This is the first study to investigate the immediate effects of auditory-cued treadmill training for one-session on cortical excitability and gait performance in patients with PD.
Moreover, this study further explored the different effects of auditory cues in freezers and non-freezers. The results showed that one-session treadmill training whether with or without auditory cues played a major role in modulated cortical excitability, increased step length and gait velocity in comfortable walking speed in PD subjects. We also found the auditory cues with treadmill training enhanced the corticospinal inhibition in both freezers and non-freezers.However, this phenomenon cannot be found in freezers when they received treadmill training without cues. Additionally, the freezers had a tendency to perform decreased step time CV after training. In contrast, the non-freezers had a tendency to perform increased step time CV after training.
In summary, the auditory-cued treadmill training may be a treatment strategy to be considered in clinical application. However, research regarding long-term training, choice of cued frequency, and type of auditory cues is needed.
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Figure 1. Flowchart of the study
(A) (B)
Figure 2. Treadmill training from (A) lateral view, and (B) posterior view
(A) (B)
(C)
Figure 3. Transcranial magnetic stimulation (TMS).
(A) a double cone coil; (B) setting of the TMS; (C) the placement of the coil over the scalp
(A) (B)
Figure 4. The placement of the inertial sensor system Physilogs® on the subject from (A) lateral view, and (B) anterior view
Figure 5. Paired-pulse TMS in the PD group (A, B).
(A) under auditory-cued condition; (B) under non-cued condition. MEP: motor evoked potentials; dotted line represents pretest and the solid line represents the posttest;
*: p<0.05 on time main effect for a comparison of PD and control group by RM-ANOVA
Figure 6. Paired-pulse TMS in the control group (A, B).
(A) under auditory-cued condition; (B) under non-cued condition. MEP: motor evoked potentials; dotted line represents pretest and the solid line represents the posttest;
*: p<0.05 on time main effect for a comparison of PD and control group by RM-ANOVA
Figure 7. Paired-pulsed TMS in the freezer (A, B) and non-freezer group (C, D).
MEP: motor evoked potentials; dotted line represents pretest and the solid line represents the posttest
Figure 8. CSP duration in the freezer (A) and non-freezer (B) group CSP: cortical silent period; *: p <0.05
Figure 9. Step time CV of CWS in the freezer and non-freezer group
Step time CV: coefficient of variation of step time; CWS: comfortable walking speed
Figure 10. Step time CV of CWS in the freezer and non-freezer group under AC (A) and NC (B) condition
Step time CV: coefficient of variation of step time; CWS: comfortable walking speed
Table 1. Summary of the cortical excitability in PD
TMS measure Compare to healthy subjects
Upper extremity74 Lower extremity77,78
Resting motor threshold (RMT) Similar Reduced / Similar
Motor evoked potentials (MEPs) Increased Increased
Cortical silent period (CSP) Reduced Reduced / Similar
Short intracortical inhibition (SICI) Reduced Similar
Intracortical facilitation (ICF) Similar Reduced
Table 2. Demographics and clinical characteristics of healthy subjects and patients with Parkinson’s disease
Age, yrs 66.88±8.89 63.89±7.79 65.29±8.20 67.33±7.05 0.766 0.471a
Gender, M/F 6/2 4/5 10/7 5/4
FOG: freezer group; nFOG: non-freezer group; Control: healthy group; M: male; F: female; L: left; R: right; MMSE: Mini-Mental State Examination; UPDRS-III: Unified Parkinson's Disease Rating Scale-motor part; NFOG-Q: New Freezing of Gait Questionnaire Values are expressed as mean ± standard deviation; Mann-Whitney U test was used for the between-group comparison
a: independent t-test; *: p <0.05
Table 3. Single-pulse TMS in PD and control group
Baseline Posttest Baseline Posttest
MEP, μV
PD 827.74±634.54 854.75±661.86 911.56±517.90 851.33±677.90
0.801 0.794 0.929 0.260 0.427 0.709 Control 623.24±372.96 664.67±543.54 770.66±385.76 675.39±648.13
AMEP, μV
PD 2240.90±667.32 2312.42±610.35 2168.30±646.92 2132.00±764.46
0.645 0.686 0.086 0.624 0.665 0.153 Control 2843.57±971.49 2662.65±910.46 2840.91±726.43 2656.65±651.61
CSP, ms
PD 133.00±20.77 142.63±18.98 137.28±21.14 146.29±20.38
0.283 0.201 0.031* 0.212 0.924 0.000*
Control 134.28±12.95 140.91±20.03 133.71±17.91 132.28±13.95 Note:
AC: auditory-cued condition; NC: non-cued condition; MEP: motor evoked potentials; AMEP: active motor evoked potentials; CSP:
cortical silent period; PD: patients with Parkinson’s disease group; Control: healthy group
Values are expressed as mean ± standard deviation; p value was displayed; *: p <0.05 examined by three-way RM-ANOVA
Table 4. Single-pulse TMS in freezers and non-freezers group
Baseline Posttest Baseline Posttest
MEP, μV
FOG 828.93±601.98 966.60±695.89 851.39±401.66 710.13±504.58
0.132 0.073 0.853 0.325 0.757 0.833 nFOG 826.81±695.10 767.75±662.35 958.37±613.42 961.16±799.80
AMEP, μV
FOG 2074.37±791.41 2200.69±719.86 1932.67±444.48 1891.10±723.00
0.699 0.582 0.769 0.412 0.394 0.786 nFOG 2370.43±567.51 2399.32±538.92 2351.57±741.73 2319.36±783.22
CSP, ms
FOG 130.16±17.72 140.00±17.20† 137.36±22.11 143.36±12.57
0.443 0.793 0.477 0.790 0.360 0.000*
nFOG 135.21±23.68 144.68±21.04† 137.22±21.70 148.57±25.43† Note:
AC: auditory-cued condition; NC: non-cued condition; MEP: motor evoked potentials; AMEP: active motor evoked potentials; CSP:
cortical silent period; FOG: freezer group; nFOG: non-freezer group
Values are expressed as mean ± standard deviation; p value was displayed; *: p <0.05 examined by three-way RM-ANOVA; ; †: p <0.05 for within-group comparison by paired t-test.
Table 5. Paired-pulse TMS in PD and control group
Baseline Posttest Baseline Posttest
SICI(2ms) , %
PD 17.85±12.43 24.91±21.20 22.93±20.65 26.73±24.49
0.687 0.567 0.064 0.967 0.208 0.003*
Control 12.52±7.04 31.44±39.87 19.56±23.45 42.49±31.66
SICI(3ms) , %
PD 28.63±25.09 28.45±22.62 22.58±14.19 28.23±21.41
0.927 0.540 0.470 0.413 0.756 0.156
Control 17.54±14.30 22.12±17.78 14.92±12.87 26.80±15.69
ICF(7ms) , %
PD 80.69±44.65 92.79±87.15 80.88±51.02 75.12±40.75
0.202 0.497 0.494 0.699 0.982 0.285
Control 61.95±29.94 59.54±31.22 53.61±32.69 84.25±47.72
ICF(10ms) , %
PD 85.19±36.52 94.74±54.09 83.78±43.14 94.64±56.64
0.135 0.112 0.152 0.117 0.128 0.009*
Control 80.06±30.27 87.07±35.93 87.98±66.12 145.38±109.94
ICF(12ms) , %
PD 84.91±67.01 85.58±42.61 78.89±35.72 111.15±90.93
0.320 0.340 0.213 0.864 0.979 0.009*
Control 76.04±44.48 130.56±118.00 78.00±70.95 110.09±79.54 Note:
AC: auditory-cued condition; NC: non-cued condition; SICI: short intracortical inhibition; ICF: intracortical facilitation; PD: patients with Parkinson’s disease group; Control: healthy group
Values are expressed as mean ± standard deviation; p value was displayed; *: p <0.05 examined by three-way RM-ANOVA
Table 6. Paired-pulse TMS in freezers and non-freezers group
Baseline Posttest Baseline Posttest
SICI(2ms) , %
FOG 14.91±15.72 14.76±13.32 15.71±14.44 20.01±23.84
0.366 0.916 0.453 0.748 0.346 0.211
nFOG 20.13±9.54 32.81±23.43 28.55±23.71 31.95±25.06
SICI(3ms) , %
FOG 19.64±12.83 17.01±15.38 12.11±7.74 24.23±25.24
0.454 0.453 0.719 0.518 0.428 0.551
nFOG 35.62±30.51 37.35±24.05 30.71±12.73 31.34±18.88
ICF(7ms) , %
FOG 89.66±44.79 61.79±24.86 77.65±55.58 86.75±47.63
0.053 0.391 0.315 0.618 0.652 0.871
nFOG 73.72±45.93 116.89±110.83 83.40±50.48 66.08±34.67
ICF(10ms) , %
FOG 93.44±30.93 97.98±47.81 76.15±33.50 99.66±72.72
0.276 0.572 0.614 0.817 0.889 0.128
nFOG 78.76±40.95 92.23±61.28 89.72±50.56 90.74±44.84
ICF(12ms) , %
FOG 93.59±91.05 88.79±38.60 84.18±35.93 142.56±124.40
0.399 0.295 0.339 0.295 0.290 0.079
nFOG 78.17±45.67 83.08±47.66 74.78±37.16 86.72±48.59
Note:
AC: auditory-cued condition; NC: non-cued condition; SICI: short intracortical inhibition; ICF: intracortical facilitation; FOG: freezer group; nFOG: non-freezer group
Values are expressed as mean ± standard deviation; p value was displayed; *: p <0.05 examined by three-way RM-ANOVA
Table 7. Gait performance with comfortable walking speed in PD and control group
Baseline Posttest Baseline Posttest
CV, %
PD 5.55±1.71 6.37±1.80 6.34±2.70 5.88±1.63
0.098 0.950 0.267 0.976 0.673 0.558
Control 6.40±0.85 5.20±2.18 5.99±1.89 6.03±2.14
Speed, m/s
PD 0.98±0.21 1.00±0.20 0.96±0.20 0.99±0.21
0.521 0.950 0.212 0.843 0.637 0.006*
Control 1.19±0.19 1.27±0.17 1.19±0.17 1.25±0.17
Cadence, steps/min
PD 114.71±8.14 114.37±7.25 113.96±6.61 112.52±7.76
0.426 0.244 0.134 0.093 0.970 0.835
Control 111.44±10.87 114.10±9.78 114.15±7.35 113.83±8.18
Slength, m
PD 1.00±0.21 1.03±0.21 0.99±0.20 1.04±0.21
0.662 0.543 0.736 0.347 0.383 0.000*
Control 1.26±0.18 1.30±0.15 1.23±0.17 1.29±0.15
Note:
AC: auditory-cued condition; NC: non-cued condition; CV: coefficient of variation of step time; Slength: stride length; PD: patients with Parkinson’s disease group; Control: healthy group
Values are expressed as mean ± standard deviation; p value was displayed; *: p <0.05 by three-way RM-ANOVA
Table 8. Gait performance with comfortable walking speed in freezers and non-freezers group
Baseline Posttest Baseline Posttest
CV, %
FOG 116.20±7.28 115.60±6.12 113.62±8.06 112.05±9.08
0.932 0.207 0.791 0.458 0.286 0.203
nFOG 113.39±9.05 113.28±8.34 114.27±5.52 112.94±6.92
Slength, m
FOG 0.95±0.27 0.97±0.26 0.90±0.23 0.97±0.25
0.631 0.214 0.910 0.238 0.739 0.002*
nFOG 1.05±0.14 1.09±0.16 1.06±0.15 1.11±0.15
Note:
AC: auditory-cued condition; NC: non-cued condition; CV: coefficient of variation of step time; Slength: stride length; FOG: freezer group;
nFOG: non-freezer group
Values are expressed as mean ± standard deviation; p value was displayed; *: p <0.05 by three-way RM-ANOVA
Table 9. Gait performance with fast walking speed in PD and control group
Baseline Posttest Baseline Posttest
CV, %
PD 6.3±1.91 5.86±1.97 6.18±2.33 6.34±2.49
0.084 0.035* 0.184 0.207 0.013* 0.114
Control 4.70±1.59 4.99±1.83 8.49±4.57 5.16±2.15
Speed, m/s
PD 1.28±0.30 1.26±0.26 1.28±0.28 1.28±0.26
0.646 0.543 0.641 0.195 0.922 0.203
Control 1.68±0.26 1.63±0.26 1.65±0.30 1.64±0.28
Cadence, steps/min
PD 127.96±11.38 126.64±9.67 127.25±9.27 125.60±7.73
0.652 0.124 0.853 0.493 0.400 0.038*
Control 130.79±11.04 129.82±9.54 134.48±5.66 131.94±7.50
Slength, m
PD 1.17±0.25＃ 1.17±0.24† 1.18±0.24＃ 1.20±0.24†
0.380 0.023* 0.492 0.109 0.300 0.458
Control 1.51±0.22 1.48±0.22 1.44±0.25 1.47±0.22
Note:
AC: auditory-cued condition; NC: non-cued condition; CV: coefficient of variation of step time; Slength: stride length; PD: patients with Parkinson’s disease group; Control: healthy group
Values are expressed as mean ± standard deviation; p value was displayed; *: p <0.05 by three-way RM ANOVA; ＃: p <0.05 for between-group comparison of baseline by independent t test; †: p <0.05 for between-group comparison of posttest by independent t test
Table 10. Gait performance with fast walking speed in freezers and non-freezers group
Baseline Posttest Baseline Posttest
CV, %
FOG 125.84±10.94 124.90±9.39 125.37±7.87 123.95±7.86
0.928 0.895 0.735 0.818 0.462 0.095
nFOG 129.84±12.07 128.19±10.19 128.92±10.54 127.07±7.76
Slength, m
FOG 1.10±0.32 1.10±0.29 1.11±0.30 1.14±0.29
0.775 0.657 0.860 0.508 0.182 0.174
nFOG 1.23±0.17 1.24±0.18 1.23±0.17 1.25±0.18
Note:
AC: auditory-cued condition; NC: non-cued condition; CV: coefficient of variation of step time; Slength: stride length; FOG: freezer group;
nFOG: non-freezer group
Values are expressed as mean ± standard deviation; p value was displayed; *: p <0.05 by three-way RM ANOVA