrolling in this study and the – 15% DSW session was their first time walking at that decline. Thus, for comparable walking durations, – 15% DSW may provide the advantage of greater exercise intensity compared to LW and – 7.5% DSW. Greater exercise intensity is advantageous for activity-based interventions (Davies et al., 2016; Leech, Kinnaird, Holleran, Kahn, & Hornby, 2016), and may contribute to better outcomes (Carda, Invernizzi, Baricich, Cognolato, & Cisari, 2013; Samaei et al., 2016).

Experiment 1 correlation analysis revealed that individuals who showed greater acute H-reflex depression after 1 session of DSW 15% had greater physical activity, walked longer distances during the PreTrain 2MWT, and walked at faster treadmill speeds. Experiment 2 revealed that participants with a greater PreTrain Strength demonstrated greater % depression of H-reflexes after DSW training. Also, participants with greater acute Soleus H-reflex depression following one – 15% DSW session displayed greater H-reflex depression after multiple sessions of DSW training. These findings also suggest that seeking DSW rehabilitation therapy as early as possible (before the deterioration of walking function) may assist in regaining walking function or may prevent further disabilities. These findings suggest that lower limb strength and magnitude of acute H-reflex depression after a single session of – 15% DSW walking session may serve as predictors of an individual’s ability to benefit from long-term DSW training interventions.

Our study demonstrates that clinical walking function (2MWT and TUG) improved after six sessions of DSW training; though 25FTW improved after DSW training, the PostTrain values were not statistically different from PreTrain (Table 3). Previous studies have shown that different types of treadmill training interventions (body-weight supported, fast LW) induce improvements in clinical walking function in PwMS (Gervasoni et al., 2014; Pilutti et al., 2011; van den Berg et al., 2006). However, previous treadmill training studies induced improvements in walking function after much greater dosage ranging from 12 to 36 training sessions over 4 to 12 weeks (Gervasoni et al., 2014; Pilutti et al., 2011; van den Berg et al., 2006). Though we have shown improvements in clinical walking function only after six DSW training sessions suggesting that DSW may be as or more effective compared to other treadmill training interventions, direct comparisons between interventions are required for future studies. Improvements in clinical walking function observed after DSW training occurred without concurrent increases in lower limb strength. This was not surprising given that six sessions of treadmill training, even with DSW, may not be sufficient to cause measurable changes in muscle strength. Based on our findings, future studies may evaluate whether PwMS who have lower limb muscle weakness benefit from completing a strengthening program prior to initiating DSW training program. Although not statistically significant, participants reported less impact of their MS on walking after the training, as shown by the reduction in MSWS-12 scores (Table 3).

A novel finding from our study is that DSW can modulate Soleus H-reflexes in PwMS, demonstrating the capacity for neuroplasticity in spinal segmental circuitry within a single session of treadmill walking exercise. We observed a relationship between 2MWT scores, physical activity scores, and treadmill training speed with Soleus H-reflex % depression after one session of – 15% DSW. These findings suggest that PwMS who engage in more physical activity, or who are able to walk further or more, may demonstrate greater capacity for spinal plasticity. On the other hand, perhaps individuals with greater capacity for spinal plasticity have more intact spinal circuitry and therefore a stronger neural substrate supporting locomotor control and activity. Moreover, note that most study participants took fewer than 3,000 steps per day (average steps per day 3,304±2,743). Potentially, the effectiveness of DSW for reducing spasticity and inducing spinal plasticity may be enhanced if preceded or combined with a prescription of stepping activity for subjects that have lower strength and lower physical activity scores.

The current study was designed for observational purposes and has limitations. For Experiment 1, the treadmill walking order was not randomized. The session order was always LW, -7.5% DSW, and – 15% DSW. This was done because eccentric-based exercises can induce delayed-onset-muscle soreness, and we attempted to avoid this by slowly building tolerance to the DSW exercise while also familiarizing participants with treadmill walking and keeping session order same for all participants. We did not test H-reflexes on muscles other than Soleus or on the less affected limb. For example, testing tibialis anterior H-reflexes would enable us to determine whether our findings are generalizable across other lower extremity muscles and completing H-reflex tests on the less affected limb may have allowed us to compare the degree of spasticity on the opposing limb. However, we chose not to measure H-reflexes on the less affected limb because the purpose of our study was aimed to observe improvements on the more affected limb. Our sample size was limited and relatively homogenous in terms of gender and race which could limit the generalizability of the current findings. We also included subjects with an EDSS of 0 and 1 with the intent to extrapolate findings for PwMS that do not have an enhanced form of the disease. Experiment 2 was designed as an exploratory study and is limited by the lack of a control intervention group. Our intent for Experiment 2 was to see if H-reflexes can change after a series of DSW walking sessions, and prior experimentation concluded that LW had negligible effect on changes in the H-reflex in healthy individuals after one session (Arnold et al., 2017; Sabatier et al., 2015). A few of the participants were not able to maintain the frequency of training sessions (3 sessions per week) required by the study resulting in the average time in between consecutive walking training sessions across participants to be 4.01±2.36 days.

There is a need to develop new gait rehabilitation interventions that promote neuroplasticity and improve walking function and quality of life in PwMS. Our study shows that DSW has promise as an exercise intervention for PwMS. Combined results from Experiments 1 and 2 illustrate several advantages of DSW as an exercise intervention for PwMS. Six sessions of DSW training induced improvements in clinical walking function. DSW at a greater decline (– 15%) induced a greater magnitude of acute Soleus H-reflex depression compared to the other 2 slope conditions. DSW also provided the advantage of achieving greater exercise intensity (HR and RPE) and was well-tolerated by all participants. Future investigations are needed to compare the effects of LW and DSW treadmill training protocols on clinical walking function and spinal excitability in a larger sample of PwMS. Nevertheless, our results suggest that DSW can transiently modulate spinal excitability and is a feasible exercise intervention for improving clinical walking function in PwMS is warranted.

Conflict of interest

The authors declare no conflicts of interest.

Footnotes

Acknowledgments

We would like to thank all the study participants who contributed their time for the completion of this study, as well as Marina Moldavskiy for her expertise and assistance with participant recruitment. Study support provided by NIH R03HD083 and National Multiple Sclerosis Society Pilot Grant PP2321. MRB was supported by NIH awards K12HD055931 and R03HD083727. TMK was supported by National Institute of Child Health and Human Development grant K01 HD079584 and R03HD083727.

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