Clin Auton Res DOI 10.1007/s10286-014-0236-z
RESEARCH ARTICLE
Treadmill gait training improves baroreflex sensitivity in Parkinson’s disease Mohan Ganesan • Pramod Kumar Pal • Anupam Gupta • Talakad N. Sathyaprabha
Received: 11 November 2013 / Accepted: 27 February 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Background Partial weight supported treadmill gait training (PWSTT) is widely used in rehabilitation of gait in patient with Parkinson’s Diseases (PD). However, its effect on blood pressure variability (BPV) and baroreflex sensitivity (BRS) in PD has not been studied. Aim To evaluate the effect of conventional and treadmill gait training on BPV components and BRS. Methods Sixty patients with idiopathic PD were randomized into three groups. Twenty patients in control group were on only stable medication, 20 patients in conventional gait training (CGT) group (Stable medication with CGT) and 20 patients in PWSTT group (Stable medication with 20 % PWSTT). The CGT and PWSTT sessions were given for 30 min per day, 4 days per week, for 4 weeks (16 sessions). Groups were evaluated in their best ‘ON’ states. The beat-to-beat finger blood pressure (BP) was recorded for 10 min using a Finometer instrument (Finapres Medical Systems, The Netherlands). BPV
and BRS results were derived from artifact-free 5-min segments using Nevrocard software. Results BRS showed a significant group with time interaction (F = 6.930; p = 0.003). Post-hoc analysis revealed that PWSTT group showed significant improvement in BRS (p \ 0.001) after 4 weeks of training. No significant differences found in BPV parameters; systolic BP, diastolic BP, co-variance of systolic BP and low frequency component of systolic BP. Conclusions Four weeks of PWSTT significantly improves BRS in patients with PD. It can be considered as a non-invasive method of influencing BRS for prevention of orthostatic BP fall in patients with PD. Keywords Parkinson’s disease Blood pressure variability Baroreflex sensitivity Treadmill training Gait training
Introduction M. Ganesan T. N. Sathyaprabha (&) Department of Neurophysiology, Laboratory for Autonomic Functions, National Institute of Mental Health and Neurosciences, Hosur Road, Bangalore 560029, India e-mail:
[email protected] M. Ganesan Department of Physical Therapy, College of Applied Health Sciences, University of Illinois, Chicago 60612, USA P. K. Pal Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore 560029, India A. Gupta Department of Neurological Rehabilitation, National Institute of Mental Health and Neurosciences, Bangalore 560029, India
Gait training has successfully shown to improve gait and motor scores in patients with Parkinson’s disease (PD) [1]. Fall-related injury in PD affects quality of life and independence [2]. The cause of falls in PD is multifactorial, comprising gait and balance abnormalities, impairment in postural reflexes, and orthostatic hypotension (OH) [3–5]. Various strategies have been suggested to prevent falls and improve balance in PD such as the use of visual and auditory cues, task-oriented approaches, Tai chi etc. [6–8]. In addition, several strategies for OH can be used in individuals with PD including both non-pharmacological and pharmacologic measures [9]. However, some patients might respond poorly; therefore, additional therapies to deal with OH in PD are still needed.
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The term ‘baroreflex’ is defined as a negative neural feedback reflex mechanism by which baroreceptors regulate blood pressure that includes response to a change in blood pressure. It produces vasodilation and a decrease in heart rate when blood pressure increases and vasoconstriction and an increase in heart rate when blood pressure decreases [10]. Pressure-sensitive receptors, located in the carotid sinus and aortic arch, consist of afferent fibers traveling in the glossopharyngeal and vagal nerves that are activated when the vessel walls are stretched due to increases in blood pressure [10]. Baroreflex sensitivity (BRS) is defined as a measure of sensitivity of the cardiac limb of the baroreflex and measured by the change in inter-beat interval per unit change in systolic pressure either occurring spontaneously or after a maneuver [11, 12]. Low blood pressure variability (BPV) and a decrease in BRS significantly contribute to OH in PD [13]. There is a need to address the feasibility of altering the BPV and BRS by means of therapeutic strategies. Literature data suggests that implementation of an exercise program enhances BRS in individuals with cardiac diseases [14, 15]. Moreover, the positive effect of partial weight supported treadmill training (PWSTT) on heart rate variability (HRV) and BPV has been suggested in patients with spinal cord injury [16]. However, there is a knowledge gap about the effect of training on BPV and BRS in patients with PD. Thus, we hypothesize that
Fig. 1 Representation of the flow chart of the study design. NI no intervention, CGT conventional gait training, PWSTT partial weight supported treadmill gait training, SBP systolic blood pressure, DBP diastolic blood pressure, LF low frequency, CV co-variation, BRS baroreflex sensitivity
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both the conventional gait training (CGT) and PWSTT will improve BPV and BRS in patients with PD.
Methodology The schematic flow chart of the study design is given in Fig. 1. This was an open-label randomized controlled trial in which 60 individuals with PD were recruited from the Movement Disorders Clinic and Neurology Outpatient Department. The diagnosis of PD was confirmed by a movement disorder specialist using UK brain bank criteria. The study obtained approval from the Institutional Ethics Committee, and all participants provided written informed consent. Patients with mini-mental status examination score B24, Beck’s depression inventory score C17, Goetz dyskinesia score [3, Hoehn and Yahr Stage (H&Y) [3, abnormal electrocardiogram/echocardiography, unpredictable motor fluctuations and orthopedic problems influencing gait training were excluded from the study. Stable dosage of dopaminomimetic drugs was maintained for all the participating patients throughout the study period. The outcome measures and the training were performed during the best ‘ON’ period after the regular medications. The subjects who fulfilled inclusion and exclusion criteria were randomly divided into three groups: no intervention (NI), CGT and PWSTT.
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Fig. 2 Representation of the a conventional gait training with marking to guide steps b partial weight supported weight training including unweighing unit and treadmill unit
Interventions The interventions were given in the balance and gait training laboratory located in the Department of Neurological Rehabilitation. The representation of CGT and PWSTT is shown in Fig. 2. The details of training have been published elsewhere [6]. In brief, the CGT consisted of gait training in the parallel bars using markings on the floor to guide the step and stride length (Fig. 2a), and progressing later to outside the parallel bars. Verbal auditory cues were given to guide the stepping (with emphasis on longer steps). Turning strategies and arm swinging were taught and encouraged during walking. The PWSTT (Gait Trainer, Biodex Medical System) consisted of a treadmill with visual biofeedback of step length and an unweighing support system (Biodex Medical System, New York) (Fig. 2b). This arrangement permitted free movement of the patients’ arms and legs. The horizontal movement was provided by a slow moving treadmill. The treadmill’s constant rate of movement provided rhythmic input, which reinforced a co-ordinated reciprocal pattern of movement. The CGT and PWSTT training was given during the ‘ON’ period of medication. The patients in the CGT and PWSTT groups received training for 30 min in each session. Each patient had four sessions per week for 4 weeks (a total of 16 sessions). In both groups, patients had a 5-min warm-up and 5-min cool-down period during each session.
Outcome measurement The blood pressure was recorded in supine position by beat-to-beat finger pressure using the Finometer (Finapres Medical Systems, The Netherlands), a non-invasive beatto-beat blood pressure monitor [17, 18] at the Autonomic Laboratory located at the Department of Neurophysiology.
External calibration was performed before starting the procedure to ensure correct measurement. The finger cuff was fitted on to the middle finger of left hand of the patient and hand cuff to the arm at the chest level. For every patient ‘return to flow’ (RTF) calibration was done after 2 min of basal recordings followed by 10 min basal recording. The recordings were stored in a computer and analyzed offline using an automatic program. We used Nevrocard software (version 2.1.0) for analysis of BPV and BRS. The outcome measures included were: (1) mean systolic blood pressure (SBP), (2) mean diastolic blood pressure (DBP), (3) co-variation of SBP (SBPCV), (4) low frequency component of SBP (LFSBP) and (5) spontaneous BRS. The BRS values were derived using sequence method. Sequence BRS method is based on the occurrence of spontaneous fluctuations in blood pressure accompanied with concordant RR interval changes [19, 20]. Spontaneous sequences of three or more cycles allow the accurate calculation of the linear regression slope between blood pressure and RR interval changes, termed as the ‘spontaneous BRS’. This reflects baroreflex regulation under physiological conditions. The BRS values for increasing systolic BP and decreasing systolic BP were calculated as the slope of the linear regression lines between the R–R intervals and the systolic BP values at rest. Sequences of at least three consecutive intervals with 0.5 mmHg BP changes, and 5 ms R–R interval changes were analyzed only if the correlation coefficients were higher than 0.85. To find the highest coefficient, systolic BP was correlated with the same R–R interval and the two following R–R intervals [21]. The BRS was calculated as the mean value of the obtained slopes. Both the ‘up sequence’ and ‘down sequence’ were included in the total BRS component. All the outcome measurements were performed at baseline and after 4 weeks.
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Data analysis A 2 9 2 mixed factorial repeated measures analysis of variance (RMANOVA) was used to assess the significant changes in the study parameters. Bonferroni adjustment was done for post-hoc comparison. The alpha value was set at 0.01. The effect size of treatment was found by partial eta-squared (gq2) value. A gq2 of [0.2 was considered a large effect and [0.1 was a medium effect. SPSS 15.0 statistical software was used for the analysis of the data.
Results The mean age of the participants was 58.15 ± 8.7 years, height was 160 ± 6.9 cm, weight was 60.38 ± 10.5 and BMI was 23.55 ± 3.8. The demographics and clinical features at base line were published earlier [6]. No significant differences were observed between groups in the demographics and clinical details after the random distribution of the groups (Table 1). Twelve patients with PD could not have finger BP recordings due to a technical problem. No adverse effects during the training or out of the sessions were reported by the participants in any of the treatment groups during the study period. Results of BPV variables were obtained from analysis of beat-to-beat blood pressure recording from Finometer. The results of BPV components (i.e., mean SBP, mean DBP, SBPCV, and LFSBP) are shown in Table 2. No significant group effect, time effect, and interaction effects were observed in the BPV variables. The effect size for changes in pre- and post-training values of BPV was given in Table 2. The results of BRS have been shown in Table 2. BRS showed significant interaction effect (F = 6.930; p = 0.003)
and time effect (F = 9.943, p = 0.003). Bonferroni adjusted post-hoc comparison showed that there was significant improvement only in PWSTT group following 4 weeks of training compared to baseline. No significant changes were found in NI group and CGT group. The effect size of 4 weeks training on BRS in NI group was (gq2) 0.003, CGT was (gq2) 0.001 and PWSTT was (gq2) 0.376. Figure 3 represents the sequence method plot of BRS at baseline and after 4 weeks of PWSTT training in an individual with PD. This reflects the increase in number of the sequence of BRS after 4 weeks of training. The percentage improvement in BRS following 4 weeks training was 80.4 % for PWSTT group and 3.7 % for CGT group. The UPDRS scores showed a significant interaction effect (F = 28.42; p \ 0.001) between the groups. The post-hoc comparison showed significant improvement (reduction) in both the CGT (p = 0.005) and PWSTT (p \ 0.001) groups compared to baseline. After the 4-week training, the improvement in CGT was 6.51 % (pre-score 30.70 ± 5.04; post-score 28.70 ± 4.69) and PWSTT was 21.43 % (prescore 31.95 ± 4.26; post-score 25.10 ± 4.79) compared to baseline. The group comparison showed that PWSTT group was significantly improved compared to NI (p = 0.001) and CGT (p = 0.040) after 4 weeks of training. No significant difference were observed in CGT compared to NI (p = 0.732). In addition, no correlation was found between the improvement in BRS and improvement in UPDRS scores (r = -0.003; p = 0.992) in PWSTT group.
Discussion The present study result showed that 4 weeks of PWSTT enhances BRS in patients with PD. In our study we used
Table 1 Demographics and clinical details of the patients with Parkinson’s disease NI
CGT
PWSTT
p value
Age (years)
59.1 ± 6.8
57.7 ± 10.3
57.6 ± 9.1
0.841
Gender (women:men)
4:16
5:15
5:15
0.999
BMI (kg/m2)
23.2 ± 3.8
23.4 ± 4.4
24.1 ± 3.5
0.743
Mean age of onset (years)
53.6 ± 7.5
52.8 ± 9.1
51.9 ± 10.6
0.845
Duration of disease (years)
5.5 ± 3.4
4.9 ± 3.1
5.7 ± 3.9
0.728
Hoehn and Yahr stage (stage 2:stage 2.5)
16:4
17:3
17:3
0.999
Levodopa equivalent dosage (mg)
698.3 ± 227.1
577.1 ± 291.8
625.7 ± 315.1
0.394
UPDRS motor score Subjects with fall history: without fall (number falls)
30.15 ± 3.88 2:18 (4)
30.05 ± 3.90 3:17 (5)
30.35 ± 3.80 3:17 (4)
0.424 0.806
Subjects with HT: without HT
4:16
5:15
4:16
0.656
Subjects with DM: without DM
4:16
6:15
5:15
0.859
ANOVA test was used for Age, BMI, age of onset, duration of disease, Levodopa equivalent dosage, UPDRS; Fisher Exact test was used for other variables BMI body mass index, NI no intervention, CGT conventional gait training, PWSTT partial weight supported treadmill training, UPDRS unified Parkinson diseases rating scale, HT hypertension, DM diabetes mellitus
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73.97 ± 9.84
PWSTT
6.23 ± 4.84
6.7 ± 3.75
6.76 ± 6.34
6.13 ± 2.97
CGT
PWSTT
11.06 ± 4.13
7.01 ± 5.71
7.03 ± 3.55
6.04 ± 4.84
5.01 ± 3.26
7 ± 5.23
5.1 ± 3.52
4.99 ± 3.94
NI
PWSTT
CGT
NI
4.15 ± 1.11
4.14 ± 1.37
4.46 ± 1.62
CGT
PWSTT
4.16 ± 1.12
3.86 ± 1.15
70.49 ± 9.39
4.04 ± 1.54
NI
73.13 ± 11.95 73.34 ± 14.35
128.06 ± 20.22
132.27 ± 22.99
128.4 ± 16.90
After 4 weeks (4W) Mean ± SD
F = 0.770 p = 0.470
F = 0.798 p = 0.457
F = 0.429 p = 0.654
F = 0.013 p = 0.987
F = 0.49; p = 0.953
Group Effect
F = 9.943 p = 0.003
F = 0.024 p = 0.619
F = 0.527; p = 0.472
F = 0.053; p = 0.820
F = 0.488; p = 0.489
Time effect
F = 6.930; p = 0.003
F = 0.619; p = 0.543
F = 0.171; p = 0.843
F = 0.053; p = 0.453
F = 0.508; p = 0.605
Interaction effect
\ 0.001
0.816
0.733
0.492
0.383
0.938
0.429
0.983
0.634
0.249
0.660 0.744
0.292
0.728
0.623
BL- 4W p value
CGT-PWSTT
NI-PWSTT
NI-CGT
CGT-PWSTT
NI-PWSTT
NI-CGT
CGT-PWSTT
NI-PWSTT
NI-CGT
CGT-PWSTT
NI-CGT NI-PWSTT
CGT-PWSTT
NI-PWSTT
NI-CGT
Group
1
1
1
0.565
0.554
1
1
1
1
1
1 1
1
1
1
BL p value
0.083
0.071
1
1
1
1
1
1
1
1
1 1
1
1
1
4W p value
0.376
0.001
0.003
0.011
0.017
0.000
0.014
0.000
0.005
0.029
0.004 0.002
0.025
0.003
0.005
Effect size (gp2)
p \ 0.01 considered for significant
NI no intervention, CGT conventional gait training, PWSTT partial weight supported treadmill training, SBP systolic blood pressure, DBP diastolic blood pressure, LF low frequency, BRS baroreflex sensitivity, CV coefficient of variation
BRS (ms/ mmHg)
LFSBP (mmHg2)
SBPCV (mmHg)
71.82 ± 15.89 72.36 ± 10.66
132.61 ± 20.02
PWSTT
NI CGT
130.77 ± 20.52
CGT
DBP (mmHg)
130.52 ± 22.35
NI
SBP (mmHg)
Baseline (BL) Mean ± SD
Groups
Parameters
Table 2 Comparison of blood pressure variability and baroreflex sensitivity in all the study groups
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Fig. 3 Schematic representation of BRS sequences of patients with PD. a Baseline BRS, b After 4 weeks PWSTT training BRS sequences. SBP systolic blood pressure, BRS baroreflex sensitivity
the mean values of SBP, DBP, SBPCV and LFSBP as commonly proposed outcome measures to quantify blood pressure variability [22, 23]. However, no significant differences [24, 25] have been clearly documented in clinical studies focusing on the diagnostic and prognostic evaluation of patients with cardiovascular diseases [26, 27]. In humans, the quantification of BRS is usually done either with conventional pharmacological methods or through modern approaches based on computer analysis of spontaneously occurring blood pressure and heart rate fluctuations [24, 25]. In the present study we used computer analysis of spontaneous blood pressure and pulse interval changes obtained from the Finometer, a non-invasive beatto-beat blood pressure monitor. Though various methods have been used to analyze the BRS, spontaneous BRS derived from the sequence method had shown to be better correlated with the pharmacological method [25]. We used systolic BP in the sequence method, which is more reliable and consistent [24]. BRS showed a significant enhancement after 4 weeks of PWSTT training compared to baseline. Though a significant group difference was not observed, the finding of time and interaction effects suggests the possibility that longer durations of training may lead to significantly greater benefits with PWSTT compared to NI and CGT groups. The results indicate that BRS can be influenced by specific training. Even a seemingly insignificant change in arterial pressure (i.e., 5 mmHg) triggers baroreflex in humans. The time constants needed to activate changes through carotid baroreceptor are less than 0.5 s in healthy subjects [28]. In view of these facts, the measure of BRS may respond earlier than the BPV measures. This may be the reason for training-related improvements in BRS in the absence of changes in other BPV parameters studied. Studies have
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suggested exercise-induced improvement in BRS in diabetics [29], patients with chronic heart failure [30] and patients with myocardial infarction [31]. Various studies have described the alterations of cardiac and vascular autonomic control in patients with PD [22, 32, 33] even during sleep [34] and the premotor phase [35]. However, this is the first study to investigate the effects of physical therapies like PWSTT and CGT in PD. It is known that patients with PD have chronotropic insufficiency (i.e., blunted heart rate response to maximum exercise), which affects their ability to engage in maximum exercise [36], even in the premotor phase of PD [35]. Since the exercise training in the current study involved self-selected comfortable walking speed and rest after every 10-min session, it is assumed that the subjects did not reach maximum exertion. It is possible that due to the submaximal nature of the training, the chronotropic insufficiency would have not hindered the training sessions. In supporting this view, a study by Werner et al. [36] reported no significant difference between the exercise heart rate in PD and healthy controls during submaximal treadmill exercises. Barbic et al. [22] reported blunted SBPLF change in response to tilt in PD patients despite the absence of OH. In the present study, the BPV and BRS were tested in resting state not in response to any tilt/stimulus. Hence, it is possible that tilt/stimulus-induced change may reflect changes earlier than measuring the resting state BPV and BRS. Studies have reported low BRS in patients with PD compared with age-matched control group. Moreover, these patients develop OH in later stages [13, 37]. Literature data suggests that the diminished BRS and degeneration of sympathetic nervous system significantly influences the OH in individual with PD [37, 38]. Findings from our study suggest that PWSTT has the potential for improving BRS.
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This form of gait training therefore may reduce the risk of orthostatic intolerance or hypotension in patients with PD. Hence, PWSTT can be considered as a non-invasive method of influencing BRS for prevention of orthostatic blood pressure fall in patients with PD. We postulate that altered vascular stretching capability in lower limbs might be the reason for a decrease in BRS following PWSTT. The probable reason for the improvement only in PWSTT group is that the subjects in PWSTT group preferred a relatively faster walking speed and the use of a smaller base of support (BOS) than subjects in the CGT group. It is assumed that due to the higher walking speed and smaller base of support, the demands to the lower extremity muscles and vascular activity would have increased, altering the stretching capability of vessel walls of lower extremity and in turn affecting the BRS. It is also possible that similar results can be obtained with treadmill training without partial weight support. Further research is required to compare the effect using a similar methodology on treadmill training with and without partial weight support. The research shows an effect on BRS; however, it does not suggest that this can be used as a treatment for OH at this point. The reasons include the fact that the patients were not selected on the basis of the presence of OH or even on the presence of altered BRS. Furthermore, in PD, OH is the result of reduced sympathetic tone due to central and peripheral cell loss. Therefore, even if BRS gain is amplified, it may not be enough to counteract gravity’s effect during orthostatic testing. Therefore, these issues need further exploration. However, this is the first study to address the possible effect of PWSTT on BRS in patients with PD, and the results suggest that this is an area for future exploration. Conflict of interest On behalf of all authors, the corresponding author states that there is no conflict of interest.
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