4.1 Demographics and baseline characteristics of patients and healthy adults
Subjects with PD were recruited from April 2018 to July 2018 through department of Neurology and Physical Therapy Center of National Taiwan University Hospital.
Twenty-seven patients met the inclusion criteria, but 9 patients refused to participate in this study. Eighteen patients agreed to withdraw their medication for at least 8 hour before the experiments. Nine patients were allocated to freezer (FOG) group and the other nine patients were allocated to non-freezer (nFOG) group. Nine healthy subjects participated in this study. All of subjects understood the experimental procedures and signed the consent form. One subjects in the FOG group dropped out during training due to fatigue even if he took a rest. Therefore, 8 subjects in the FOG group, 9 subjects in the nFOG group, and 9 subjects in the control group completed the two training across one week.
No one reported any adverse event or discomfort. The flow chart is presented in Figure 1.
Subjects’ baseline demographic information and clinical characteristics are summarized in Table 2. There were no statistically differences between the PD and control group in age (p =0.766) and MMSE (p =0.862). Comparison between the FOG and nFOG group also showed there were no significant differences in disease duration (p =0.906), Hoehn and Yahr scale (p =0.703), and UPDRS-motor part (p =0.155). The FOG group
presented significantly poorer performance on MMSE (p =0.034) and NFOGQ (p <0.001) compared to nFOG group.
4.2 Transcranial magnetic stimulation
The TMS variables were compared between the PD and control group first. Then the comparison between the FOG and nFOG group was conducted.
4.2.1 Motor evoked potentials
The 2x2x2 three-way RM-ANOVA analysis demonstrated there were no significant differences in MEP (p =0.801) and active MEP (p =0.645) between the PD and control group (Table 3) as well as between the FOG and nFOG group (MEP: p =0.132; active MEP: p =0.699) (Table 4).
4.2.2 Cortical silent period
RM-ANOVA analysis yielded no Group x Cue x Time interaction on CSP duration for a comparison of the PD and control group (p =0.283), but significant effects of the group x time interaction (p =0.031) and time (p <0.001) were noted (Table 3). Post hoc analysis indicated that CSP duration significantly increased in the PD group (p <0.001) after training, but not in the control group (p =0.392).
Furthermore, for a comparison of the FOG and nFOG group, RM-ANOVA analysis
revealed no Group x Cue x Time interaction on CSP duration (p =0.283). However, a significant time main effect for lengthened CSP duration in FOG and nFOG group (p
<0.001) was noted (Table 4).
4.2.3 Intracortical inhibition and facilitation
RM-ANOVA analysis yielded no Cue x Group x Time interaction on SICI(2ms), SICI(3ms), ICF(7ms), ICF(10ms), and ICF(12ms) (all variables: p >0.05) between the PD and control group (Table 5 and Figure 5, 6). Nevertheless, there were significant time main effects for SICI(2ms) (p =0.003),ICF(10ms) (p =0.009), and ICF(12ms) (p =0.009), indicating both the PD and control groups decreased SICI(2ms), increased ICF(10ms), and ICF(12ms) after training.
Moreover, RM-ANOVA analysis demonstrated there were no significant differences between the FOG and nFOG group in any of the variables for ppTMS (Table 6 and Figure 7).
4.3 Gait performance
The gait variables were compared between the PD and control group first. Then the comparison between the FOG and nFOG group was conducted.
4.3.1 Comfortable walking speed (CWS)
RM-ANOVA analysis revealed there were no significant effect of Cue x Group x Time interaction on step time CV, speed, cadence, and stride length in CWS for a comparison of the PD and control groups. A significant time main effects were found for speed (p =0.006) and stride length (p <0.001), indicating both the PD and control groups increased speed and stride length after training (Table 7).
In terms of a comparison of FOG and nFOG group, RM-ANOVA analysis yielded no significant Cue x Group x Time interaction effect on step time CV, speed, cadence, and stride length (all variables: p >0.05) in CWS (Table 8). A significant time main effect on stride length (p =0.002) were found, indicating both the FOG and nFOG group increased stride length after training. Moreover, a significant effect of Group x Time interaction on step time CV (p =0.034) was noted. 2x2 (Group x Time) RM-ANOVA analysis for the FOG and nFOG group further indicated there was no Group x Time interaction (p =0.056) on step time CV as well as group (p =0.077) and time (p =0.751) main effect. However, the step time CV in the FOG group presented a downward tendency after training, whereas the non-freezers presented an opposite picture (Figure 9).
4.3.2 Fast walking speed (FWS)
RM-ANOVA analysis yielded no significant Cue x Group x Time interaction effect on step time CV, speed, cadence, and stride length in FWS for a comparison of the PD
and control groups (Table 9). A significant time main effect was found for decreased cadence (p =0.038) after the PD and control groups receiving the training. There were significant effects of Cue x Group interaction (p =0.035) and Cue main effect (p =0.013) in step time CV. 2x2 (Cue x Group) RM-ANOVA analysis for the PD and control group further showed there was no significant Cue x Group interaction but a significant cue main effect was found for step time CV (p =0.041), indicating both PD and control groups presented decreased step time CV in AC condition. Additionally, 2x2x2 (Group x Cue x Time) RM-ANOVA analysis yielded a significant effect of Cue x Group interaction for stride length (p =0.023). Further analysis through 2x2 (Cue x Group) RM-ANOVA revealed there were Cue x Group interaction (p =0.011) and group main effect (p <0.001).
The cue main effect did not yield significant (p =0.253). Post hoc analysis revealed the PD group had significant shorter stride length in comparison of the control group (p
<0.001).
In terms of comparison of FOG and nFOG group, RM-ANOVA analysis demonstrated that there was no significant effect of Cue x Group x Time on step time CV, speed, cadence, and stride length in FWS. The main effect of Cue and Time did not reach significant in all of the above variables (Table 10).