CLINICAL TRIAL

published: 29 August 2019

doi: 10.3389/fneur.2019.00902

Progressive Modular Rebalancing

System and Visual Cueing for Gait
Rehabilitation in Parkinson’s
Disease: A Pilot, Randomized,
Controlled Trial With Crossover
Mariano Serrao 1,2*, Francesco Pierelli 1,3 , Elisabetta Sinibaldi 1 , Giorgia Chini 2 ,
Stefano Filippo Castiglia 1 , Marina Priori 1,2 , Dario Gimma 1 , Giovanni Sellitto 1 ,
Alberto Ranavolo 4 , Carmela Conte 5 , Michelangelo Bartolo 6 and Giuseppe Monari 1
1
Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy, 2 Movement
Analysis Laboratory, Policlinico Italia, Rome, Italy, 3 IRCCS Neuromed, Pozzilli, Italy, 4 Department of Occupational and
Environmental Medicine, Epidemiology and Hygiene, INAIL, Rome, Italy, 5 IRCCS Don Carlo Gnocchi Foundation, Milan, Italy,
6
Neurorehabilitation Unit, Department of Rehabilitation, HABILITA Zingonia, Lombardy, Italy

Edited by:
Introduction: The progressive modular rebalancing (PMR) system is a comprehensive
Nicola Smania, rehabilitation approach derived from proprioceptive neuromuscular facilitation principles.
University of Verona, Italy
PMR training encourages focus on trunk and proximal muscle function through direct
Reviewed by:
perception, strength, and stretching exercises and emphasizes bi-articular muscle
Madeleine E. Hackney,
Emory University School of Medicine, function in the improvement of gait performance. Sensory cueing, such as visual cues
United States (VC), is one of the more established techniques for gait rehabilitation in PD. In this study,
Federica Piras,
Fondazione Santa Lucia (IRCCS), Italy
we propose PMR combined with VC for improving gait performance, balance, and trunk
*Correspondence:
control during gait in patients with PD. Our assumption herein was that the effect of VC
Mariano Serrao may add to improved motor performance induced by the PMR treatment. The primary
[email protected]
aim of this study was to evaluate whether the PMR system plus VC was a more effective
Specialty section:
treatment option than standard physiotherapy in improving gait function in patients with
This article was submitted to PD. The secondary aim of the study was to evaluate the effect of this treatment on motor
Neurorehabilitation,
function severity.
a section of the journal
Frontiers in Neurology Design: Two-center, randomized, controlled, observer-blind, crossover study with a
Received: 01 April 2019 4-month washout period.
Accepted: 05 August 2019
Published: 29 August 2019 Participants: Forty individuals with idiopathic PD in Hoehn and Yahr stages 1–4.
Citation: Intervention: Eight-week rehabilitation programs consisting of PMR plus VC (treatment
Serrao M, Pierelli F, Sinibaldi E,
Chini G, Castiglia SF, Priori M,
A) and conventional physiotherapy (treatment B).
Gimma D, Sellitto G, Ranavolo A, Primary outcome measures: Spatiotemporal gait parameters, joint kinematics, and
Conte C, Bartolo M and Monari G
(2019) Progressive Modular trunk kinematics.
Rebalancing System and Visual
Secondary outcome measures: UPDRS-III scale scores.
Cueing for Gait Rehabilitation in
Parkinson’s Disease: A Pilot, Results: The rehabilitation program was well-tolerated by individuals with PD and most
Randomized, Controlled Trial With
Crossover. Front. Neurol. 10:902.
participants showed improvements in gait variables and UPDRS-III scores with both
doi: 10.3389/fneur.2019.00902 treatments. However, patients who received PMR with VC showed better results in

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Serrao et al. PMR Gait Rehabilitation in PD

gait function with regard to gait performance (increased step length, gait speed, and
joint kinematics), gait balance (increased step width and double support duration), and
trunk control (increased trunk motion) than those receiving conventional physiotherapy.
While crossover results revealed some differences in primary outcomes, only 37.5%
of patients crossed over between the groups. As a result, our findings should be
interpreted cautiously.
Conclusions: The PMR plus VC program could be used to improve gait function and
severity motor of motor deficit in individuals with PD.
Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03346265.

Keywords: neurorehabilitation, Parkinson’s disease, gait analysis, progressive modular rebalancing system,
sensory cues

INTRODUCTION Furthermore, some cognitive rehabilitative techniques including

action observation therapy and motor imagery have recently been
Gait disturbances are considered one of the most disabling proposed to facilitate gait and motor performance in patients
aspects of Parkinson’s disease (PD) (1, 2) and can strongly with PD (34).
impact a patient’s independence and quality of life (3). The These previous findings then suggest that a variety of
mechanisms underlying gait deficits are multi-factorial and often rehabilitative procedures can be effective and the optimal type
caused by a multisystem lesion involving both dopaminergic of physiotherapy activity has not yet been determined (32, 33).
and non-dopaminergic mechanisms (4–9), related not only to As such, a single multifaceted, structured, and comprehensive
bradykinesia, rigidity, abnormal trunk control, and postural rehabilitative approach, acting on the different aspects of motor
instability (1, 2, 10–12) but also to cognition (13–16). control (e.g., balance, muscle strength, flexibility, trunk and
Perhaps even more significant than clinical and functional joint mobility, and muscle endurance) is needed for treating
impacts of gait impairment, this pathological consequence of gait disturbances and motor impairment in patients with PD.
PD also determines social and economic costs due to falls The European Physiotherapy Guidelines for PD has proposed
and trauma. The significance of treating gait disturbances is specific areas of intervention to address this need. These
reinforced by prior work showing that gait outcomes are related guidelines propose a series of exercises that can be combined
to longevity (17), cognitive decline (18), and adverse events into one rehabilitation program; however, they are currently
(19). Therefore, rehabilitative interventions for the treatment or not functionally connected to each other in a single structured
attenuation of gait impairments should be one of the primary foci rehabilitation procedure.
of inpatients with PD. The progressive modular rebalancing (PMR) system is an
One of the longest studied and most documented techniques exercise-based therapy based on proprioceptive neuromuscular
for gait rehabilitation in PD is the use of sensory cueing (20, 21). facilitation (PNF) principles (35–37). PNF was further developed
Several studies have shown improvement in electromyographic into an alternate approach (38) mainly focusing on trunk
and spatiotemporal parameters of gait in PD patients undergoing mobility, strength, endurance, and functional connection with
gait training with auditory, visual, and tactile cues (22–27). proximal muscles. It may be particularly appropriate for
While the mechanisms responsible for the improvements patients with PD in whom the abnormal activation of trunk
in gait due to sensory cueing are not fully understood, it rotator and extensor muscles, trunk motion, ability to roll
is believed that individuals with PD have lower activity in over on the bed, and axial rigidity are all associated with
certain brain areas that are responsible for the internal pathways a high risk of falls (39, 40). PMR proposes a trunk-specific
needed to implement automatic and sequential movements exercise program that is preliminary and preparatory for
(28). For instance, during sensory cueing for walking with gait exercises. The link between trunk and gait exercises
visual cues (VC), patients with PD likely focus their attention is proposed as proximal movement stimulation, which is
on the discrete goal of each foot, hit a VC placed on the performed through rhythmic stimulation of scapular and pelvic
floor, and then use exteroceptive information (i.e., position girdle movements. PMR gait exercises are performed with a
of the next foot placement location) to plan each step focus on interlimb coordination and reactive postural control
individually at a cortical level (25). In addition to gait- and are preceded by exercises aimed at strengthening the
oriented training (21, 29), several different approaches using bi-articular musculature involved in walking through PNF
exercise therapy have been proposed aiming at improving patterns (41).
mobility, muscular strength, resistance, balance, and aerobic In this regard, the European Physiotherapy Guidelines for
conditioning, and endurance and axial alignment (30–33). PD reported only one trial on trunk muscle strength training
This heterogeneous mix of rehabilitation approaches also for gait improvement and recommended the identification
revealed indirect improvements in gait function (32, 33). and correction of trunk muscle weakness in the design of

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Serrao et al. PMR Gait Rehabilitation in PD

rehabilitation programs, as traditional abdominal crunches alone 4-month washout period (patients did not have to perform
were not effective (42). any rehabilitative treatment), after which patients who received
In the present study, a rehabilitation program was proposed treatment A switched to treatment B and vice versa. A computer-
for patients with PD based on the combination of PMR and VC based randomization schedule was used. All patients were
aimed at improving gait performance by improving balance and assessed at the same center. Randomization was stratified
trunk control during gait movement. Our hypothesis was that the according to a block of 20 numbers, so that each block comprised
effect of VCs may interact with improved motor performance 10 patients randomly assigned to treatment A and 10 patients
induced by the PMR treatment. Specifically, it is hypothesized assigned to treatment B. Since all the subjects were evaluated at
that patients may improve their bi-articular hip muscle function the same center, allocation was performed by an investigator not
and trunk and balance control through the PMR system and thus involved in subject recruitment or assessment at the end of the
better exploiting the information (spatial and temporal) delivered baseline assessment.
by the VC, resulting in improvements in specific gait parameters, Both clinical (neurological visit and scale administration)
joint kinematics, and trunk motion. and instrumental (gait analysis) assessments were performed at
The primary aim of this pilot trial was to establish whether baseline, before rehabilitative treatment (T0), 4 weeks after the
an 8-week PMR exercise program focused on improving gait beginning of the rehabilitative treatments (T1), and at 8 weeks (at
function in addition to VC training in people with PD was the end of rehabilitation program) (T2) (Figure 1B). Medication
more effective than a same-duration program of conventional use remained constant throughout the study period, and all the
physiotherapy including VC as recommended by European treatments were performed at the same time of the day for each
Physiotherapy Guidelines for PD. patient during the ON phase.
The secondary aim was to evaluate the effect of these Participants were asked to maintain their daily pre-enrollment
interventions on the disease severity. activity level.
Assessors, for both clinical and instrumental evaluations, were
MATERIALS AND METHODS blinded to the allocation of treatment.

Participants Intervention
Sixty individuals with idiopathic PD admitted for outpatient The exercise program was conducted three times per week for
rehabilitation were assessed for eligibility at two rehabilitation 60 min over an 8-week period. Physical therapists with expertise
centers between May 2015 and December 2017. Forty subjects in PD administered the exercise programs (ES, SFC, MP, DG,
were ultimately included in the study. The inclusion criteria and GS).
were as follows: (i) diagnosis of idiopathic PD according to UK
bank criteria (43), (ii) Hoehn and Yahr stages 1–4 (44), and (iii) Treatment A
UPDRS-III gait sub-score of 1 or higher (45). All patients were in Treatment A was performed 3 days/week. Each session was
a stable drug program and acclimated to their current medication 60 min in duration and consisted of a combined exercise program
use for at least 2 weeks. Exclusion criteria were as follows: (i) of 40 min of PMR (47) and 20 min of gait training performed
cognitive deficits (defined as scores of <26 on the Mini-Mental with VC.
State Examination), (ii) moderate or severe depression (defined Each session was divided into muscular stretching exercises,
as scores of >17 on the Beck Depression Inventory), and (iii) aiming at increasing the step length and the mobility of the trunk,
orthopedic and/or other gait-influencing diseases such as other and tailored progressive exercise therapy. Stretching exercises
neurological diseases, arthrosis, or total hip joint replacement. were performed based on the contract–hold–relax principles, and
A mandatory requirement for inclusion in the study was trunk muscles were lengthened. Perception exercises reciprocally
also the ability to walk independently for at least 8 m along the activating anterior elevation and posterior depression of both the
laboratory pathway without showing freezing of gait. shoulder and pelvis complex were performed. Trunk strength
The study was approved by the ethics committee of Hospital exercises were performed based on postural steps, moving from
Policlinico Umberto I of Rome/Sapienza University of Rome the supine to the upright position, and specific extensor muscle
(Approval Number: 2346454) and patients provided written recruitment exercises. Recruitment exercises aiming to reach and
informed consent. All procedures conformed to the Helsinki maintain specific symmetrical positions (like supine bridging or
Declaration. The study was registered with ClinicalTrials.gov the reverse tabletop pose) were performed by patients presenting
(clinical trial identifier: NCT03346265). The detailed participant camptocormia, and asymmetrical positions (like side sitting or
flow is shown in Figure 1A. side bridging) were performed by patients presenting with the
Pisa syndrome. Physical therapists guided the patients during the
Study Design walking training by stimulating upper limb movements at the
This was a pilot, two-center, randomized, blind observer, same time. Walk training was also performed for the knees to
controlled trial with crossover, following the recommendations better recondition reciprocal hip movements.
of the Consolidated Standards of Reporting Trials (46). A further detailed description of the PMR technique with
Subjects participated in a baseline assessment session (T0, motor patterns is reported in Table 1.
before rehabilitative treatment) and were randomly allocated For the VC training, white parallel transverse lines (white,
to an 8-week rehabilitation program (A or B) followed by a 800 × 19 mm) were placed on the floor perpendicular to a dark

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FIGURE 1 | Outline of the study design. (A) The flow diagram of the patients enrolled for the study. (B) When both the clinical and the instrumental assessments were
performed: at baseline, before rehabilitative treatment (T0), at 4 weeks after the beginning of the rehabilitative treatments (T1), and at 8 weeks (at the end of
rehabilitation program) (T2).

walkway path at intervals equal to 40% of the patient’s height. of physical performance, and improvement in the ability to
Lines were moved further apart by 0.05 m per stride every 3 or perform transfer, balance, gait, and manual activities, reduce
4 days and did not bend through the chicane. Participants were pain, and delay the onset of physical limitations.
asked to walk across the lines matching their step length to the Exercises included the following: standing up from and sitting
interval between the stripes, turn, and return to the start line. down on the floor; standing and walking on foam with and
without perturbation (pushes and pulls) to the trunk; sitting
Treatment B down onto and rising from a chair (while dual tasking); getting
Conventional physiotherapy was administered according to into and out of bed; rolling over in bed; walking and taking
the European Physiotherapy guidelines for PD (http://www. large steps with large amplitude arm swings; walking around
appde.eu/european-physiotherapy-guidelines.asp) and focused and over obstacles; walking with sudden stops and changes in
on the following areas based on the stage of the disease: self- walking direction (including walking backwards); walking and
management support, prevention of inactivity and fear of falls, maintaining balance while conducting dual tasks (such as talking,
maintaining or improving global motor activities, improvement carrying an object, or turning head left to right to wall-mounted

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TABLE 1 | A detailed description of the progressive modular rebalancing technique with motor patterns.

STRETCHING EXERCISES

Gluteus medius stretching: Gluteus maximus and adductor magnus stretching: The therapist flexes,
The therapist flexes, adduces, and externally rotates the limb to be stretched. abducts, and internally rotates the hip to be stretched. The contralateral hip is
The contralateral leg is extended, adducted, and externally rotated and the knee extended, abducted, and internally rotated, the knee flexed. The therapist asks
flexed. The therapist asks to extend, abduct, and internally rotate the hip to be to extend, adduce, and externally rotate the hip to be stretched against his
stretched against his body and, after relaxing, gains range of motion 3–5 times. resistance, to hold, and, after relaxing, gains range of motion. Repetitions:
3–5 times.

Biceps femoris stretching: Semitendinous and semimembranosus stretching: The therapist flexes,
The therapist flexes, adduces and externally rotates the leg to be stretched with abducts, and internally rotates the leg to be stretched with an extended knee.
an extended knee. The contralateral leg is extended, adducted, and externally The contralateral hip is extended, abducted, and internally rotated, and the knee
rotated and the knee flexed. The therapist asks to extend, abduct, and internally flexed. The therapist asks to extend, adduce, and externally rotate the hip to be
rotate the hip to be stretched against his body and, after relaxing, gains range of stretched against his resistance, to hold, and, after relaxing, gains range of
motion 3–5 times. motion. Repetitions: 3–5 times.

Iliopsoas stretching: Quadriceps femoris stretching: The therapist extends, abducts, and internally
The therapist extends, abducts, and internally rotates the hip to be stretched, rotates the hip to be stretched and flexes the knee. The contralateral leg is
and the knee is extended. The contralateral leg is flexed, abducted, and flexed, abducted, and internally rotated, asking the patient to hold it. The
internally rotated, asking the patient to hold it. The therapists ask to flex, adduce, therapists ask to flex, adduce, and externally rotate the hip and to extend the
and externally rotate the hip to be stretched against his resistance, to hold, and, knee to be stretched against his resistance, to hold, and, after relaxing, gains
after relaxing, gains range of motion. Repetitions: 3–5 times. range of motion by flexing the knee. Repetitions: 3–5 times.

Rotary torso muscles stretch: Torso extensor muscles stretch: The patient is side sitting, the therapist is in
The patient is side sitting, the therapist is behind him and rotates his torso, asks front of him and flexes his torso by flexing his head and extending his arms, asks
to rotate against him, to hold, and then, after relaxing, gains range of motion to lift up patient’s arms and look at that against his resistance, to hold, and then,
toward the concave side. Repetitions: 3–5 times. after relaxing, gains range of motion toward the concave side. Repetitions:
3–5 times.

(Continued)

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TABLE 1 | Continued

Obliquus muscles stretch:

The patient is side sitting. The therapist is standing in front of him and pulls the patient’s arm up high and tilts the torso toward the concave side. The therapist asks to
extend, abduct, and internally rotate the patient’s arm, then to hold, and then, after relaxing, inclines the trunk further toward the concave side. Repetitions: 3–5 times.

TRUNK POSTURAL ALIGNMENT EXERCISES

Exercises for the erector spinae muscles: Reverse tabletop pose exercise: After stretching the shoulder, arm, and lower
The patient is long sitting, the therapist is behind him and asks him to hold an limb muscles and performing the supine bridge exercise, the goal is to reach and
isometric contraction against his resistance at the end of a bilateral maintain this position with extended and 90◦ flexed knees, flexed head, and
flexion–abduction–external rotation pattern for 5 s at least. well-adduced shoulder blades.

Side bridge exercise:

After having stretched out the obliquus muscles of the tilted side and having recruited those of the weakest side, performing this exercise on the
weakest side is the goal for patients presenting Pisa Syndrome. The exercise can be performed bearing on the elbow or by flexing the knee too.

WALKING TRAINING

Stimulation of the movements of the shoulder complex: Stimulation of the movements of the pelvic complex: The therapists
The therapists rhythmically ask the patient to anteriorly elevate his shoulder rhythmically ask the patient to anteriorly elevate his pelvis toward or posteriorly
toward his nose or posteriorly depress it by adducing his shoulder blade toward depress it. First, the patient has to perceive the passive movement performed by
the column. First, the patient has to perceive the passive movement performed the therapist and then has to perform it actively against resistance. When the
by the therapist and then has to perform it actively against resistance. When the patient can perform the two movements separately, the therapist asks him to
patient can perform the two movements, the therapist asks him to reciprocally reciprocally activate anterior elevation and posterior depression.
activate anterior elevation and posterior depression.

(Continued)

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TABLE 1 | Continued

Walking training on the knees: Half-kneeling pose: The patient has to reach the half-kneeling position from
The therapists guide the patients in walking on the knees by alternatively the kneeling one. The therapist facilitates the passage using two upper limb
stimulating a flexion–adduction–extra rotation pattern of the upper limb on the patterns: flexion–adduction–external rotation of the upper limb on the bearing
bearing side and an extension–abduction internal rotation pattern of the upper side and extension–abduction internal rotation pattern of the upper limb on the
limb on the swinging side. swinging side.

Distal guided path:

The therapist facilitates the patient in walking using two upper limb patterns: flexion–adduction–external rotation of the upper limb on the bearing side and
extension–abduction internal rotation pattern of the upper limb on the swinging side.

Examples of progressive modular rebalancing exercises.

dots or photos and reporting on what is seen); turning around in you would use in your daily life,” “look forward,” and “do not turn
open, narrow, and small spaces; and climbing steps or stairs. or stop”) were provided. The same instructions were given to all
The VC training was performed as an integral part of the participants. Before the recording session, the subjects practiced
conventional physiotherapy and consisted of visual white lines for a few minutes to familiarize themselves with the procedure.
placed on the ground in the same way as in treatment A. This was Five trials were recorded for each locomotor task. All patients
performed three times a week for 30 min as recommended in the were recorded in ON state.
European Physiotherapy guidelines. The VCs were discretionally We focused on evaluating three important aspects of gait
executed by the physiotherapists during the course of each function: gait performance (e.g., speed, step length, hip joint
treatment session. range-of-motion [RoM]), gait balance (gait related-parameters,
The rehabilitation program is composed of a 60 min session e.g., step width and double support duration), and trunk control
once a day, performed 3 days/week. (trunk kinematics).
Participants within this program were encouraged to progress,
based on stated progression criteria. Progression in range of Outcome Assessment
motion exercises, stretching exercises, upper and lower limb Primary Outcomes
strengthening exercises, and improving balance, standing, sitting, The following kinematic parameters were measured: stance
transferring, and walking was encouraged in all participants. phase duration (%), double support phase duration (%), cadence
(step/min), step length, step width (m), mean speed (m/s),
spatial asymmetry index, temporal asymmetry index, hip, knee
Gait Analysis and ankle flexion–extension RoM and trunk flexion–extension,
Gait analysis was performed using an eight-ray infrared lateral bending, and rotation RoM.
optoelectronic SMART-DX 500 motion analysis camera and
system (BTS, Milan, Italy) with a sampling rate of 300 Hz. The Secondary Outcomes
system detected the motion of 22 passive spherical markers, Disease severity was evaluated using the UPDRS-III (45). A
placed over prominent bony landmarks according to the neurologist with expertise in movement disorders and blinded to
international recommendations and validated biomechanical patients’ allocation administered the UPDRS scale.
models (48). Anthropometric data were collected from each
participant (48). Statistical Analysis
Patients were asked to walk barefoot at a comfortable speed A power analysis using the G∗ Power computer program (49),
along a walkway. As we were interested in natural locomotion, based on preliminary data from the T1 assessment (50) indicated
only general qualitative instructions (e.g., “walk at natural speed a total sample of 24 participants to detect medium effects

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(d = 0.5) with 80% power using an unpaired t-test between in Group B; p > 0.05 for the difference in primary endpoint).
means of α = 0.05. Due to the number of gait parameters The assessments from the eight patients who dropped out were
considered as the primary outcomes of this pilot study, we input forward in the final analysis. All patients were taking oral
calculated the sample size according to Whitehead et al. (51), who administrations of levodopa (18 patients), dopamine agonists
identified a conservative minimum sample size of 20–40 subjects (5 patients), or both (17 patients). No significant differences in
for a pilot trial. Thus, we chose to consider a sample size ranging demographics were noted between groups at T0 (all, p > 0.05)
from a minimum of 24–40 subjects. or in clinical characteristics, UPDRS-III, H–Y scale, and total
Intention-to-treat analysis (ITT) was conducted, with the ITT Levodopa Equivalent Dose (LED) (all, p > 0.05) (Table 2A).
population defined as all randomized patients who provided at
least one baseline efficacy assessment and attended at least one Primary Outcomes (Gait Parameters)
treatment session. A significant main effect of time∗ group interaction was found
The Shapiro-Wilk and Levene tests were used to assess in speed, right and left stance duration, right and left double
normality and homogeneity of variance, respectively, for all support duration, left step length, cadence, step width, spatial
measures. Baseline characteristics were compared between the asymmetry, right and left hip RoM, right and left knee RoM,
groups using either a Student t-test (parametric data) or right and left ankle RoM, trunk flexion–extension, and trunk
Mann–Whitney U-test (non-parametric data) or, for categorical bending (Table 2B).
variables, using the Fisher exact test. Post hoc analysis revealed no significant differences between
We assessed the effect of the rehabilitative treatments on groups at T0 for almost all variables with the exception of right
both the primary and secondary outcomes through an ANOVA and left hip RoM. Significant improvements in almost all gait
mixed-effect model taking into account longitudinal repeated parameters were found in Group A compared to Group B at
measures including the effect of time (T0–T2) within each both or either T1 or T2, except for right ankle RoM and trunk
treatment group and interaction between time and intervention. rotation, which were not different between the two treatment
Missing values were imputed with the last observation carried groups (Figure 2).
forward (i.e., baseline, intermediate evaluation). Greenhouse- A significant main effect of time was found in speed, left
Geisser correction was applied, when deemed necessary, to stance duration, spatial asymmetry, trunk flexion–extension,
circumvent violations of sphericity (i.e., inequalities in the trunk bending, trunk rotation, right and left step length, right and
variance of the differences between factors). The Bonferroni left hip RoM, right and left knee RoM, and right and left ankle
correction for multiple testing was applied for pairwise RoM (Table 2B).
comparisons to account for the familywise error rate. Post hoc analysis revealed significant improvements at both or
A crossover design was used to reduce both the impact either T1 and T2 compared to T0 (Figure S1) in speed, left stance
of inter-individual variability by exposing each subject to two duration, right and left step length, trunk flexion–extension RoM,
different interventions and the effect of the disease progression trunk bending, trunk rotation, right and left hip RoM, right and
by exposing subgroups to different treatment sequences. left knee RoM, and right and left ankle RoM.
Furthermore, a 4-month rest period (wash-out) between the
rehabilitative treatments was introduced to reduce a potential
carryover effect and reproduce a hypothetical basal condition Secondary Outcomes (UPDRS Scores)
after the former intervention. To test for possible carryover No significant time∗ group interaction was found on UPDRS-III
effects, we calculated the sum of the values measured in the two (Figure 2, Table 2B).
periods for each subject and compared across the two sequence A significant main effect of time was found on the UPDRS-
groups using a test for independent samples. III score (Table 2B). Post-hoc analysis revealed significant
Statistical significance was set at p < 0.05 for two-sided tests, improvement (lower values) of the UPDRS-III scores at T2
and all analyses were performed using SPSS 20.0 (IBM SPSS). compared to that at T0 (Figure S1). UPDRS-III score changed
from 15.7 points at T0 to 14.4 at T1 to 14.1 at T2 (Table 2B).

RESULTS Patient Crossover

In this study, 15 patients (37.5%) crossed over between the groups
Twenty patients (12%) of the total 60 identified were not (8 patients from A to B and 7 patients from B to A) (Figure 1A).
enrolled, as they did not meet the inclusion criteria, or declined There was no difference in demographic characteristics
to participate. Forty patients consented to participate and between treatment groups (sex: 5F/3M vs. 4F/3M; age: 71.8 ±
were enrolled (Figure 1A, Table 2A). According to the H–Y 7.5 vs. 67.7 ± 6.3; weight: 66.3 ± 7.2 vs. 73.7 ± 17.1; height:
classification, there were 11 patients in stage 1, 13 patients in stage 1.60 ± 0.06 vs. 1.60 ± 0.05; disease duration: 7.0 ± 4.4 vs. 9.4
2, 12 patients in stage 3, and 4 patients in stage 4. Eight of these ± 3.4; respectively, all, p > 0.05). No significant differences were
patients failed to complete T2 and thus were considered as having revealed at the baseline evaluation between treatment A and
missing values and inputted with the intermediate observation treatment B groups in the UPDRS-III (12.3 ± 6.2 vs. 12.6 ± 4.6,
carried forward (two patients in group A and six patients in p > 0.05) and H–Y (2.4 ± 0.8 vs. 1.9 ± 1.2, p > 0.05) scale scores.
group B) (Figure 1A). A total of 32 patients completed the 8- No carryover effect was found for either gait variables or
week treatment (treatment adherence: 90.5% in Group A, 68.4% UPDRS scores (p > 0.05).

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Serrao et al.
TABLE 2 | This table (A) summarizes complete patient anthropometric and clinical characteristics (mean ± standard deviation).

Table 2A Anthropometric and clinical characteristics

Group Gender Age (years) Weight (kg) Height (m) Most affected side Disease Modified H–Y Total LED
duration
(years)
A 10F/11M 68.857 ± 8.627 69.808 ± 11.559 1.623 ± 0.080 8r/7l/6bil 8.952 ± 4.899 2.9 ± 0.9 593.7 ± 331.5
B 8F/11M 71.158 ± 7.522 75.463 ± 13.735 1.606 ± 0.071 5r/5l/9bil 8.536 ± 3.508 2.9 ± 1.2 623.5 ± 328.6

Table 2B Gait variables analysis

Time evaluation Main effect (time) Main effect (time*treatment)

Parameter Treatment T0 T1 T2 F p F p

Speed (m/s) A 0.743 ± 0.258 0.918 ± 0.210 0.952 ± 0.199 F (2,76) = 10.664 <0.001 F (2,76) = 15.075 <0.01
B 0.736 ± 0.305 0.726 ± 0.337 0.714 ± 0.349
r stance duration A 63.962 ± 4.786 61.857 ± 3.008 61.614 ± 2.905 F (1.542,58.591) = 2.070 0.146 F (1.542,58.591) = 7.913 0.004
(% cycle)
B 64.721 ± 3.853 65.332 ± 5.016 65.447 ± 5.193
l stance duration A 63.809 ± 3.796 61.633 ± 2.854 61.576 ± 2.855 F (1.491,56.648) = 5.315 0.014 F (1.491,56.648) = 5.253 0.014
(% cycle)
B 64.926 ± 3.984 65.021 ± 5.414 64.826 ± 5.573
9

r doub. supp. duration A 14.148 ± 4.722 11.790 ± 2.917 11.481 ± 2.618 F (1.589,60.378) = 2.071 0.144 F (1.589,60.378) = 7.841 0.002
(% cycle)
B 15.047 ± 3.757 15.542 ± 5.287 16.126 ± 5.877
l doub. supp. duration A 13.814 ± 3.953 11.781 ± 2.625 11.676 ± 2.885 F (1.710,64.986) = 2.329 0.113 F (1.710,64.986) = 4.492 0.019
(% cycle)
B 14.732 ± 4.195 14.847 ± 5.360 15.284 ± 6.401
Spatial asymmetry A 0.086 ± 0.092 0.065 ± 0.044 0.054 ± 0.048 F (1.544,58.669) = 3.470 0.049 F (1.544,58.669) = 0.551 0.535
B 0.133 ± 0.098 0.086 ± 0.007 0.102 ± 0.078
Temporal asymmetry A 0.026 ± 0.022 0.026 ± 0.025 0.027 ± 0.024 F (2,76) = 0.016 0.853 F (2,76) = 0.103 0.902
B 0.027 ± 0.018 0.026 ± 0.020 0.030 ± 0.026
Cadence (step/min) A 102.988 ± 17.050 110.196 ± 11.729 110.398 ± 13.082 F (1.625,61.742) = 1,843 0.173 F (1.625,61.742) = 5.523 0.010
B 100.11 ± 15.646 98.507 ± 18.335 97.802 ± 18.573
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r step length (m) A 0.389 ± 0.103 0.449 ± 0.085 0.471 ± 0.071 F (1.654,62.843) = <0.001 F (1.654,62.843) = 3.598 0.041
18.116
B 0.366 ± 0.122 0.385 ± 0.139 0.398 ± 0.144

PMR Gait Rehabilitation in PD

l step length (m) A 0.391 ± 0.099 0.463 ± 0.078 0.485 ± 0.065 F (1.688,64.152) = <0.001 F (1.688,64.152) = 8.786 0.001
15.698
B 0.403 ± 0.122 0.406 ± 0.142 0.419 ± 0.151
Step width (m) A 0.165 ± 0.019 0.171 ± 0.022 0.174 ± 0.025 F (1.550,58.890) = 0.094 0.863 F (1.550,58.890) = 4.265 0.027

(Continued)
Frontiers in Neurology | www.frontiersin.org

Serrao et al.
TABLE 2 | Continued

Table 2B Gait variables analysis

Time evaluation Main effect (time) Main effect (time*treatment)

Parameter Treatment T0 T1 T2 F p F p

B 0.165 ± 0.020 0.160 ± 0.020 0.158 ± 0.019

Trunk flexion–extension RoM (◦ ) A 4.339 ± 0.546 4.260 ± 0.063 5.172 ± 0.848 F (1.499,59.961) = <0.001 F (1.499,59.961) = 0.001
20.241 10.142
B 4.276 ± 0.155 4.215 ± 0.092 4.392 ± 0.400
Trunk bending RoM (◦ ) A 3.844 ± 0.532 4.183 ± 0.043 4.698 ± 0.774 F (1.572,59.728) = <0.001 F (1.572,59.728) = 6.352 0.006
17.530
B 4.096 ± 0.077 4.142 ± 0.053 4.304 ± 0.382
Trunk rotation RoM (◦ ) A 7.797 ± 1.612 8.325 ± 0.200 9.486 ± 2.644 F (1.237,47.012) = 5.523 <0.001 F (1.237,47.012) = 1.083 0.318
B 7.578 ± 0.345 8.367 ± 0.194 8.840 ± 0.589
r hip RoM (◦ ) A 32.175 ± 1.417 31.668 ± 0.348 33.885 ± 1.954 F (1.424,54.108) = <0.001 F (1.424,54.108) = 5.909 0.010
10

47.544
B 30.785 ± 0.717 31.994 ± 0.382 33.737 ± 1.465
l hip RoM (◦ ) A 32.591 ± 2.773 31.669 ± 0.251 35.567 ± 2.646 F (2,76) = 42.921 <0.001 F (2,76) = 6.245 0.003
B 31.066 ± 0.565 32.046 ± 0.386 33.665 ± 1.394
r knee RoM (◦ ) A 45.199 ± 2.355 45.272 ± 0.261 45.155 ± 2.292 F (2,76) = 4.090 0.21 F (2,76) = 5.582 0.023
B 44.271 ± 0.682 45.556 ± 0.336 45.593 ± 0.667
l knee RoM (◦ ) A 44.648 ± 2.046 45.913 ± 0.355 47.875 ± 2.632 F (2,76) = 54.147 <0.001 F (2,76) = 0.298 0.744
B 44.599 ± 0.817 46.261 ± 0.432 47.796 ± 1.364
r ankle RoM (◦ ) A 23.237 ± 1.697 23.039 ± 0.141 23.849 ± 1.587 F (2,76) = 14.857 <0.001 F (2,76) = 2.321 0.105
B 22.572 ± 0.318 23.054 ± 0.208 24.001 ± 0.883
l ankle RoM (◦ ) A 22.967 ± 1.969 23.128 ± 0.082 24.333 ± 1.516 F (2,76) = 25.302 <0.001 F (2,76) = 0.682 0.509
B 22.329 ± 0.348 22.998 ± 0.110 24.071 ± 0.845
UPDRS III A 14.619 ± 5.334 13.810 ± 5.419 13.429 ± 5.287 F (1.622,61.629) = 6.556 0.005 F (1.622,61.629) = 3.258 0.606
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B 16.882 ± 7.859 15.118 ± 6.879 13.524 ± 5.259

PMR Gait Rehabilitation in PD

This table (B) shows comparisons (mixed ANOVA) between the baseline (T0), T1, and T2 follow-up evaluations and between the two groups of patients (A and B). Main effects of time and time*treatment are reported. Bold p-values
denote statistically significant differences.
Serrao et al. PMR Gait Rehabilitation in PD

FIGURE 2 | The spatio-temporal parameters and trunk and lower limb joint kinematics at the baseline (T0), T1, and T2 evaluations. This figure shows the mean and
the standard deviation values of the 21 patients of group A (which performed PMR + sensory treatment) compared to the 19 patients of group B (which performed
standard physiotherapy treatment) at the three evaluations (T0, T1, T2). Asterisks (*) denote statistically significant differences.

Due to the small number of subjects who crossed over, the over between the groups, there still were some differences in the
non-parametric Mann–Whitney U-test was used to compare gait primary outcomes.
parameters, expressed as a percentage difference from the after- The results are in concordance with previous data from
washout baseline values between the two treatments, at T1 and Cochrane and systematic reviews, which reported that patients
T2. A significantly greater improvement in trunk rotation RoM with PD showed a short-term positive effect on gait and
(T1: Cohen’s d = 1.28; T2: Cohen’s d = 1.36) and right ankle balance functions and on motor function severity from
RoM (T1: Cohen’s d = 6.50; T2: Cohen’s d = 5) was found with several different rehabilitative techniques (32, 33). However, as
treatment A when compared with treatment B (Figure 3). No revealed in this study, PMR plus VC seems to be significantly
significant differences were found for the other parameters. better than conventional physiotherapy in improving almost
all performance-related gait parameters, balance-related gait
DISCUSSION parameters, and trunk motion (Figures 2–4, Table 2). Thus, the
PMR technique should be considered in addressing gait function
The present findings showed that a rehabilitative approach in patients with PD. The European Physiotherapy Guideline for
based on PMR plus VC for rehabilitation of gait function in Parkinson’s disease (52) identified five core areas in which a
people with PD appears to be more beneficial when compared rehabilitation program should lead to improvements, depending
to conventional physiotherapy executed according to European on the patient’s cognitive condition and the stage of the disease:
guidelines. Specifically, these findings can be summarized as physical capacity, weight transfer, manual activities, balance, and
follows: (i) both treatments improved gait function and motor gait. Improvements in these areas can be expected to lead to
function severity; (ii) patients who received PMR with VC improved performance in activities of daily living. However, the
presented with better results in gait performance (increased interventions used previously are largely heterogeneous (e.g.,
step length, speed, and joint kinematics), gait balance (increased stretching, muscle strengthening, balance, postural exercises,
step width and double support duration), and trunk control occupational therapy, cueing, treadmill training) and, taken as
(increased trunk motion) than those who received conventional a whole, are not part of a unique and directed rehabilitation
physiotherapy; and (iii) although only 37.5% of patients crossed system. In addition, presently, there is still no consensus

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Serrao et al. PMR Gait Rehabilitation in PD

FIGURE 3 | Trunk and ankle joint kinematic improvements at T1 and T2 evaluations. This figure shows the mean percentage difference and the standard deviation
values of the eight patients of group A compared to the seven patients of the group B. Asterisks denote statistically significant differences (*p < 0.05, **p < 0.01).

FIGURE 4 | Trunk kinematics in the three spatial planes. From left to the right: sagittal, frontal, and transverse planes, respectively. This figure shows trunk angles at
baseline (T0, light gray line) and at T1 (dark gray line) and T2 (black line) follow-up evaluations in a representative patient. Data were normalized to the cycle duration
and represented as a percentage of the gait cycle. In the first, second, and third panels, the vertical segments represent the flexion–extension, bending, and rotation
RoM, respectively.

about the optimal approach for PD patients (33). PMR is a clinical scales alone are not exhaustively sensitive in determining
context-adaptable rehabilitation method in which both patient changes in some motor aspects induced by physiotherapy and,
assessment and exercise are trunk-centered. This aims to thus, must be supplemented by objective instrumental measures.
progressively recover first the control of the trunk and then However, given that most patients were in stages 1 through
its relationship with the limbs, combining them in multiple 3 and only four patients were in stage 4, it is conceivable that
motor schemes performed in different postural configurations our results from the PMR plus VC only support it as an effective
(see Table 1). Notably, in addition to an improvement in the gait method in patients in stages 1–3 H–Y. As such, we point out that
spatiotemporal parameters and joint kinematics, we also found a our results may not be applicable to more severe cases of PD.
significant improvement in trunk motion (Figure 4). Since a high The main limitation of this study is the small sample
percentage of patients with PD show postural abnormalities and size at crossover. Although the number of eligible individuals
poor trunk control (8), which predispose them to a high risk of was relatively high, many patients were excluded due to
fall (53), special attention should be paid to these aspects of motor transportation problems from the crossover portion of the
control. Indeed, the head and trunk comprise 60% of the overall study. The limitation of the small sample size at crossover,
mass of the body. Thus, one’s ability to precisely coordinate even given that it was partly offset by the adoption of sensitive
trunk movements during walking contributes significantly to quantitative measures of motion, suggests that the results should
creating a more energy-efficient gait pattern, coupling action of be interpreted with substantial caution. However, the crossover
the trunk, and pelvis as a resonating pendulum and reducing design, which evaluates intra-individual changes, still allowed
overall momentum (54). PMR plus VC also showed better the detection of a therapy response, which may have been
improvement in balance-related gait parameters (i.e., step width missed in a similar sized parallel group study. Although the
and double support duration), suggesting a positive effect on number of subjects at crossover did not meet the sample
dynamic balance, which may prevent falls in patients with PD. size criteria and thus did not allow for the same inferential
Remarkably, while although differences in improvements of statistics used in the main portion of the study, we still found
biomechanical parameters were found, no significant differences some significant improvements with treatment A compared
emerged with respect to UPDRS-III scores. This may suggest that to treatment B (Figure 3). The trunk and right ankle RoM

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Serrao et al. PMR Gait Rehabilitation in PD

improved more with treatment A than with treatment B at T1 In conclusion, the present findings show that PMR plus
and T2. An important result from the crossover design was VC is effective in improving gait performance, balance,
that no carryover effect was found after the washout period, and trunk control and should be considered as a possible
suggesting that the effect of both treatments lasted no longer rehabilitative strategy for the treatment of PD and other
than 4 months. neurodegenerative diseases.
Another possible limitation of this study is that it is
difficult to conclude that either PMR alone or VC alone DATA AVAILABILITY
is better than conventional therapy. This study proposed
using sensory cueing, which is a well-established technique All datasets generated/analyzed for this study are included in the
for gait rehabilitation, as adjunctive treatment to the PMR manuscript and/or the Supplementary Files.
system, within a unique rehabilitation program. We suggest
that PMR treatment may result in globally improved trunk ETHICS STATEMENT
control, hip motion, strength, and endurance (in addition to
other factors), predisposing patients to the improvement of This study was carried out in accordance with the
the gait rhythm and automaticity induced by the use of the recommendations of name of guidelines, name of committee
external VC. with written informed consent from all subjects. All subjects gave
However, VC was also an integral part of the conventional written informed consent in accordance with the Declaration of
physiotherapy used in this study. The main difference was that Helsinki. The protocol was approved by the name of committee.
in treatment A, the VC was systematically executed at the end
of the PMR for 20 min, whereas in the conventional treatment, AUTHOR CONTRIBUTIONS
it was executed for 30 min and discretionally applied during
the course of each treatment session. Although both treatment MS contributed to the study design, revision, and manuscript
groups underwent VC, we cannot entirely explain or confirm elaboration. MP, DG, GS, and SC were in charge of the patient’s
the specific contribution of both the VC and PMR. For instance, enrollment and rehabilitation. GM, SC, FP, ES, and MB were in
the specific contribution of the VC could be different based on charge of the supervision and manuscript elaboration. GC, AR,
which rehabilitation treatment it was associated with. A three- and CC were in charge of data analysis, statistical analysis, and
branch trial design (conventional physiotherapy, PMR, and VC manuscript elaboration.
treatments) is needed to understand the specific contribution of
the PMR alone compared to either conventional physiotherapy SUPPLEMENTARY MATERIAL
or VC.
Despite these limitations, this study proposes a comprehensive The Supplementary Material for this article can be found
rehabilitation treatment regime in addressing key pathological online at: https://www.frontiersin.org/articles/10.3389/fneur.
outcomes of PD. Furthermore, the results are consistent 2019.00902/full#supplementary-material
and can be generalized to clinical practice. However, further Figure S1 | This figure illustrates the mean and the standard deviation values of all
studies are needed to assess the long-term effect of this 40 patients considered for treatment at the three evaluations (T0, T1, T2).
rehabilitative approach. Asterisks (∗ ) denote statistically significant differences.

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October 15, 2018). distribution or reproduction is permitted which does not comply with these terms.

Frontiers in Neurology | www.frontiersin.org 15 August 2019 | Volume 10 | Article 902