Parkinson disease (PD) is a progressive neurodegenerative process characterized by tremor, rigidity, and postural instability.1,2 Subjects with PD may present disturbances of gait.3,4 Freezing of gait (FOG) affects 27%–75% of subjects with PD5 and is considered one of the most incapacitating symptoms in idiopathic PD.6 Freezing of gait is an episodic gait phenomenon characterized by marked reduction of feet forward progression, despite the intention to walk.6 This symptom becomes progressively worse as the disease progresses. Other detrimental consequences of FOG are falls, loss of independence, and reduced quality of life.6,7
Correct movement execution depends on the peripheral sensory information and on sensorimotor integration, and abnormalities in sensory processing are frequently reported in PD.8–11 The peripheral sensory deficit in PD may be explained by the loss of cutaneous receptors, encapsulated endings, or free nerve endings.11 Particularly, plantar sensitivity in subjects with PD is highly reduced and is associated with reduced control of compensatory stepping, impaired balance,9 and increased risk of falls.12 Different methods of plantar sensory stimulation have been reported for improving gait performance and balance, including different types of insoles, as ribbed,10 textured,13 and synchronized vibrations insoles.14,15
Automated mechanical peripheral stimulation (AMPS) is a new promising approach for the treatment of PD motor symptoms. Automated mechanical peripheral stimulation is delivered by a dedicated device (Gondola; Gondola Medical Technologies SA, Switzerland), which promotes mechanical pressure stimulation applied in two areas of each foot.16–19 The immediate effects16,17,19 of AMPS for PD rehabilitation have recently been investigated.18 Studies have reported significant improvements in PD clinical scales,16,18,19 spatiotemporal gait parameters,18 and execution of the Timed Up and Go test.17 Even though previous studies have reported improvements after AMPS, no study has specifically assessed the long-term effects of 8 weeks of AMPS sessions on gait and angular kinematics of subjects with PD and FOG using a randomized placebo-controlled clinical trial design.
Subjects with PD present reductions in range of motion (ROM) across lower limb joints, as a consequence of stride length change.3 In addition, the relationship among step length, gait hypokinesia, and FOG has been suggested.20 The measurement of specific outcomes related to gait is important for a better understanding of the effects of therapies in people with PD.21 Then, the aim of this study is to assess spatiotemporal gait parameters and lower limb angular kinematics of subjects with PD and FOG treated with real or placebo AMPS.
This is an interventional, double-blinded, placebo-controlled, randomized study. The trial was registered online at ClinicalTrials.gov (Number Identifier NCT02594540) and approved by the ethics committee of the Universidade Federal de Ciências da Saúde de Porto Alegre (Protocol 1.333.131). Written informed consent was obtained from all participants before the procedures started. This study conforms to all CONSORT guidelines and reports the required information accordingly (see Checklist, Supplemental Digital Content, https://links.lww.com/PHM/A547).
Sample size was calculated to detect a difference of 0.37 m/sec on mean velocity, with a deviation of 0.3 m/sec, two-sided 5% significance level, and power of 90%.18 Fifteen subjects were included, given an anticipated dropout rate of 10%.
Researcher R1 determined whether the subject was eligible for inclusion in the trial and researcher R2 carried out the gait analysis. Both examiners were unaware of group allocation. An independent researcher (R3) randomized the participants in block sizes of 5–10 (random sequence generator tool available in https://www.random.org). Another researcher (R4) checked the participant allocation and applied the treatment in both AMPS groups. The subjects with PD were unaware of the group to which they were allocated.
An independent researcher (R5) performed the clinical evaluation before the procedures started. Clinical evaluation included the following: Mini-Mental State Examination,22 Freezing of Gait Questionnaire,23 Motor Section of the Unified Parkinson Disease Rating Scale III24 (phase OFF-Levodopa), and Hoehn & Yahr scale25 (phase OFF-Levodopa).
The inclusion criteria for participants were the following: idiopathic PD diagnosis (according to the London Brain Bank Criteria26); age between 50 and 85 yrs; able to walk 25 feet unassisted or with minimal assistance; presenting regular FOG episodes (according to the Freezing of Gait Questionnaire); and minimum score of 20 in the Mini-Mental State Examination. The exclusion criteria were the following: having secondary musculoskeletal disorders in the lower limb such as chondral injuries; ligament and ankle sprains, which could impede gait evaluation by pain or motion disability; and presence of deep brain stimulation. Healthy subjects, paired by age and sex, were included as a reference group.
Individuals with PD were recruited by convenience sampling in Porto Alegre (advertised in hospitals, associations, and other entities), and healthy age-matched controls were recruited from the local community.
Subjects with PD were randomly allocated into the following two groups: (1) AMPS (that received the real AMPS) and (2) AMPS SHAM (that received the placebo AMPS stimulation). Healthy subjects were allocated in the (3) reference group and did not receive any type of treatment. Procedures were carried out using a GONDOLA device (Gondola; Gondola Medical Technologies SA, Switzerland). Subjects with PD underwent eight sessions of real or placebo AMPS, once every 3–4 days. The total experimental period lasted 4 weeks. Participants with PD diagnosis were treated and assessed regarding their clinical measures in the “OFF” pharma state, having withdrawn from dopaminergic medication overnight. We set the “OFF” pharma state to avoid any effect of (dopaminergic) medication on FOG.6 Other types of therapy were not restricted if they had started them at least 6 months before the study.
Automated mechanical peripheral stimulation was conducted by a medical device (Fig. 1A). The system consists of feet support (left and right) with electric motors that activate metallic stimulators equipped with two 2-mm-diameter round tips (Figs. 1B, C). The AMPS treatment consisted of pressure-based stimulation in four target areas (two in each foot, corresponding to the head of the big toe and to the base of the first metatarsal bone). Stimulation pressure ranged from 0.3–0.9 N/mm, two in each foot, one after the other. The stimulation pressure was set for each subject upon appearance of the withdrawal reflex in the tibialis anterior muscle, identified by detection of a threshold contraction. Once the pressure value had been set, the value was recorded to administer the AMPS treatment.
Placebo automated mechanical peripheral stimulation (AMPS SHAM) followed the same procedure as the therapy group. However, before starting the SHAM treatment, a 12-mm-diameter rigid plastic disk was placed on the head of each steel stick. These rigid plastic discs were coupled in the metallic stimulators throughout the SHAM treatment time. The use of these rigid plastic discs aimed to increase the area of stimulation and reduce the pressure to a subliminal level (Fig. 1D).
The same operator applied the treatment in both PD groups. During the interventions, subjects were lying in supine position. The overall treatment session lasted approximately 15 minutes, including preparation (approximately 10–13 minutes) and stimulation (approximately 2 minutes). At the end of the treatment, both units of the device were removed and the subject was instructed to stand up. The operator asked the subject to take two very long steps immediately after getting up. This strategy was used in all sessions for both AMPS and AMPS SHAM groups. Then, all participants performed three walk trials of 10-m distance, receiving the instruction: “take a first step a little bit longer than usual” (we gave the same instruction to all subjects during the pretreatment measurements). Both PD groups received the same verbal command to perform the gait training. No adverse event or undesirable effect was noticed during the study.
All procedures were carried out at the Movement Analysis and Neurological Rehabilitation Laboratory at Universidade Federal de Ciências da Saúde de Porto Alegre. Gait parameters were measured in subjects with PD at baseline (PRE), after the first session (POST 1st), after the fourth session (POST 4th), and after the eighth session (POST 8th). Their gait was evaluated approximately 20–30 minutes after the AMPS stimulation and was assessed by using of a three-dimensional motion analysis system (BTS SMART DX 400 Motion Capture System) composed of six-infrared cameras. Twenty-two retro-reflective spherical markers were placed on anatomic landmarks, as described in the protocol by Davis III et al.27
The subjects were asked to walk at a self-selected speed, barefoot, along an 8-meter pathway. We recorded at least six trials. The reference group performed one gait analysis only at the beginning of the experiment. The raw data were processed by SMART analyzer software, Version 1.10.458.0 (BTS Bioengineering, Italy). Then, the following gait spatiotemporal parameters were analyzed as the following primary outcomes: stride length (meter), step length (meter), and gait speed (meter per second).
The secondary outcomes were ROM of lower limb computed by the difference between the maximum and minimum values in degrees of the following: ankle plantar/dorsiflexion; knee flexion/extension; hip ad/abduction, flexion/extension, and internal/external rotation; and pelvic obliquity, tilt, and rotation.
The Shapiro-Wilk test and Levene statistics were used to test data normality and variance homogeneity, respectively. The one-way analysis of variance assessed the differences between PD groups and the reference group. The generalized linear models were used to compare the mean differences between PD groups (factors: groups - AMPS and AMPS SHAM, and time - PRE, POST 1st, POST 4th, and POST 8th). The Bonferroni post-hoc test was applied when appropriated. The delta variance [∆ = % outcome by the formula (POST 8th − PRE)/PRE] was also analyzed after the PD groups treatment cycle by using Mann-Whitney U test or independent t test for nonparametric or parametric data, respectively. Results were presented as mean and confidence intervals (lower bound–upper bound) or median and interquartile range (25th–75th percentiles). The SPSS Statistics 20.0 (Chicago, IL) was used, and data were considered statistically significant when α < 0.05.
The recruitment period was from December 2015 to March 2016. Interventions and evaluations were carried out from April 2016 to September 2016. The flow diagram is shown in Figure 2. Thirty subjects with PD and 14 healthy age-matched subjects were screened to participate. The sample characteristics are shown in Table 1.
Subjects with PD showed differences in all spatiotemporal parameters and joint angles (ROM) at PRE condition when compared to the reference group (P < 0.05) (Table 2). Subjects with PD were similar at baseline (P > 0.05), except for hip internal-external rotation (P = 0.031).
Group-time interaction analysis showed that only participants of the AMPS group improved hip internal-external rotation in POST 8th when compared with PRE condition (P = 0.000). The improvement in hip rotation was also observed in POST 1st (P = 0.000) and POST 4th (P = 0.002) when compared with POST 8th only for the AMPS group. No other joints presented significant differences (P > 0.05). Likewise, the AMPS group increased stride length, step length, and gait speed when PRE was compared with POST 1st (P = 0.010, P = 0.008, P < 0.001, respectively), POST 4th (P = 0.002, P = 0.002, P < 0.001, respectively), and POST 8th (P = 0.000 for all variables). In addition, all spatiotemporal parameters improved in POST 1st (P = 0.018, P = 0.025, P = 0.000 for stride length, step length, and gait speed, respectively) and POST 4th (P = 0.000 for all variables) when compared with POST 8th in the AMPS group. We did not observe any difference for AMPS SHAM group over time in joints ROM and spatiotemporal parameters (P > 0.05). Regarding groups, we found significant difference between AMPS and AMPS SHAM in POST 1st condition only in hip internal-external rotation variable (P = 0.018). We did not find difference between AMPS and AMPS SHAM groups in other joints and spatiotemporal parameters (P > 0.05).
Nevertheless, the mean-change analysis [∆ = (POST 8-PRE)/PRE] revealed that AMPS underwent a higher improvement compared with AMPS SHAM group in variables as stride length (U = 52.000, P = 0.011), step length (U = 51.000, P = 0.010), gait speed (U = 47.000, P = 0.006), and hip internal-external rotation ROM (U = 169.000, P = 0.023). Table 2 summarizes these results.
In this study, we verified the effects of AMPS therapy in spatiotemporal and kinematic gait parameters of subjects with PD and FOG. Although we did not observe differences between groups in spatiotemporal parameters and joint angles ROM after treatment, AMPS seemed to promote faster walk in subjects with PD, with longer steps and strides. In addition, AMPS increased hip internal-external rotation. This is the first randomized sham-controlled clinical trial set to evaluate long-term effects of AMPS in subjects with PD and FOG. Moreover, this is the first time that the effects of AMPS on gait kinematic variables in the three movement planes have been reported. These findings are clinically relevant because they provide a better understanding of how AMPS impacts gait. In addition, they may help clinicians decide whether AMPS should be used in subjects with PD and FOG.
Automated mechanical peripheral stimulation treatment improved spatiotemporal gait parameters, thereby supporting the results of earlier publications.16,18 Kleiner et al.16 showed the immediate positive effects of AMPS on stride length and gait speed of subjects with PD. Stocchi et al.18 demonstrated that AMPS improved gait speed, step, and stride length when subjects were submitted to six sessions of treatment. In addition, the spatiotemporal improvements were sustained 10 days after the last stimulation.18
The parkinsonian gait is generally characterized by reductions in stride and step length as well as by restrictions on ROM across all lower limb joints and pelvis, in all movement planes.3,28 Freezing of gait is an incapacitating gait symptom that is strongly associated with falls.6 Subjects with PD and FOG present reduced step length and a successive step-to-step amplitude reduction (sequence effect). Moreover, the step-to-step variability is an important factor inducing FOG in subjects with PD.20 Our findings demonstrated that AMPS was able to improve stride and step length, with a significant increase of hip movements in the transverse plane. Even though the improvement of hip internal-external rotation may be related to the values presented at baseline, participants allocated to the AMPS group increased their step and stride length, and this represents a positive effect on FOG occurrence. The improvement of these key kinematic gait variables compensates the most common movement disorder in PD: hypokinesia. Moreover, the improvement in gait speed reduces bradykinesia (the slow gait pattern) only in the AMPS group, but not in the AMPS SHAM group.
The relation between motor impairment and sensory deficit, particularly in touch-pressure plantar sensory systems, is well-known in subjects with PD.9,29 The gait improvement, as a result from AMPS stimulation, could be explained based on the following: (a) the remarkable sensory deficit corresponding to the first metatarsal site in PD9 and (b) the peak pressure under the hallux in the push-off phase of gait.29 Both topics used in AMPS treatment are the sites of greatest vibratory and touch-pressure sensitivity thresholds in subjects with PD.9,30 Thus, AMPS stimulation in these two specific areas on each of the feet could lead to betterments in plantar sensitivity and impact positively on gait. Quattrocchi et al.19 reported that a single session of AMPS was able to induce acute modifications in brain connectivity. The authors showed that AMPS may enhance resting state functional connectivity in brain regions related to visuospatial integration and processing, sensory-motor integration, and anticipation of body position during movements. Thereby, AMPS could enable brain compensatory pathways and attenuate symptoms such as akinesia.19
Based on our results, it is possible to conclude that AMPS positively affects gait kinematics of subjects with PD and FOG. This study has some limitations that could restrict the generalization of our findings. No follow-up evaluations were carried out after the end of the treatment, including the Freezing of Gait Questionnaire. In addition, based on this study, there is no information on how long the effects of AMPS last after the treatment. Although we have only investigated the effects of AMPS immediately after stimulation, AMPS could be indicated for subjects with PD as a complementary treatment.
In summary, this study addressed spatiotemporal gait parameters and lower limbs kinematics in individuals with PD and FOG treated with real or placebo AMPS. The current results demonstrate that AMPS improves gait issues in this population. Noninvasive peripheral stimulation, such that provided by AMPS, may play an important role in PD rehabilitation strategies. Future studies should investigate whether gait improvement is related to a long-term change in brain sensorimotor integration as well as modifications on plantar sensitivity.
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