Study design
This was a pre-registered single-centre parallel group randomized controlled trial with pre-intervention (T0), post-intervention (T1), 5-week post-intervention retention (T2), and 1-year post-intervention follow-up (T3) tests. Participants were randomly assigned to either 5 weeks of CT or FP.
Participants
Participants were recruited from the outpatient population of rehabilitation center Reade (Amsterdam, the Netherlands). Inclusion criteria were first-ever ischemic stroke ≥ 3 months before study entrance, Functional Ambulation Categories (FAC) score ≥ 4, hemiparesis and walking and/or balance deficits established by a physician. Exclusion criteria were orthopedic and other neurological disorders that affect walking (e.g., Parkinson’s disease), other treatments that could influence the effects of the interventions (e.g., recent Botulin toxin treatment of the lower extremity), contra-indication to physical activity (e.g., heart failure, severe osteoporosis), moderate or severe cognitive impairments as indicated by a Mini-Mental State Examination score below 21, severe uncorrected visual deficits, or inability to understand and execute simple instructions [21]. All participants provided written informed consent before the start of the trial. The protocol for the study was approved by the Medical Ethical Reviewing Committee of the VU University Medical Centre (Amsterdam, the Netherlands; protocol number 2013/53 and the Central Committee on Research Involving Human Subjects, CCMO, protocol number NL 42461.029.13). Serious adverse events (SAES) and adverse events (AES) were monitored during this trial.
Sample size
The study of Yang et al. [6] allowed for a sample size calculation for post hoc analyses for significant group effects on walking speed with independent t tests. We aimed for a relative, clinically relevant, improvement in walking speed of 0.50 km/h (∆) with a common standard deviation (SD) of 0.47 km/h. The sample size calculation that was carried out resulted in a sample size of 14 participants in each group to achieve 80% power with a two-tailed α of 0.05 [21]. Considering a drop out of 10–25%, we decided to recruit 20 participants in each group, resulting in a total of 40 participants
Randomization and blinding
After having provided informed consent, participants were randomly assigned to one of the two interventions using an automated, custom-made minimization algorithm written in MATLAB. This minimization of group differences used time after stroke, age, and FAC score as stratifying factors, which collectively determined 80% of group allocation. Due to the nature of the intervention, the assessors, physical therapists, and participants were not blinded to group allocation.
Interventions: treadmill-based C-Mill therapy (CT) and overground FALLS program (FP)
CT is a treadmill-based training with a specific emphasis on practicing walking adaptability, using gait-dependent projector-generated context on the instrumented treadmill surface to elicit step adjustments. CT encompasses various exercises to practice avoidance of projected visual obstacles, foot positioning on a step-to-step basis to regular or irregular sequences of visual stepping targets (goal-directed stepping) with or without obstacles, gait acceleration, and deceleration by maintaining position within a projected walking area that moves along the treadmill, walking with tandem steps, and an interactive walking-adaptability game [8, 12]. C-Mill therapy is a patient-tailored type of training in that the therapist can adjust the difficulty of the different exercises by manipulating content parameters such as the obstacle size or available response time for obstacle negotiation. Therapists were encouraged to increase the level of difficulty as tolerated by the participant by either changing content parameters or increasing the treadmill belt speed.
FP is an overground walking therapy program aimed at reducing the number of falls in people after stroke by including walking-adaptability exercises. The program incorporates an obstacle course consisting of exercises to practice obstacle avoidance, foot positioning while walking over uneven terrain, tandem walking, and slalom walking. Therapists in this program are encouraged to increase the level of difficulty by adding cognitive and motor dual-tasks or to use visual constraints, as described in the predefined training protocol [9]. The program also incorporates exercises to simulate walking in a crowded environment and to practice falling techniques (one session per week).
Both interventions were matched in therapy session duration (90 min) and frequency (twice per week). CT group trained in pairs of two participants and the FP group trained in groups of 4–6 participants. Participants in both groups alternately trained and rested and received similar therapist attention (mean participant-to-therapist ratio, 2:1). Further details of the interventions can be found in the study protocol [21]. Participants successfully completed the intervention if they completed at least 7 out of the 10 training sessions.
Procedure and set-ups
At T0, T1, T2, and T3, participants performed three different walking tasks (see [21, 22] for more details): (1) the standard 10MWT [23], (2) a context-specific 10MWT with stationary physical context (10MWT context), and (3) a context-specific Interactive Walkway assessment with suddenly appearing projected obstacles in a gait-dependent manner (IWW obstacles) to assess walking adaptability under time pressure [24, 25]. All three tasks were performed both with and without the simultaneous performance of a cognitive task, resulting in six walking conditions (Table 1). Tasks were performed in a randomized order. The standard 10MWT (task 1) and 10MWT context (task 2) were both performed three times at a self-selected comfortable walking speed (Fig. 2A,B). The 10MWT context (task 2) comprised three physical obstacles, a tandem-walking path, and three stepping targets. Participants were instructed to step over the obstacles, step onto the targets, and step in-between the tandem-path lines.
The IWW obstacles (task 3) (with and without cognitive task) comprised two suddenly appearing visual obstacles in the form of a projected red rectangle, presented in both a gait-dependent (i.e., at a predicted foot-placement position) and a position-dependent (i.e., at an unpredictable but predefined position) manner. Ten runs were performed, including three dummy trials without obstacles (to retain unpredictability), at a self-selected comfortable walking speed (Fig. 2C). Participants were instructed to step over the suddenly appearing projected obstacle images.
The cognitive dual-task was a serial-3 subtraction task, which had to be performed by counting backwards out loud. The number to start with was varied to avoid task-familiarization. Participants practiced this subtraction task for 30 s while sitting. During all dual-task conditions, participants were instructed to simultaneously perform both tasks as effectively as possible at a self-selected walking speed. Additionally, a 60-s subtraction task was performed while sitting to determine the degree of cognitive-motor interference (i.e., using sitting as the single-task reference for cognitive-task performance, see below). This 60-s seated subtraction task was randomized with the six walking conditions.
Primary and secondary outcome measures
The primary outcome measure was walking speed (m/s) as determined with the standard 10MWT (averaged over the 3 repetitions as recommended [23]). Secondary outcome measures were measures for context-specific walking speed, walking-adaptability performance, cognitive dual-task performance, cognitive-motor interference, participants’ experience, and amount of walking practice. As specified in Table 1, context-specific walking speed (in m/s) was determined with 10MWT context (averaged over the 3 repetitions) and IWW obstacles trials (averaged over trials, involving the first 10 projected obstacles, excluding dummy trials). Walking-adaptability performance was assessed from the 10MWT context as the sum of subscores obtained for obstacle avoidance, tandem walking, and targeted stepping, averaged over the three repetitions (range 0–10, 1 point per obstacle, 1 point per target, and max 4 points for tandem walking) and from the IWW obstacles as the sum of the points received for the first 10 obstacles to obtain the same scoring range as for the 10MWT context assessment (range 0–10). Walking adaptability was scored manually by two observers through visual inspection of sagittal video recordings and averaged in case of discrepancies. Details regarding the walking-adaptability performance scores can be found in a previous publication (2018) [22] and in Table 1.
Cognitive dual-task performance (the number of correct subtractions per second; sub/s) and cognitive-motor interference (dual-task effects) scores, as determined with the 10MWT with and without context both with and without the cognitive task and IWW obstacles with and without cognitive task [22] (Fig. 2), were again averaged over the 3 repetitions and the trials involving the first 10 projected obstacles excluding dummy trials, respectively. Cognitive-motor interference during dual-task walking was quantified using the average of the respective dual-task effects of walking speed, the walking-adaptability performance score, and the cognitive-task performance (with sitting as single-task reference), that is, motor (walking speed, walking adaptability) and cognitive scores were combined to reflect overall task performance. Following [26], dual-task effects were defined as 100% × (dual-task performance − single-task performance)/single-task performance, with a negative cognitive-motor interference score indicating overall poorer dual-task than single-task performance.
Participants’ experience and attitude towards the interventions were assessed with a purpose-designed evaluation questionnaire consisting of 1–10 rating scales and multiple-choice questions assessing participants’ experience, attitude towards the interventions, improvements, and discomforts during and after training (see Additional file 1: Appendix 1).
The hypothesis of there being different amounts of walking practice per session between CT and FP was tested by comparing the total number of steps and the number of adaptive steps taken per session for two subgroups (CT n = 10 and FP n = 10). This process measure was obtained using the treadmill’s inbuilt step counter (CT) and by counting the number of steps (FP) using video recordings of a random selection of training sessions by two observers (averaged in case of discrepancies).
Statistical analysis
Participant characteristics and baseline performance were compared between the two intervention groups using independent t-tests for normally distributed interval variables, Mann-Whitney U tests for ordinal and non-normal interval variables and Fisher’s exact tests for nominal variables. We used a different statistical analysis (with correction for baseline values) compared to the one described in the study protocol [15], because of the large variation in the baseline (pre-intervention) outcome measures within the groups. We describe “between-groups” and “change-over-time” analyses separately.
Between-group analyses
For comparing the effects of the interventions on the outcome measures, we calculated per intervention group changes in outcome measures by subtracting baseline values (T0) from the values at each time point (T1, T2, and T3). These change scores of the outcome measures were analyzed using ANCOVA with correction for baseline values. We analyzed ordinal and non-normally distributed variables, notably the participants’ experience and attitude towards the interventions, using Mann-Whitney U tests. The amount of walking practice was compared between intervention groups using independent t-tests for the total number of steps and the number of adaptive steps taken per training session.
Change-over-time analyses
To analyze the change over time in the primary outcome measure walking speed and secondary outcome measures context-specific walking speed, walking-adaptability performance, cognitive dual-task performance, and cognitive-motor interference (for all participants, compared to baseline, averaged over groups), we performed paired samples t-tests or Wilcoxon signed rank tests for ordinal or non-normally distributed variables at each time point (T1, T2, and T3).
The level of significance was set at p < 0.05, while 0.05 < p < 0.075 was seen as a tendency towards significance. Effect sizes are presented as partial ƞ2 for ANCOVA or r for the other tests. This trial was not an intention-to-treat analysis because dropouts were excluded from the analysis and only complete case data were used.