F-wave and motor-evoked potentials during motor imagery and observation in apraxia of Parkinson disease Ayşegül Gündüz, MD, MSc, Meral E. Kızıltan, Prof. MD, Istanbul University, Cerrahpasa School of Medicine, Department of Neurology
Correspondence to: Aysegul Gunduz Department of Neurology, Cerrahpasa School of Medicine, Istanbul University e-mail: [email protected] Department of Neurology, Cerrahpasa School of Medicine, Istanbul University 34098 K.M.Pasa /Istanbul/Turkey Tel. Number: +902124143162 Fax number: +902126330176
Running title: F-waves and MEPs in PD apraxia
Keywords: Parkinson disease, Parkinsonism, Apraxia, F-waves, motor-evoked potentials, transcranial magnetic stimulation Financial disclosure: None Conflict of interest: None
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/mus.24663
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F-wave and motor-evoked potentials during motor imagery and observation in apraxia of Parkinson disease ABSTRACT Introduction: The amplitudes of F-waves and motor-evoked potentials (MEP) increase during imagination or active motor performance. The aim of this study was to investigate Fwave and MEP facilitation during the assessment of apraxia. Subjects and methods: Eight Parkinson disease (PD) patients with apraxia, 11 patients without apraxia, and eight healthy volunteers were enrolled. F-waves and MEPs were recorded during 4 states (resting, imagination, observation, and active movement). Results: The mean amplitude of the F-waves increased significantly during imagination and active movement compared with at rest in healthy individuals (P = 0.028) and the nonapraxia group (P = 0.005). PD patients with apraxia did not have similar facilitation. The mean amplitude of the MEPs also showed a similar loss of facilitation in PD with apraxia. Conclusions: Loss of facilitation during the preparation for movement is closely related to the gold standard clinical praxis battery. This provides additional support and a potential electrophysiological assessment method for apraxia in PD.
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Introduction Apraxia is the loss of ability to perform learned skilled actions in the presence of normal perception, cooperation, coordination, motor-sensory systems, and mentation.1,2 It is generally related to lesions in the dominant hemisphere. The parieto-occipital cortex and sensory-motor areas play a role in normal praxis. A recent hypothesis proposed a closed-loop circuit, including cortical and subcortical structures.3 The cortical areas in this hypothesis include the inferior frontal cortex, the posterior parietal cortex, and areas related to normal speech functions. McGeogh and colleagues4 hypothesized that dysfunction of mirror neurons is the underlying basic pathological mechanism of apraxia. Mirror neurons, first discovered in the ventral premotor region (F5) of macaque monkeys, are a group of cells that discharge during specific goal-directed hand and mouth movements.5 In humans, evidence of mirror neurons was derived indirectly from functional neuroimaging studies.6 The amplitudes of F-waves and motor-evoked potentials (MEP) increase during the imagination or active performance of movement in normal individuals. In addition, the MEP onset latency shortens with active performance.7-9 Nonmotor symptoms including cognitive deficits are as frequent as motor symptoms in Parkinson disease (PD). Recent studies of PD revealed the development of isolated memory, visuospatial, or executive deficits even during the early stages of the disease.10 Ideomotor apraxia and ideational apraxia are aspects of the symptomatology of early PD.11,12 The aim of this study was to analyze the serial changes in various parameters related to MEP and F-waves during rest and during imagination, observation, and performance of specific movements during the electrophysiological assessment of apraxia in PD. Patients and Methods
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Patients: Eight idiopathic PD patients with apraxia (apraxia group), 11 idiopathic PD patients without apraxia (nonapraxia group), and 8 healthy subjects (control group) were included in the study. The presence of apraxia was determined using the Mayo Clinic praxis assessment test, which was validated for Turkish populations.13 All 3 groups were similar with regard to mean age at examination, gender, and hand dominance. Participants with any disorders that might
change
the
results
of
electrophysiological
investigations
or
in
whom
electrophysiological investigations were contraindicated were excluded from the study. Cognitive performance was assessed using the mini-mental state examination (MMSE) and clock drawing test, and patients with findings suggestive of dementia were excluded. The duration of PD at the time of the examination, the affected side, the predominant symptom at PD onset, and the type of PD were also gathered from the medical records. Parkinsonian features were scored according to the motor section of the Unified Parkinson Disease Rating Scale (UPDRS). The worst (highest) score from a limb was recorded. The severity of PD was assessed according to Hoehn-Yahr staging. All clinical findings were similar between the 2 patient groups. The demographic and clinical findings of the participants are presented in Table 1. The mean Mayo clinic praxis assessment test score was 97.5±3.1 in the PD group with apraxia, whereas the other 2 groups achieved maximum scores. The study was approved by the local ethics committee, and all participants provided informed consent. Electrophysiological assessments: All electrophysiological recordings were performed on a Neuropack Sigma MEB-5504k (Nihon Kohden Medical, Tokyo, Japan) using silver-silver chloride surface electrodes. All subjects were examined in a quiet room and were asked to remain awake and relaxed. All investigations were performed under optimal dopaminergic treatment. Rigidity was examined at different times during the electrophysiological 4
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investigations to confirm the optimal conditions. Muscle activity was also followed using audiovisual feedback on the electromyography (EMG) machine. All examinations were performed bilaterally under the following 4 states: 1. At rest. The resting state consisted of complete mental and muscular relaxation. 2. During imagination of movement. For imagination of movement, patients simulated thumb abduction mentally with the abductor policis brevis (APB) as the primary muscle. Patients were trained prior to the experiment. 3. During observation of movement. For observation of movement, an actor performed thumb abduction, and patients were asked to only observe while maintaining complete mental and muscle relaxation. 4. During active movement. For active movement, the patient performed active thumb abduction.
F-waves: Recording electrodes were placed over the bilateral APB muscles in a belly-tendon configuration. The median nerve was stimulated at the wrist with the ground electrode on the palm. The stimulus duration was 0.2 ms (3 Hz square pulse), and stimulus intensity was 15– 20 mA. The instrument was set with a sweep ranging from 10–20 ms per division. The gain was 100–500 µV per division, depending on the response. High- and low-pass filters were set at 2 Hz and 2 kHz, respectively. A total of 20 recordings were obtained. The recordings were performed in 2 successive sets of 10 because of the recording capacity of the EMG machine. Motor evoked potentials (MEPs): Subjects were evaluated using transcranial magnetic stimulation (TMS) with the recording electrodes located over the bilateral APB muscles. Single pulses were generated using MAGSTIM 2002 monophasic TMS equipment (Medelec, UK) and a standard 90-mm circular stimulation coil (3193–00). To normalize vigilance during 5
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TMS sessions, the investigator asked subjects to remain alert with their eyes open and to count the stimuli. The subjects reported the stimulus number, which was confirmed at the end of each session. The stimulus was applied over the vertex (scalp MEP), and the motor thresholds were determined. The MEP recordings were performed using the minimum intensity required to evoke a 1 mV amplitude response. The analysis time was adjusted to 10 ms/div, and the amplitude sensitivity was 200-500 µV. High- and low-pass filters were set at 20 Hz and 3 kHz, respectively. Stimuli were repeated 8 times with a minimum interstimulus interval of 20 s, and the minimal onset latency (ms) and peak-to-peak amplitudes (mV) were measured. The analysis time was 10 ms/div, and the amplitude sensitivity was 1 mV. Statistical analysis: The peak-to-peak amplitudes and the onset latencies of the MEP response, latency, and persistence, and the amplitude of the F-waves were measured and compared among groups using Kruskal-Wallis tests. The Mann-Whitney U test was used for post hoc analysis. Serial changes in the F-wave and MEP response peak-to-peak amplitudes and onset latencies, as well as the F-wave persistence from rest to imagination, from rest to observation, and from rest to active movement were compared within each group using Wilcoxon tests. All data analyses were performed using SPSS 15.0 statistical software. Results The onset latency, amplitude, and persistence of the F-waves recorded over the dominant extremities during rest, imagination, observation, and active movement did not differ among groups, except for the mean F-wave amplitude during active movement, which was significantly lower in the apraxia group (Table 2). Post hoc analysis showed that the difference was between the apraxia and nonapraxia groups (P=0.023). The mean onset latency and amplitude of MEPs recorded over the dominant extremities during rest, imagination, observation, and active movement were also similar, except for MEP onset latency during rest
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(Table 2). MEP onset latency was shorter in the nonapraxia group compared to apraxia group (P=0.007). F-waves: F-wave amplitudes over the dominant upper extremity during imagination, observation, and in the active state were higher compared with the resting state in healthy individuals and PD patients without apraxia. The increases from rest to imagination and active movement in healthy individuals (P=0.028 for both conditions) and from rest to active movement in the nonapraxia group (P=0.005) were statistically significant. However, PD patients with apraxia did not experience similar facilitation, and the examinations exhibited decrease in amplitudes (Figure 1a). F-wave persistence also showed a similar trend, but there were no significant differences (Figure 1b). The onset latencies did not show significant changes between states. Recordings made over nondominant extremities or symptomatic extremities also showed similar increases in comparison with rest during the other 3 states in both healthy individuals and the nonapraxia group, while in the apraxia group there were similar decreases (data not shown). MEP responses: The mean MEP amplitudes over the dominant upper extremity during imagination, observation, and active states were higher than those during the resting state in healthy individuals (P=0.176, P=0.018, and P=0.018, respectively) and in PD patients without apraxia. The difference between the resting state and active movement reached statistical significance in PD patients without apraxia (P=0.046). Examinations in PD patients with apraxia also showed facilitation from rest to active movement, but the degree was lower than in the other 2 groups (Figure 2a). The changes from rest to imagination and active movement were statistically significant. In contrast, the MEP onset latencies were shortened significantly from rest to imagination, observation, and active movement (Figure 2b) (P=0.043, P=0.046, and P=0.028, respectively) in healthy subjects. The MEP onset latencies in the apraxia or nonapraxia groups were also shortened in comparison to rest with imagination, observation 7
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and active movement, but not significantly. The onset latencies between rest and imagination as well as rest and observation did not differ. Recordings over the nondominant extremity or symptomatic extremity also showed increased amplitudes from rest to imagination, observation, or active movement in healthy individuals and in the nonapraxia group, whereas the apraxia group exhibited decreased amplitudes.
Discussion We have investigated changes in both F-waves and MEP responses during four states of movement. Although studies regarding changes in F-waves and MEP responses during imagination and active movement were reported previously, changes during observation have only been evaluated using MEP responses.7-9 This study has 2 important findings. First, F-wave amplitudes increased from rest to imagination, from rest to observation, and from rest to active movement in healthy individuals and PD patients without apraxia, but they decreased in PD patients with apraxia. Second, there was a loss of MEP amplitude facilitation in the apraxia group in contrast to healthy individuals who showed pronounced facilitation. The most striking finding was the loss of F-wave amplitude facilitation in the apraxia group. Under normal physiological conditions, F-waves are variable, because different factors play a role in their development, including the refractory period, the threshold value of the lower motor neurons, and the presence of upper motor neuron activity. Cortical activity probably has an affect by way of transsynaptic stimulation.14,15 Rossini and colleagues9 measured an increase in F-wave amplitudes during imagination of movement. However, Facchini and colleagues16 could not replicate their results. Our results support the findings of Rossini and colleagues in healthy subjects and PD patients without apraxia.9 8
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MEP studies provide information regarding the integrity of the primary motor cortex and motor pathways.17-19 A normal MEP amplitude reflects the normal integrity and excitability of the corticospinal pathway and motor cortex. If the target muscle contracts voluntarily, facilitation occurs, and an MEP response with a shorter latency and a larger amplitude is obtained.8,20 MEP amplitudes also increase during the imagination of movement.21 Previous studies revealed that MEP changes during different stages of movement were more stable and consistent than were F-wave changes.16 An interesting finding regarding the changes in MEP responses is the reduction in amplitude after immobilization of the related extremity.22 This suggests that subcortical and segmental pathways also play an important role in regulating excitability. F-wave potentiation was also lost in PD patients, which correlates with degree of disability.23 However, we examined PD patients when they were at their optimal dopaminergic effect and thus had minimum disability. The inferior parietal cortex in the left hemispheric fronto-parietal pantomime network is responsible for activating the appropriate motor scheme for bilateral hands.24,25 In PD, the functional connectivity of the basal ganglia is changed during both the resting and action states.26 A previous study which evaluated limb-kinetic apraxia and functional connectivity in PD, showed precentral overactivation and postcentral hypoactivation in the left perirolandic area.27 This same area also plays a role in other types of apraxia.28 Although the mechanism underlying limb-kinetic apraxia is different from that of ideomotor/ideational apraxia, we speculate that this area is an important part of the praxis network that is impaired in PD apraxia. We believe that these changes are likely independent of the dopaminergic system, because all patients were at their optimal dopaminergic response when they were tested.
9
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Neurons firing during the observation of movement are termed mirror neurons and play a role in skilled movement and praxis functions.29 Loss of this facilitation in PD patients with apraxia in our study probably originated from the dysfunction of mirror neurons, which might be associated with redundant activity in the frontal and subcortical structures. This is not surprising, since the basal ganglia may play a role in the mirror system or have their own mirror system. Local field potential measurements during observation and execution of movement in patients undergoing deep brain stimulation surgery showed changes in frequency during the observation of movement similar to the cortical changes during voluntary activity.30 Because lateralization was reported previously to be important for MEP facilitation,31 we analyzed both extremities in our subjects, and the findings over the dominant and nondominant extremities were quite similar. We also considered changes according to the extremity that presented with PD symptoms, and findings were also similar. Therefore, lateralization seems to be less important with regard to apraxia and is similar to the functions of mirror neurons.29 A possible limitation of our study was that the mean age of PD patients with apraxia was 7 years greater than the mean age of the PD patients without apraxia, but the difference was nonsignificant. One study showed that MEP and F-wave amplitudes did not change with aging.32 Age probably affects the development of praxis dysfunction. Although age is not the major or only underlying factor in the development of dementia in PD patients, it is a risk factor. Therefore, it might also facilitate isolated praxis dysfunction. Another limitation of this study was that we only investigated 2 sets of 10 F-waves. We are aware of previous recommendations that at least 100 F-waves should be evaluated.33,34 However, PD patients have mood swings, and protecting their stable attention and 10
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cooperation is very difficult over prolonged periods; therefore, we limited this part of our study.
The number of patients studied is also a limitation. However, the less frequent
development of apraxia in nondemented PD populations limited the number of patients in the apraxia group. In conclusion, we believe that the loss of facilitation during the preparation for movement is closely related to the gold standard clinical batteries and provides additional support and an electrophysiological assessment method for apraxia in early-stage PD.
11
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Abbreviations: APB, abductor policis brevis EMG, electromyography MEP, motor evoked potential MMSE, mini-mental state examination PD, Parkinson disease TMS, transcranial magnetic stimulation UPDRS, Unified Parkinson Disease Rating Scale
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Rossi S.
Clinical applications of motor evoked potentials.
Electroencephalogr Clin Neurophysiol 1998;106:180-194.
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20. Magistris MR, Rösler KM, Truffert A, Myers JP. Transcranial stimulation excites virtually all motor neurons supplying the target muscle. A demonstration and a method improving the study of motor evoked potentials. Brain 1998;121:437-450. 21. Jeannerod M, Frak V. Mental imaging of motor activity in humans. Curr Opin Neurobiol 1999;9:735-739. 22. Zanette G, Manganotti P, Fiaschi A, Tamburin S. Modulation of motor cortex excitability after upper limb immobilization. Clin Neurophysiol 2004;115:1264-1275. 23. Abbruzzese G, Vische M, Ratto S, Abbruzzese M, Favale E. Assessment of motor neuron excitability in parkinsonian rigidity by the F wave. J Neurol 1985;232:246249. 24. Moll J, de Oliveira-Souza R, Passman LJ, Cunha FC, Souza-Lima F, Andreiuolo PA. Functional MRI correlates of real and imagined tool-use pantomimes. Neurology 2000;54:1331-1336. 25. Niessen E, Fink GR, Weiss PH. Apraxia, pantomime and the parietal cortex. Neuroimage Clin. 2014;5:42-52. 26. Kahan J, Urner M, Moran R, et al. Resting state functional MRI in Parkinson's disease: the impact of deep brain stimulation on 'effective' connectivity. Brain 2014;137:11301144. 27. Foki T, Pirker W, Klinger N, et al. FMRI correlates of apraxia in Parkinson's disease patients OFF medication. Exp Neurol 2010;225:416-422. 28. Binkofski F, Kunesch E, Classen J, Seitz RJ, Freund HJ. Tactile apraxia: unimodal
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29. Gallese V, Fadiga L, Fogassi L, Rizzolatti G. Action recognition in the premotor cortex. Brain 1996;119:593-609. 30. Alegre M, Rodríguez-Oroz MC, Valencia M, et al. Changes in subthalamic activity during movement observation in Parkinson's disease: is the mirror system mirrored in the basal ganglia? Clin Neurophysiol 2010;121:414-425. 31. Sabaté M, González B, Rodríguez M. Brain lateralization of motor imagery: motor planning asymmetry as a cause of movement lateralization. Neuropsychologia 2004;42:1041-1049. 32. Smith AE, Sale MV, Higgins RD, Wittert GA, Pitcher JB. Male human motor cortex stimulus-response characteristics are not altered by aging. J Appl Physiol (1985) 2011;110:206-212. 33. Rivner MH. The use of F-waves as a probe for motor cortex excitability. Clin Neurophysiol 2008;119:1215-1216. 34. Taniguchi S, Kimura J, Yamada T, Ichikawa H, Hara M, Fujisawa R, et al. Effect of motion imagery to counter rest-induced suppression of F-wave as a measure of anterior horn cell excitability. Clin Neurophysiol 2008;119:1346-1352.
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This study was not supported by any funding or sponsors. The authors do not have any financial disclosures.
17
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Figure legends Figure 1. Serial changes in F-wave amplitude (A) and persistence (B) in Parkinson disease patients with and without apraxia and in healthy subjects. Figure 2. Serial changes in amplitude (A) and latency (B) of motor-evoked potentials in Parkinson disease patients with and without apraxia and in healthy subjects.
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Table. 1. Clinical and demographic findings of all participants PD Apraxia (+) (n=8) Mean age (±SD, years) 62.7±13.4 Age range (years) 33–75 Gender (W/M) 3/5 Dominant hand (right/left) 8/0 Affected side at onset (right/left) 5/3 Symptoms at onset (tremor/bradykinesia) 6/2 PD type (A-R/Tr) 6/2 PD duration (years, mean±SD) 5.6±5.4 PD duration (years, range) 2-16 UPDRS motor score 13.8±7.3 (mean±SD) Hoehn-Yahr stage 1.9±0.3 (mean±SD) MMSE (mean±SD) 27.7±1.5
PD Apraxia (−) (n=11) 55.2±9.6 41–70 1/10 11/0
Control group
P
(n=8) 55.2±8.6 44–66 2/6 7/1
0.160 0.160 0.331 0.291
7/4
-
0.906
9/2 4/7
-
0.829 0.138
5.9±3.6 4-15 9.5±3.5
-
0.915 0.128
1.6±0.5
-
0.218
28.3±1.1
30
0.450
PD, Parkinson disease; SD, standard deviation; A-R, akinetic-rigid; Tr, tremor dominant; UPDRS, Unified Parkinson Disease Rating Scale; MMSE, mini-mental state examination.
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Table 2. Comparison of the onset latency and amplitude of MEP and F-waves and Fwave persistence recorded over the dominant extremity during rest, imagination, observation, and active movement among groups. PD PD Control group Apraxia (+) Apraxia (−) (n=8) (n=11) (n=8)
P
Rest
28.4±1.9
27.1±2.5
25.7±2.4
0.102
Imagination
27.8±1.0
27.2±1.9
26.5±2.6
0.676
Observation
27.8±0.9
26.8±1.6
26.0±2.6
0.422
Active movement
27.9±2.3
26.9±3.1
26.9±2.6
0.671
F latency (ms)
F amplitude (µV) Rest
611.2±479.9 397.5±133.4 288.4±133.4
0.247
Imagination
343.5±210.9 471.7±252.5 427.5±150.5
0.506
Observation
367.7±119.2 371.9±207.7 341.4±178.1
0.875
Active movement
449.1±288.3 925.0±430.4 676.2±178.0
0.032
Rest
82.9±22.3
76.7±20.6
75.7±19.0
0.746
Imagination
80.0±28.9
81.9±14.0
83.3±20.7
0.876
Observation
85.8±15.6
81.1±17.6
85.0±23.4
0.792
Active movement
76.7±27.3
90.0±15.5
94.6±8.7
0.576
Rest
23.9±1.1
21.9±0.7
23.3±1.6
0.028
Imagination
23.6±1.9
21.9±0.9
22.6±1.7
0.124
Observation
23.6±1.2
22.7±2.1
22.0±2.1
0.328
Active movement
22.6±1.8
21.6±1.4
21.1±1.6
0.241
Rest
2.7±1.7
1.9±1.8
2.5±2.1
0.804
Imagination
3.4±1.9
1.7±1.9
4.3±2.8
0.130
Observation
2.9±1.4
2.5±2.5
4.8±2.5
0.139
Active movement
4.5±1.9
4.6±2.1
6.3±2.7
0.311
F persistence (%)
MEP latency (ms)
MEP amplitude (mV)
PD; Parkinson disease; MEP, motor-evoked potential; ms, millisecond; µV, microvolt; mV, millivolt. Comparisons were performed among 3 groups, and P values were calculated using the Kruskal-Wallis test. The bold font values indicate significance at the level of
Correspondence to: Aysegul Gunduz Department of Neurology, Cerrahpasa School of Medicine, Istanbul University e-mail: [email protected] Department of Neurology, Cerrahpasa School of Medicine, Istanbul University 34098 K.M.Pasa /Istanbul/Turkey Tel. Number: +902124143162 Fax number: +902126330176
Running title: F-waves and MEPs in PD apraxia
Keywords: Parkinson disease, Parkinsonism, Apraxia, F-waves, motor-evoked potentials, transcranial magnetic stimulation Financial disclosure: None Conflict of interest: None
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/mus.24663
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F-wave and motor-evoked potentials during motor imagery and observation in apraxia of Parkinson disease ABSTRACT Introduction: The amplitudes of F-waves and motor-evoked potentials (MEP) increase during imagination or active motor performance. The aim of this study was to investigate Fwave and MEP facilitation during the assessment of apraxia. Subjects and methods: Eight Parkinson disease (PD) patients with apraxia, 11 patients without apraxia, and eight healthy volunteers were enrolled. F-waves and MEPs were recorded during 4 states (resting, imagination, observation, and active movement). Results: The mean amplitude of the F-waves increased significantly during imagination and active movement compared with at rest in healthy individuals (P = 0.028) and the nonapraxia group (P = 0.005). PD patients with apraxia did not have similar facilitation. The mean amplitude of the MEPs also showed a similar loss of facilitation in PD with apraxia. Conclusions: Loss of facilitation during the preparation for movement is closely related to the gold standard clinical praxis battery. This provides additional support and a potential electrophysiological assessment method for apraxia in PD.
2
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Introduction Apraxia is the loss of ability to perform learned skilled actions in the presence of normal perception, cooperation, coordination, motor-sensory systems, and mentation.1,2 It is generally related to lesions in the dominant hemisphere. The parieto-occipital cortex and sensory-motor areas play a role in normal praxis. A recent hypothesis proposed a closed-loop circuit, including cortical and subcortical structures.3 The cortical areas in this hypothesis include the inferior frontal cortex, the posterior parietal cortex, and areas related to normal speech functions. McGeogh and colleagues4 hypothesized that dysfunction of mirror neurons is the underlying basic pathological mechanism of apraxia. Mirror neurons, first discovered in the ventral premotor region (F5) of macaque monkeys, are a group of cells that discharge during specific goal-directed hand and mouth movements.5 In humans, evidence of mirror neurons was derived indirectly from functional neuroimaging studies.6 The amplitudes of F-waves and motor-evoked potentials (MEP) increase during the imagination or active performance of movement in normal individuals. In addition, the MEP onset latency shortens with active performance.7-9 Nonmotor symptoms including cognitive deficits are as frequent as motor symptoms in Parkinson disease (PD). Recent studies of PD revealed the development of isolated memory, visuospatial, or executive deficits even during the early stages of the disease.10 Ideomotor apraxia and ideational apraxia are aspects of the symptomatology of early PD.11,12 The aim of this study was to analyze the serial changes in various parameters related to MEP and F-waves during rest and during imagination, observation, and performance of specific movements during the electrophysiological assessment of apraxia in PD. Patients and Methods
3
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Patients: Eight idiopathic PD patients with apraxia (apraxia group), 11 idiopathic PD patients without apraxia (nonapraxia group), and 8 healthy subjects (control group) were included in the study. The presence of apraxia was determined using the Mayo Clinic praxis assessment test, which was validated for Turkish populations.13 All 3 groups were similar with regard to mean age at examination, gender, and hand dominance. Participants with any disorders that might
change
the
results
of
electrophysiological
investigations
or
in
whom
electrophysiological investigations were contraindicated were excluded from the study. Cognitive performance was assessed using the mini-mental state examination (MMSE) and clock drawing test, and patients with findings suggestive of dementia were excluded. The duration of PD at the time of the examination, the affected side, the predominant symptom at PD onset, and the type of PD were also gathered from the medical records. Parkinsonian features were scored according to the motor section of the Unified Parkinson Disease Rating Scale (UPDRS). The worst (highest) score from a limb was recorded. The severity of PD was assessed according to Hoehn-Yahr staging. All clinical findings were similar between the 2 patient groups. The demographic and clinical findings of the participants are presented in Table 1. The mean Mayo clinic praxis assessment test score was 97.5±3.1 in the PD group with apraxia, whereas the other 2 groups achieved maximum scores. The study was approved by the local ethics committee, and all participants provided informed consent. Electrophysiological assessments: All electrophysiological recordings were performed on a Neuropack Sigma MEB-5504k (Nihon Kohden Medical, Tokyo, Japan) using silver-silver chloride surface electrodes. All subjects were examined in a quiet room and were asked to remain awake and relaxed. All investigations were performed under optimal dopaminergic treatment. Rigidity was examined at different times during the electrophysiological 4
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investigations to confirm the optimal conditions. Muscle activity was also followed using audiovisual feedback on the electromyography (EMG) machine. All examinations were performed bilaterally under the following 4 states: 1. At rest. The resting state consisted of complete mental and muscular relaxation. 2. During imagination of movement. For imagination of movement, patients simulated thumb abduction mentally with the abductor policis brevis (APB) as the primary muscle. Patients were trained prior to the experiment. 3. During observation of movement. For observation of movement, an actor performed thumb abduction, and patients were asked to only observe while maintaining complete mental and muscle relaxation. 4. During active movement. For active movement, the patient performed active thumb abduction.
F-waves: Recording electrodes were placed over the bilateral APB muscles in a belly-tendon configuration. The median nerve was stimulated at the wrist with the ground electrode on the palm. The stimulus duration was 0.2 ms (3 Hz square pulse), and stimulus intensity was 15– 20 mA. The instrument was set with a sweep ranging from 10–20 ms per division. The gain was 100–500 µV per division, depending on the response. High- and low-pass filters were set at 2 Hz and 2 kHz, respectively. A total of 20 recordings were obtained. The recordings were performed in 2 successive sets of 10 because of the recording capacity of the EMG machine. Motor evoked potentials (MEPs): Subjects were evaluated using transcranial magnetic stimulation (TMS) with the recording electrodes located over the bilateral APB muscles. Single pulses were generated using MAGSTIM 2002 monophasic TMS equipment (Medelec, UK) and a standard 90-mm circular stimulation coil (3193–00). To normalize vigilance during 5
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TMS sessions, the investigator asked subjects to remain alert with their eyes open and to count the stimuli. The subjects reported the stimulus number, which was confirmed at the end of each session. The stimulus was applied over the vertex (scalp MEP), and the motor thresholds were determined. The MEP recordings were performed using the minimum intensity required to evoke a 1 mV amplitude response. The analysis time was adjusted to 10 ms/div, and the amplitude sensitivity was 200-500 µV. High- and low-pass filters were set at 20 Hz and 3 kHz, respectively. Stimuli were repeated 8 times with a minimum interstimulus interval of 20 s, and the minimal onset latency (ms) and peak-to-peak amplitudes (mV) were measured. The analysis time was 10 ms/div, and the amplitude sensitivity was 1 mV. Statistical analysis: The peak-to-peak amplitudes and the onset latencies of the MEP response, latency, and persistence, and the amplitude of the F-waves were measured and compared among groups using Kruskal-Wallis tests. The Mann-Whitney U test was used for post hoc analysis. Serial changes in the F-wave and MEP response peak-to-peak amplitudes and onset latencies, as well as the F-wave persistence from rest to imagination, from rest to observation, and from rest to active movement were compared within each group using Wilcoxon tests. All data analyses were performed using SPSS 15.0 statistical software. Results The onset latency, amplitude, and persistence of the F-waves recorded over the dominant extremities during rest, imagination, observation, and active movement did not differ among groups, except for the mean F-wave amplitude during active movement, which was significantly lower in the apraxia group (Table 2). Post hoc analysis showed that the difference was between the apraxia and nonapraxia groups (P=0.023). The mean onset latency and amplitude of MEPs recorded over the dominant extremities during rest, imagination, observation, and active movement were also similar, except for MEP onset latency during rest
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(Table 2). MEP onset latency was shorter in the nonapraxia group compared to apraxia group (P=0.007). F-waves: F-wave amplitudes over the dominant upper extremity during imagination, observation, and in the active state were higher compared with the resting state in healthy individuals and PD patients without apraxia. The increases from rest to imagination and active movement in healthy individuals (P=0.028 for both conditions) and from rest to active movement in the nonapraxia group (P=0.005) were statistically significant. However, PD patients with apraxia did not experience similar facilitation, and the examinations exhibited decrease in amplitudes (Figure 1a). F-wave persistence also showed a similar trend, but there were no significant differences (Figure 1b). The onset latencies did not show significant changes between states. Recordings made over nondominant extremities or symptomatic extremities also showed similar increases in comparison with rest during the other 3 states in both healthy individuals and the nonapraxia group, while in the apraxia group there were similar decreases (data not shown). MEP responses: The mean MEP amplitudes over the dominant upper extremity during imagination, observation, and active states were higher than those during the resting state in healthy individuals (P=0.176, P=0.018, and P=0.018, respectively) and in PD patients without apraxia. The difference between the resting state and active movement reached statistical significance in PD patients without apraxia (P=0.046). Examinations in PD patients with apraxia also showed facilitation from rest to active movement, but the degree was lower than in the other 2 groups (Figure 2a). The changes from rest to imagination and active movement were statistically significant. In contrast, the MEP onset latencies were shortened significantly from rest to imagination, observation, and active movement (Figure 2b) (P=0.043, P=0.046, and P=0.028, respectively) in healthy subjects. The MEP onset latencies in the apraxia or nonapraxia groups were also shortened in comparison to rest with imagination, observation 7
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and active movement, but not significantly. The onset latencies between rest and imagination as well as rest and observation did not differ. Recordings over the nondominant extremity or symptomatic extremity also showed increased amplitudes from rest to imagination, observation, or active movement in healthy individuals and in the nonapraxia group, whereas the apraxia group exhibited decreased amplitudes.
Discussion We have investigated changes in both F-waves and MEP responses during four states of movement. Although studies regarding changes in F-waves and MEP responses during imagination and active movement were reported previously, changes during observation have only been evaluated using MEP responses.7-9 This study has 2 important findings. First, F-wave amplitudes increased from rest to imagination, from rest to observation, and from rest to active movement in healthy individuals and PD patients without apraxia, but they decreased in PD patients with apraxia. Second, there was a loss of MEP amplitude facilitation in the apraxia group in contrast to healthy individuals who showed pronounced facilitation. The most striking finding was the loss of F-wave amplitude facilitation in the apraxia group. Under normal physiological conditions, F-waves are variable, because different factors play a role in their development, including the refractory period, the threshold value of the lower motor neurons, and the presence of upper motor neuron activity. Cortical activity probably has an affect by way of transsynaptic stimulation.14,15 Rossini and colleagues9 measured an increase in F-wave amplitudes during imagination of movement. However, Facchini and colleagues16 could not replicate their results. Our results support the findings of Rossini and colleagues in healthy subjects and PD patients without apraxia.9 8
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MEP studies provide information regarding the integrity of the primary motor cortex and motor pathways.17-19 A normal MEP amplitude reflects the normal integrity and excitability of the corticospinal pathway and motor cortex. If the target muscle contracts voluntarily, facilitation occurs, and an MEP response with a shorter latency and a larger amplitude is obtained.8,20 MEP amplitudes also increase during the imagination of movement.21 Previous studies revealed that MEP changes during different stages of movement were more stable and consistent than were F-wave changes.16 An interesting finding regarding the changes in MEP responses is the reduction in amplitude after immobilization of the related extremity.22 This suggests that subcortical and segmental pathways also play an important role in regulating excitability. F-wave potentiation was also lost in PD patients, which correlates with degree of disability.23 However, we examined PD patients when they were at their optimal dopaminergic effect and thus had minimum disability. The inferior parietal cortex in the left hemispheric fronto-parietal pantomime network is responsible for activating the appropriate motor scheme for bilateral hands.24,25 In PD, the functional connectivity of the basal ganglia is changed during both the resting and action states.26 A previous study which evaluated limb-kinetic apraxia and functional connectivity in PD, showed precentral overactivation and postcentral hypoactivation in the left perirolandic area.27 This same area also plays a role in other types of apraxia.28 Although the mechanism underlying limb-kinetic apraxia is different from that of ideomotor/ideational apraxia, we speculate that this area is an important part of the praxis network that is impaired in PD apraxia. We believe that these changes are likely independent of the dopaminergic system, because all patients were at their optimal dopaminergic response when they were tested.
9
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Neurons firing during the observation of movement are termed mirror neurons and play a role in skilled movement and praxis functions.29 Loss of this facilitation in PD patients with apraxia in our study probably originated from the dysfunction of mirror neurons, which might be associated with redundant activity in the frontal and subcortical structures. This is not surprising, since the basal ganglia may play a role in the mirror system or have their own mirror system. Local field potential measurements during observation and execution of movement in patients undergoing deep brain stimulation surgery showed changes in frequency during the observation of movement similar to the cortical changes during voluntary activity.30 Because lateralization was reported previously to be important for MEP facilitation,31 we analyzed both extremities in our subjects, and the findings over the dominant and nondominant extremities were quite similar. We also considered changes according to the extremity that presented with PD symptoms, and findings were also similar. Therefore, lateralization seems to be less important with regard to apraxia and is similar to the functions of mirror neurons.29 A possible limitation of our study was that the mean age of PD patients with apraxia was 7 years greater than the mean age of the PD patients without apraxia, but the difference was nonsignificant. One study showed that MEP and F-wave amplitudes did not change with aging.32 Age probably affects the development of praxis dysfunction. Although age is not the major or only underlying factor in the development of dementia in PD patients, it is a risk factor. Therefore, it might also facilitate isolated praxis dysfunction. Another limitation of this study was that we only investigated 2 sets of 10 F-waves. We are aware of previous recommendations that at least 100 F-waves should be evaluated.33,34 However, PD patients have mood swings, and protecting their stable attention and 10
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cooperation is very difficult over prolonged periods; therefore, we limited this part of our study.
The number of patients studied is also a limitation. However, the less frequent
development of apraxia in nondemented PD populations limited the number of patients in the apraxia group. In conclusion, we believe that the loss of facilitation during the preparation for movement is closely related to the gold standard clinical batteries and provides additional support and an electrophysiological assessment method for apraxia in early-stage PD.
11
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Abbreviations: APB, abductor policis brevis EMG, electromyography MEP, motor evoked potential MMSE, mini-mental state examination PD, Parkinson disease TMS, transcranial magnetic stimulation UPDRS, Unified Parkinson Disease Rating Scale
12
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References 1. Heilmann KM, Valenstein E, Rothi LJG, Watson RT. Intentional Motor Disorders and the Apraxias. In: Bradley WG, Daroff RB, Fenichel GM, Jankovic J, editors. Neurology in Clinical Practice. Principles of Diagnosis and Management. Philadelphia: Butterworth-Heinemann; 2004. Vol 1, pp. 117-30. 2. Leiguarda RC, Marsden CD. Limb apraxias: higher-order disorders of sensorimotor integration. Brain 2000;123:860-879. 3. Buxbaum LJ. Ideomotor apraxia: a call to action. Neurocase 2001;7:445-458. 4. McGeoch PD, Brang D, Ramachandran VS. Apraxia, metaphor and mirror neurons. Med Hypotheses 2007;69:1165-1168. 5. Gallese V, Fadiga L, Fogassi L, Rizzolatti G. Action recognition in the premotor cortex. Brain 1996;119:593-609. 6. Filimon F, Nelson JD, Hagler DJ, Sereno MI. Human cortical representations for reaching: mirror neurons for execution, observation, and imagery. Neuroimage 2007;37:1315-1328. 7. Hara M, Kimura J, Walker DD, Taniguchi S, Ichikawa H, Fujisawa R, et al. Effect of motor imagery and voluntary muscle contraction on the F wave. Muscle Nerve 2010;42:208-212. 8. Maertens de Noordhout A, Pepin JL, Gerard P, Delwaide PJ. Facilitation of responses to motor cortex stimulation: effects of isometric voluntary contraction. Ann Neurol 1992;32:365-370. 9. Rossini PM, Rossi S, Pasqualetti P, Tecchio F. Corticospinal excitability modulation to hand muscles during movement imagery. Cereb Cortex 1999;9:161-167.
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10. Aarsland D, Bronnick K, Williams-Gray C, Weintraub D, Marder K, Kulisevsky J, et al. Mild cognitive impairment in Parkinson disease: a multicenter pooled analysis. Neurology 2010;75:1062-1069. 11. Leiguarda RC, Pramstaller PP, Merello M, Starkstein S, Lees AJ, Marsden CD. Apraxia in Parkinson's disease, progressive supranuclear palsy, multiple system atrophy and neuroleptic-induced parkinsonism. Brain 1997;120:75-90. 12. Uluduz D, Ertürk O, Kenangil G, Ozekmekçi S, Ertan S, Apaydin H, et al. Apraxia in Parkinson's disease and multiple system atrophy. Eur J Neurol 2010;17:413-418. 13. Kokmen E, Ozekmekci FS, Cha RH, O'Brien PJ. Testing for apraxia in neurological patients: a descriptive study in two diverse cultures. Eur J Neurol 1998;5:175-180. 14. Mesrati F, Vecchierini MF. F-waves: neurophysiology and clinical value. Neurophysiol Clin 2004;34:217-243. 15. Nakazumi Y, Watanabe Y. F-wave elicited during voluntary contraction as a monitor of upper motor neuron disorder. Electromyogr Clin Neurophysiol 1992;32:631-635. 16. Facchini S, Muellbacher W, Battaglia F, Boroojerdi B, Hallett M. Focal enhancement of motor cortex excitability during motor imagery: a transcranial magnetic stimulation study. Acta Neurol Scand 2002;105:146-151. 17. Barker AT, Freeston IL, Jabinous R, Jarratt JA. Clinical evaluation of conduction time measurements in central motor pathways using magnetic stimulation of human brain. Lancet 1986;1:1325-6. 18. Kobayashi M, Pascual-Leone A. Transcranial magnetic stimulation in neurology. Lancet Neurol 2003;2:145-156. 19. Rossini PM,
Rossi S.
Clinical applications of motor evoked potentials.
Electroencephalogr Clin Neurophysiol 1998;106:180-194.
14
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20. Magistris MR, Rösler KM, Truffert A, Myers JP. Transcranial stimulation excites virtually all motor neurons supplying the target muscle. A demonstration and a method improving the study of motor evoked potentials. Brain 1998;121:437-450. 21. Jeannerod M, Frak V. Mental imaging of motor activity in humans. Curr Opin Neurobiol 1999;9:735-739. 22. Zanette G, Manganotti P, Fiaschi A, Tamburin S. Modulation of motor cortex excitability after upper limb immobilization. Clin Neurophysiol 2004;115:1264-1275. 23. Abbruzzese G, Vische M, Ratto S, Abbruzzese M, Favale E. Assessment of motor neuron excitability in parkinsonian rigidity by the F wave. J Neurol 1985;232:246249. 24. Moll J, de Oliveira-Souza R, Passman LJ, Cunha FC, Souza-Lima F, Andreiuolo PA. Functional MRI correlates of real and imagined tool-use pantomimes. Neurology 2000;54:1331-1336. 25. Niessen E, Fink GR, Weiss PH. Apraxia, pantomime and the parietal cortex. Neuroimage Clin. 2014;5:42-52. 26. Kahan J, Urner M, Moran R, et al. Resting state functional MRI in Parkinson's disease: the impact of deep brain stimulation on 'effective' connectivity. Brain 2014;137:11301144. 27. Foki T, Pirker W, Klinger N, et al. FMRI correlates of apraxia in Parkinson's disease patients OFF medication. Exp Neurol 2010;225:416-422. 28. Binkofski F, Kunesch E, Classen J, Seitz RJ, Freund HJ. Tactile apraxia: unimodal
apractic disorder of tactile object exploration associated with parietal lobe lesions. Brain 2001;124:132-144. 15
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29. Gallese V, Fadiga L, Fogassi L, Rizzolatti G. Action recognition in the premotor cortex. Brain 1996;119:593-609. 30. Alegre M, Rodríguez-Oroz MC, Valencia M, et al. Changes in subthalamic activity during movement observation in Parkinson's disease: is the mirror system mirrored in the basal ganglia? Clin Neurophysiol 2010;121:414-425. 31. Sabaté M, González B, Rodríguez M. Brain lateralization of motor imagery: motor planning asymmetry as a cause of movement lateralization. Neuropsychologia 2004;42:1041-1049. 32. Smith AE, Sale MV, Higgins RD, Wittert GA, Pitcher JB. Male human motor cortex stimulus-response characteristics are not altered by aging. J Appl Physiol (1985) 2011;110:206-212. 33. Rivner MH. The use of F-waves as a probe for motor cortex excitability. Clin Neurophysiol 2008;119:1215-1216. 34. Taniguchi S, Kimura J, Yamada T, Ichikawa H, Hara M, Fujisawa R, et al. Effect of motion imagery to counter rest-induced suppression of F-wave as a measure of anterior horn cell excitability. Clin Neurophysiol 2008;119:1346-1352.
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This study was not supported by any funding or sponsors. The authors do not have any financial disclosures.
17
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Figure legends Figure 1. Serial changes in F-wave amplitude (A) and persistence (B) in Parkinson disease patients with and without apraxia and in healthy subjects. Figure 2. Serial changes in amplitude (A) and latency (B) of motor-evoked potentials in Parkinson disease patients with and without apraxia and in healthy subjects.
18
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Table. 1. Clinical and demographic findings of all participants PD Apraxia (+) (n=8) Mean age (±SD, years) 62.7±13.4 Age range (years) 33–75 Gender (W/M) 3/5 Dominant hand (right/left) 8/0 Affected side at onset (right/left) 5/3 Symptoms at onset (tremor/bradykinesia) 6/2 PD type (A-R/Tr) 6/2 PD duration (years, mean±SD) 5.6±5.4 PD duration (years, range) 2-16 UPDRS motor score 13.8±7.3 (mean±SD) Hoehn-Yahr stage 1.9±0.3 (mean±SD) MMSE (mean±SD) 27.7±1.5
PD Apraxia (−) (n=11) 55.2±9.6 41–70 1/10 11/0
Control group
P
(n=8) 55.2±8.6 44–66 2/6 7/1
0.160 0.160 0.331 0.291
7/4
-
0.906
9/2 4/7
-
0.829 0.138
5.9±3.6 4-15 9.5±3.5
-
0.915 0.128
1.6±0.5
-
0.218
28.3±1.1
30
0.450
PD, Parkinson disease; SD, standard deviation; A-R, akinetic-rigid; Tr, tremor dominant; UPDRS, Unified Parkinson Disease Rating Scale; MMSE, mini-mental state examination.
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Table 2. Comparison of the onset latency and amplitude of MEP and F-waves and Fwave persistence recorded over the dominant extremity during rest, imagination, observation, and active movement among groups. PD PD Control group Apraxia (+) Apraxia (−) (n=8) (n=11) (n=8)
P
Rest
28.4±1.9
27.1±2.5
25.7±2.4
0.102
Imagination
27.8±1.0
27.2±1.9
26.5±2.6
0.676
Observation
27.8±0.9
26.8±1.6
26.0±2.6
0.422
Active movement
27.9±2.3
26.9±3.1
26.9±2.6
0.671
F latency (ms)
F amplitude (µV) Rest
611.2±479.9 397.5±133.4 288.4±133.4
0.247
Imagination
343.5±210.9 471.7±252.5 427.5±150.5
0.506
Observation
367.7±119.2 371.9±207.7 341.4±178.1
0.875
Active movement
449.1±288.3 925.0±430.4 676.2±178.0
0.032
Rest
82.9±22.3
76.7±20.6
75.7±19.0
0.746
Imagination
80.0±28.9
81.9±14.0
83.3±20.7
0.876
Observation
85.8±15.6
81.1±17.6
85.0±23.4
0.792
Active movement
76.7±27.3
90.0±15.5
94.6±8.7
0.576
Rest
23.9±1.1
21.9±0.7
23.3±1.6
0.028
Imagination
23.6±1.9
21.9±0.9
22.6±1.7
0.124
Observation
23.6±1.2
22.7±2.1
22.0±2.1
0.328
Active movement
22.6±1.8
21.6±1.4
21.1±1.6
0.241
Rest
2.7±1.7
1.9±1.8
2.5±2.1
0.804
Imagination
3.4±1.9
1.7±1.9
4.3±2.8
0.130
Observation
2.9±1.4
2.5±2.5
4.8±2.5
0.139
Active movement
4.5±1.9
4.6±2.1
6.3±2.7
0.311
F persistence (%)
MEP latency (ms)
MEP amplitude (mV)
PD; Parkinson disease; MEP, motor-evoked potential; ms, millisecond; µV, microvolt; mV, millivolt. Comparisons were performed among 3 groups, and P values were calculated using the Kruskal-Wallis test. The bold font values indicate significance at the level of
