Clinical trial NCT06127602: The REACTplusNMES Trial: a Double-blinded RCT
Official title: NeuroMuscular Electrical Stimulation to Facilitate Perturbation-based REACtive Balance Training for Fall Risk Reduction Post-stroke: the REACTplusNMES Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Stroke, Ischemic
Stroke Hemorrhagic
Stroke, Cerebrovascular
Keywords: Reactive balance
Falls
Perturbation training
NMES
FES
Stroke
Fall prevention
Neuroplastic
Neuromuscular
Lead sponsor: University of Illinois at Chicago
Sponsor class: OTHER
First posted: 2023-11-13
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Double-blinded Randomized Controlled Trial
Primary purpose: TREATMENT

Brief summary: The aim of this study is to compare the effectiveness of 6-weeks of reactive balance training (REACT) with and without neuromuscular electrical stimulation (NMES) to paretic lower limb muscles on biomechanical, clinical, neuromuscular and neuroplastic outcomes of reactive balance control. This project is a Phase-I study and incorporates a double-blinded, randomized controlled trial design.

Methods: Forty-six individuals with chronic stroke will be recruited and screened for determining their eligibility for the study. Once enrolled, they will be randomized into either of the two groups: intervention group (23 participants) and control group (23 participants). Both groups will undergo series of pre-training assessments which includes a postural disturbance in the form of a slip- or trip-like perturbations and walking tests in laboratory environment. After the pre-training assessment, individuals will undergo 6-weeks of training (2 hour per session, 2 sessions per week). The intervention group will receive NMES with the REACT training and the control group will receive ShamNMES. NMES will be applied to the different muscle groups of the paretic lower limb using an advanced software which is able to synchronize muscle activation with the time of perturbation onset and according to the phases of gait. After training, both groups will again be tested on all the assessments performed pre training.

This study will help us understand the immediate therapeutic and mechanistic effects of REACT+NMES and inform stroke rehabilitation research and clinical practice. Our study will provide foundational evidence for future use of NMES to implement clinically applicable neuromodulation adjuvants to reactive balance training, which could be leveraged for designing more effective future interventions for fall-risk reduction.

Detailed description: 1.0 Background/Scientific Rationale Interventions such as conventional balance and exercise training constitute a major part of stroke rehabilitation and improve volitional balance control and gait in people with chronic hemiparetic stroke (PwCHS). However, they seldom target reactive balance (compensatory postural responses such as stepping) that forms the first line of defense while recovering from a balance loss. Reactive balance in PwCHS is affected by deficits in perturbation-evoked neuromuscular and biomechanical responses especially during gait. Further, previous research has shown that stability and adaptions to repeated perturbations is more affected on paretic compared to non-paretic limb. Thus, paretic limb deficits are postulated to be key contributors of falls in ambulatory PwCHS. Perturbation-based reactive balance training (REACT) is widely recognized as an intervention that reduces falls by improving fall-resisting skills. In the past five years, there is a 3-fold increase in perturbation training research in PwCHS (mostly low impairment). Thus, limited evidence exists for PwCHS with severe motor impairment who might not show similar tolerance or learning abilities.

Complementing REACT with interventions known to facilitate paretic limb performance and motor learning (i.e., neuromuscular electrical stimulation, NMES) can improve therapeutic effects of REACT and hence its clinical translation for PwCHS and other populations that could benefit from fall-risk reduction. While it is established that REACT programs and NMES can induce motor learning in behavioral variables, there is limited evidence on neuroplastic changes and exact neural mechanisms underlying these behavioral changes (especially during REACT). Similar to the precision medicine approach, modifiable causative factors, contributors, and mediators to falls must be targeted when designing effective falls prevention interventions that reduce training times and/or facilitate the inclusion of persons with high impairment.

This project aims to describe whether a specific pattern of lower limb muscle stimulation could modify the recovery response after an unexpected perturbation in the form of a slip and/or trip in individuals with stroke. Also, this study aims to examine the effectiveness of 6-weeks of reactive balance training (REACT) with and without neuromuscular electrical stimulation (NMES) to paretic lower limb muscles on biomechanical, clinical, neuromuscular and neuroplastic outcomes of reactive balance control.

2.0 Objectives/Aims

The specific aims of this study are below:

Aim 1: To examine effects of synchronous REACT+NMES on reactive balance control and clinical outcomes among people with chronic stroke with moderate to severe motor impairment.

H1.1: REACT+NMES will induce greater improvement in biomechanical outcomes of reactive balance (reactive stability, limb support) resulting in fewer laboratory falls post-training than REACT+ShamNMES (at 6 weeks).

H1.2: The improvements in reactive balance control in REACT+NMES will translate to greater improvement in clinical outcomes of balance (mini-BEST test), gait (10m walk test) and falls-efficacy (Activities specific Balance Confidence scores) than REACT. H1.3: The improvements in reactive balance control will also translate to reduced falls during overground gait-slips after REACT+NMES.

Aim 2: To examine neuromuscular and neuroplastic effects of REACT+NMES in PwCHS with moderate to severe motor impairment.

H2.1. REACT+NMES will induce greater neuromuscular (muscle synergy #s and activations) and neuroplastic (perturbation evoked potentials- PEPs) changes post-training than REACT (at 6 weeks).

H2.2: Baseline PEP amplitude and training-induced neuroplastic changes in PEP's will correlate with the training-induced improvements in biomechanical and neuromuscular responses.

3.0 Research Design This study trial employs a two-arm, double-blinded, randomized controlled trial (RCT) design This study will examine efficacy and feasibility of REACT-NMES intervention compared to REACT+ShamNMES among PwCHS with moderate to severe motor impairment (Aim 1 and 2) A sample size of 46 chronic stroke survivors will be enrolled, undergo initial screening and pre-training assessment, and then randomized into two groups (intervention and control). Next, both groups will undergo 6-weeks of in-lab reactive balance training (2x/week, total 12 sessions). After training, participants in both groups will undergo a post-training assessment, which will include all the tests performed in the pre-training assessment.

Study overview: All participants will undergo the following procedures.

* Session 1 (Week 1): Initial screening (2 hours)
* Session 2 (Week 2): Pre-test (total 4 hours)
* Session 3-15 (Week 3-8): Training sessions (2 hours/session, 2 times/week for 6 weeks) (total: 24 hours)
* Session 16 (Week 9): Post-test (total 4 hours)

Eligibility criteria: Inclusion Criteria:

* Age group: 18-90 years.
* Presence of hemiparesis.
* Onset of stroke (\> 6 months).
* Ability to walk at least for 2 minutes on the treadmill with or without ankle foot orthosis.
* Can understand and communicate in English.
* Cognitively and behaviorally capable of complying with the regimen (Mini-Mental State Examination \> 25/30).
* No history or recent use (i.e., past 6 weeks) of any Neuromuscular electrical stimulation device to leg muscles during walking (e.g., Bioness, Walkaide).

Exclusion Criteria:

* Subjects will not proceed with the test if any of the following occurs at baseline measurement: 1) HR \> 85% of age-predicted maximal heart rate (HRmax) (HRmax = 220 - age), 2) systolic blood pressure (SBP) \> 165 mmHg and/or diastolic blood pressure (DBP) \> 110 mmHg during rest, or 3) oxygen saturation (measured by pulse oximeter) \< 95% during rest.
* Body weight of more than 250 lbs.
* Spasticity (Ashworth scale \> 2).
* Loss of protective sensations on the paretic leg (indicated by inability to perceive the 5.07/10 g on Semmes-Weinstein Monofilament) or inability to feel the NMES.
* Severe osteoporosis (indicated by T score \< -2)
* Cognitive impairment (indicated by Mini-Mental State Exam score\<25)
* Global Aphasia (indicated by \<71% on the Mississippi Aphasia Screening Test).
* Subjects with Chedoke McMaster Leg Assessment Scale score (\> 4).

Primary outcomes:
measure: Change in Falls
timeFrame: Pre-training (during week 2 i.e., Session 2), Post-training (during week 9 i.e., Session 16)
measure: Change in Reactive Stability
timeFrame: Pre-training (during week 2 i.e., Session 2), Post-training (during week 9 i.e., Session 16)
measure: Change in Proactive Stability
timeFrame: Pre-training (during week 2 i.e., Session 2), Post-training (during week 9 i.e., Session 16)
measure: Change in Vertical Limb support
timeFrame: Pre-training (during week 2 i.e., Session 2), Post-training (during week 9 i.e., Session 16)
measure: Change in Muscle synergies
timeFrame: Pre-training (during week 2 i.e., Session 2), Post-training (during week 9 i.e., Session 16)
measure: Change in Perturbation-evoked potentials
timeFrame: Pre-training (during week 2 i.e., Session 2), Post-training (during week 9 i.e., Session 16)
measure: Change in time-frequency power
timeFrame: Pre-training (during week 2 i.e., Session 2), Post-training (during week 9 i.e., Session 16)
Secondary outcomes:
measure: Change in Margin of Stability
timeFrame: Pre-training (during week 2 i.e., Session 2), Post-training (during week 9 i.e., Session 16)
measure: Change in Step length
timeFrame: Pre-training (during week 2 i.e., Session 2), Post-training (during week 9 i.e., Session 16)
measure: Change in Step initiation time
timeFrame: Pre-training (during week 2 i.e., Session 2), Post-training (during week 9 i.e., Session 16)
Other outcomes:
Locations:
city: Chicago
country: United States
facility: University of Illinois at Chicago
state: Illinois
Study officials:
affiliation: University of Illinois at Chicago
name: Tanvi Bhatt
role: PRINCIPAL_INVESTIGATOR
References:
citation: Varas-Diaz G, Bhatt T. Application of neuromuscular electrical stimulation on the support limb during reactive balance control in persons with stroke: a pilot study. Exp Brain Res. 2021 Dec;239(12):3635-3647. doi: 10.1007/s00221-021-06209-2. Epub 2021 Oct 5.
citation: Pereira S, Mehta S, McIntyre A, Lobo L, Teasell RW. Functional electrical stimulation for improving gait in persons with chronic stroke. Top Stroke Rehabil. 2012 Nov-Dec;19(6):491-8. doi: 10.1310/tsr1906-491.
citation: Dusane S, Bhatt T. Effect of Multisession Progressive Gait-Slip Training on Fall-Resisting Skills of People with Chronic Stroke: Examining Motor Adaptation in Reactive Stability. Brain Sci. 2021 Jul 7;11(7):894. doi: 10.3390/brainsci11070894.
citation: Kesar T, Chou LW, Binder-Macleod SA. Effects of stimulation frequency versus pulse duration modulation on muscle fatigue. J Electromyogr Kinesiol. 2008 Aug;18(4):662-71. doi: 10.1016/j.jelekin.2007.01.001. Epub 2007 Feb 21.
citation: Kottink AI, Oostendorp LJ, Buurke JH, Nene AV, Hermens HJ, IJzerman MJ. The orthotic effect of functional electrical stimulation on the improvement of walking in stroke patients with a dropped foot: a systematic review. Artif Organs. 2004 Jun;28(6):577-86. doi: 10.1111/j.1525-1594.2004.07310.x.