- Email: [email protected]
The time course of the return of upper limb bradykinesia after cessation of subthalamic stimulation in Parkinson's disease
ARTICLE IN PRESS
Parkinsonism and Related Disorders 13 (2007) 438–442 www.elsevier.com/locate/parkreldis
Short communication
The time course of the return of upper limb bradykinesia after cessation of subthalamic stimulation in Parkinson’s disease Zoltan Keresztenyia,b,1, Peter Valkovicˇa,c,1, Thomas Eggerta, Ulrich Steuded, Joachim Hermsdo¨rfere, Jozsef Laczkob, Kai Bo¨tzela, a
Department of Neurology, Ludwig-Maximilians University, Munich, Germany b Department of Biomechanics, Semmelweis University, Budapest, Hungary c 2nd Department of Neurology, Comenius University, Bratislava, Slovakia d Department of Neurosurgery, Ludwig-Maximilians University, Munich, Germany e Clinical Neuropsychology Research Group, Hospital Mu¨nchen-Bogenhausen, Munich, Germany Received 22 March 2006; received in revised form 27 November 2006; accepted 10 December 2006
Abstract To investigate the time span within which bradykinesia re-occurs, we registered movement parameters immediately after the termination of deep brain stimulation of the subthalamic nucleus (STN) in nine Parkinson patients with chronically implanted bilateral STN electrodes. Two repetitive movements were investigated: finger-tapping and forearm pronation–supination. When stimulation was switched off, the amplitude and velocity of the investigated movements significantly declined, but the frequency did not. The time course of this decline was modeled by an exponential function that yielded time constants between 15 and 30 s. The effect of stimulation had completely disappeared within 1 min. These results suggest that it is necessary to wait at least for 1 min after the end of stimulation before performing further assessments. r 2007 Elsevier Ltd. All rights reserved. Keywords: Parkinson’s disease; Subthalamic stimulation; Bradykinesia
1. Introduction High-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for levodopa-responsive motor symptoms in advanced Parkinson’s disease (PD) [1]. To position the electrode during surgery, and to optimize stimulation parameters postoperatively, stimulation is frequently switched on and off. After switching the stimulator off, Parkinsonian symptoms usually recur within minutes and gradually worsen over 30 min, whereas clinical improvement after activating the stimulator takes less time [2]. Thus, it would be of considerable clinical relevance to determine the ‘‘immediate’’ effect of the termination of DBS on bradykinesia. Our study had three aims. First, to investigate two simple Corresponding author. Tel.: +49 89 70953673; fax: +49 89 70953677. 1
E-mail address: [email protected] (K. Bo¨tzel). Both authors contributed equally to this paper.
1353-8020/$ - see front matter r 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.parkreldis.2006.12.003
sequential movements, routinely used in the clinical assessment and also included in the unified PD rating scale (UPDRS) [3]: thumb-index tapping (TIT; item 23) and alternate forearm pronation–supination (PS; item 25). Second, the impact of physical fatigue (during continuous stimulation) on the performance in both tasks was determined. Third, because distal and more proximal muscles were differently engaged in both movements, we also investigated whether STN–DBS has a different effect on distal than on more proximal muscle groups. 2. Methods 2.1. Subjects Nine male patients with advanced-stage PD, a mean age of 61.3 years (range, 49–69), and mean duration of PD of 15.4 years (range, 10–20) took part. The subjects gave their written informed consent to participate in the study in agreement with the Declaration of Helsinki and the study was approved by the local ethics committee. Patients with tremor, which could
ARTICLE IN PRESS Z. Keresztenyi et al. / Parkinsonism and Related Disorders 13 (2007) 438–442 possibly influence the results of the tests, were not included. All had had bilateral STN-stimulating electrodes chronically implanted for an average of 16.7 months before assessment (range, 5–42). Implantation was performed using MRI-guided stereotaxy, microelectrode registration and macrostimulation [4]. Postoperative testing was during the week following the implantation and lasted for 4 days. A standardized protocol was used to assess several aspects of bradykinesia as well as rigidity and tremor at all electrodes and at increasing voltages. Then medication was reintroduced, as necessary. All patients had an enduring and clinically significant benefit from DBS (Table 1). To avoid any possible interference between medication and DBS, the patients were tested after their medication had been withdrawn for at least 12 h. The motor scores of the UPDRS were determined in the offmedication, on-stimulation setting immediately before the tests began. Thereafter, the stimulator ipsilateral to the tested arm was switched off, to rule out confounding effects of the stimulation of the not tested half of the body. Then approximately 15 min passed before the movement registration began. The UPDRS assessment was repeated in the off-stimulation state immediately after the first ‘‘stimulation-off’’ trial was completed (see below; Table 1).
2.2. Movement registration Movement registration was based on a method developed in a previous study with healthy adults [5]. Two alternating movements were studied: (1) TIT and (2) alternate forearm PS. Only the most severely affected arm was examined in this study. These movements were recorded using an ultrasonic device that continuously calculated the three-dimensional spatial positions of tiny markers (diameter height: 7 6 mm, weight: 1 g) attached by flexible cables to moving body parts (CMS 20S, Zebris, Isny, Germany). Two markers were used in each task, and their threedimensional coordinates were sampled with a frequency of 100 Hz each. The subject sat at a table in a comfortable position. During TIT, two markers were taped to the distal phalanxes of the thumb and index fingers and the forearm rested in a stationary position on the table. During alternate forearm PS, the elbow rested on the table and was flexed approximately 901. One marker was fixed to each end of a paperboard cylinder (length diameter: 21 4 cm, weight: 16 g), which was held by the subject. PS then appeared as a rotation of the line connecting the two markers. Subjects were instructed to perform the required movements as fast as possible and with the largest amplitude. The trials lasted 5 min and consisted of the repetition of a 4-s active movement with a pause of 6 s between the movement epochs. This design was chosen because continuous movement for several minutes was considered too exhausting for the subjects. The start and stop commands for each 4-s movement
439
epoch were presented on a computer screen in front of the subject together with a short acoustic signal at the beginning of each command; the reaction time was not taken into account. Before recording began, the examiner demonstrated the requested movement and subjects practiced for a few short trials.
2.3. Test sequence Four tests were always performed in the same sequence: TIT stim-off, TIT stim-on, PS stim-on, PS stim-off with pauses of 10–20 min between these trials. In stim-off trials, the stimulator was switched off exactly after the second 4-s movement epoch finished. This instance was denoted as T0. The receiver of the Medtronic N’Vision programmer had been fixed to the skin over the stimulator, and the experimenter operated this device without patient’s awareness.
2.4. Data analysis and statistics Data were analyzed off-line using software programmed in MATLABs (The MathWorks, Inc., Natick, MA). For the TIT movement, the distance between the two markers was calculated, and amplitude, frequency, and peak velocity of each individual movement were determined. These data were averaged for each 4-s movement epoch, and a value corresponding to the time elapsed between T0 and the middle of the movement epoch was assigned to them. For each 4-s movement epoch of the PS movement, the three-dimensional data were transformed so that the variance in the x–y plane of rotation was maximized and minimized in the z-dimension (main axis transformation after eigenvector-determination). By this procedure any tilt of the plane of the microphones and the movement plane was compensated for. Thereafter the angle between a line connecting the two markers and the horizontal was determined, and the angular amplitude, frequency, and peak velocity were calculated for each movement and averaged for each 4s movement cycle. The corresponding time value was assigned. The amplitude, peak velocity, and frequency of the second movement epoch were taken as the baseline (i.e., 100%) and all values were normalized. The normalized parameters were indicated by the abbreviations AMP, VEL, and FRE. To detect differences between the tests with and without stimulation, the mean and confidence intervals for all normalized parameters were computed and displayed. To analyze whether a systematic change over time occurred in any of the normalized parameters during the different conditions, they were analyzed using Friedman’s ANOVA for repeated measures (STATISTICA, StatSoft Inc., Tulsa, OK; po0.05). A significance below 0.05 indicated that a change over time occurred during this
Table 1 Clinical and deep brain stimulation characteristics of the patients Patient no.
1 2 3 4 5 6 7 8 9
Stimulation parameters Pulse width R/L (ms)
Rate R/L (Hz)
Amplitude R/L (V)
60/60 60/60 60/60 60/60 60/60 60/60 60/60 60/60 60/60
130/130 130/130 160/160 130/160 130/130 130/130 130/130 130/130 130/130
2.5/3.5 3.5/3.3 3.0/3.0 3.0/3.0 3.1/3.1 2.9/3.1 2.8/3.0 3.8/3.5 2.3/3.0
UPDRS ON/OFF
Side tested
Daily medication (mg)
22/50 34/67 33/50 26/53 23/39 26/57 31/46 28/51 37/56
R L R R L R L L R
L 400, AMA 200 L 300 L 600 L 400, PER 0.75 L 400 L 500 — L 500 L 300
R/L—right/left; L—levodopa; AMA—amantadine; PER—pergolide. UPDRS ON/OFF refers to the effect of stimulation only, since medication was withdrawn at least 12 h before the UPDRS assessment. UPDRS: unified Parkinson’s Disease Rating Scale.
ARTICLE IN PRESS Z. Keresztenyi et al. / Parkinsonism and Related Disorders 13 (2007) 438–442
Amp ¼ 100 DAmp expðt=tÞ. In the third step, to detect any significant influences of the factors ‘‘test’’ and ‘‘parameter’’ on D and t, one repeated measures ANOVA was computed for each (see Section 3). The significance levels in these repeated measures ANOVAs were computed using the so-called MANOVA approach to repeated measures, which is insensitive to potential violations of the ‘‘compound symmetry’’ or ‘‘sphericity’’ assumption of the ordinary repeated measures approach. The corresponding multivariate F-tests were based on Wilk’s lambda (l). Post-hoc comparisons were performed using the Scheffe´ test.
3. Results
140 120 100 80 60 40 20 0
0
50
100 150 200 250 Time [s]
Normalized Amplitude [%]
B
140 120 100 80 60 40 20 0
0
20
40 60 80 100 120 Time [s]
Normalized Amplitude [%]
Normalized Amplitude [%]
A
140
Normalized Amplitude [%]
The average UPDRS motor score increased from 28 to 52 (increase of 80%) after the DBS was switched off (Table 1; Wilcoxon test: po0.008). The analysis of the experimental outcome parameters revealed the following results. The curves of tests with and without stimulation significantly differed on the basis of non-overlapping confidence intervals for AMP and VEL, but not for FRE (Fig. 1). MANOVA revealed a significant change over time of AMP and VEL for all stim-off tests but also for PS stim-on. In contrast, FRE showed an inconclusive pattern: significant temporal changes were observed for PS stim-off as well as for TIT stim-on.
140
On the basis of these results, coefficients D and t were fitted for AMP, VEL, and FRE in the tests with significant temporal changes (Table 2). The decay of performance (D) was in the range of 60–80% for AMP and VEL values in the stim-off tests. The corresponding time constants in these tests were approx. 30 s for TIT and 15–18 s for PS tests (Table 2, Fig. 1). The two repeated measures ANOVAs, which were computed to define the effect that the two within-subjects factors test (TIT stim off/PS stim off/PS stim on) and parameter (AMP vs. VEL) had on the two coefficients (t, D) as dependent variables gave the following results. There was a main effect of test on D (l ¼ 0.298, F(2,7) ¼ 8.247; po0.02), showing that D was larger during PS stim-on than under TIT stim-off or PS stim-off (Scheffe´ test: po0.003). D only tended to be somewhat higher for VEL than for AMP but this effect was not significant. The repeated measures ANOVA of the dependent variable t only showed a marginally significant effect of the factor parameter (l ¼ 0.619, F(1,8) ¼ 4.927; po0.057). There was no significant main effect of the factor test (l ¼ 0.563, F(2,7) ¼ 2.720; po0.134). 4. Discussion Our findings demonstrate that the performance of repetitive upper limb movements deteriorates by 60–80% within a minute after switching the stimulator off. This decline can be modeled by an exponential decay function with time constants in the range of 15–30 s. Physical fatigue
120 100 80 60 40 20 0
0
50
100 150 200 250 Time [s]
120 100 80 60 40 20 0
0
20
40 60 80 100 120 Time [s]
Normalized Amplitude [%]
condition and in this case the data of individual patients were approximated by an exponential decay model, characterized by the time constant t and the percent decay (D). The constant D is the difference between the baseline and the asymptotic value of the exponential fit. The constant t is the time after which the exponential function has dropped to 36.8% of the difference between baseline and D. The fitted decay function for the normalized amplitude was
140
Normalized Amplitude [%]
440
140
120 100 80 60 40 20 0
0
50
100 150 200 250 Time [s]
0
20
40 60 80 100 120 Time [s]
120 100 80 60 40 20 0
Fig. 1. Group average time courses and confidence intervals of the means AMP (left column), VEL (middle column), and FRE (right column) during performance of thumb-index tapping (upper row A) and pronation–supination (lower row B). Solid line: stim-off trials; dashed line: stim-on. Different time scaling between A and B was used because of the inability of 6 of 9 patients to continue the performance of pro-sup movements for approx. 120 s after discontinuation of DBS. A clear difference between the performance in on and off trials is evident only for the parameters AMP and VEL, but not for FRE.
ARTICLE IN PRESS Z. Keresztenyi et al. / Parkinsonism and Related Disorders 13 (2007) 438–442
441
Table 2 Constants characterizing the decline in patient performance Amplitude
TIT stim-off TIT stim-on PS stim-off PS stim-on
Peak velocity
Frequency
D (%)
t (s)
Error
D (%)
t (s)
Error
D (%)
t (s)
Error
65.9718.5 / 68.5722.3 29.8728.6
32.0723.7 / 18.2724.6 114.37115.0
6.1 / 6.3 11.9
72.8715.2 / 80.178.5 31.0728.3
30.4722.2 / 15.2714.4 54.0754.6
5.6 / 5.8 12.1
/ 12.7714.2 45.9742.5 /
/ 69.87100.3 64.57100.5 /
/ 6.5 9.6 /
Constants D and t are given separately for each normalized parameter (AMP, VEL, FRE) after approximation by an exponential decay model for each curve with significant decay of the corresponding normalized parameter. t—time constant; ‘‘error’’ describes mean squared error between the experimental data and the model fit.
during stim-on trials resulted in a decay of about 30% and was significantly less than in the tests after the termination of stimulation. Of the parameters used for evaluation, we found that amplitude and velocity of repetitive movements are reliable values, whereas frequency is not. Frequency decays less and more slowly than the other two parameters. This is similar for lower limb movements in PD patients: stepping frequency may even increase in bradykinetic phases when stride length decreases [6]. The advantage of measuring movement frequency is that it is easy to determine in the clinical setting, whereas amplitude and velocity measurements require certain technical devices. This problem can be solved by using a task in which the distance (amplitude) between sequential movements is fixed; for example, the hand-tapping test can be assessed by a device with two manual counters or the finger-tapping test can use the keyboard of the computer. Such an approach showed excellent correlation with therapeutic interventions and was also feasible for follow-up studies [7]. It would be useful to develop recording devices that can determine amplitude and velocity of simple repetitive limb movements on-line. It is worth noting, however, that these results are valid only for the evaluation of patients after anti-Parkinson medication washout and cannot be generalized for patients on medication. Whereas our experiments focused on the decay of performance within the first minutes, others have investigated the performance over longer intervals. When the UPDRS motor score was assessed over 4 h following cancellation of STN–DBS, bradykinesia and rigidity showed a dramatic return during the first minutes [8]. However, UPDRS scores continued to worsen during the following hours. In another study, investigating the movement time in a reaction time task, the strongest increase also occurred within the first minutes, and a plateau was reached within 30 min [2]. Despite use of different methods, this indicates that several mechanisms with different time constants constitute the benefit of STN stimulation on motor parameters. One of these mechanisms may be a desinhibition of substantia nigra compacta neurons by STN stimulation, which then causes an increase of striatal
dopa metabolites during the following 40 min [9]. These long-term effects cannot be investigated during the implantation or during post-operative tests. In view of this situation our data suggest it is best to wait at least 1 min after the stimulator has been switched off before further assessments are made, when the short-term effect of stimulation can be safely assumed to have completely vanished. It should be noted that the tasks we used made unequal force demands and required the engagement of different muscles. PD patients normally tend to have more difficulty with impaired finger movements than with more proximal bradykinesia [10]. The literature disagrees as to which muscles are most affected by STN stimulation. In our present study the decay and time constants were not significantly different in the more proximal vs. the more distal task. This finding corresponds to our previous results, which showed that both a concomitant reaching and grasping task can be equally accelerated by the presence of DBS (in that case globus pallidus stimulation) when the object to be grasped is stationary [11]. In contrast, another study showed that more proximal arm movements rely more on the effect of STN–DBS than finger movements [12]. Further studies, which are directly addressing this aspect, will have to clarify this discrepancy. References [1] Deuschl G, Schade-Brittinger C, Krack P, Volkmann J, Schafer H, Bo¨tzel K, et al. A randomized trial of deep-brain stimulation for Parkinson’s disease. N Engl J Med 2006;355:896–908. [2] Lopiano L, Torre E, Benedetti F, Bergamasco B, Perozzo P, Pollo A, et al. Temporal changes in movement time during the switch of the stimulators in Parkinson’s disease patients treated by subthalamic nucleus stimulation. Eur Neurol 2003;50:94–9. [3] Fahn S, Elton RL. Committee MotUD: unified Parkinson’s Disease Rating Scale. In: Fahn S, Marsden CD, Calne D, Goldstein M, editors. Recent developments in Parkinson’s disease. Florham Park, NJ: MacMillan Health Care Information; 1987. p. 153–63. [4] Machado A, Rezai AR, Kopell BH, Gross RE, Sharan AD, Benabid AL. Deep brain stimulation for Parkinson’s disease: surgical technique and perioperative management. Mov Disord 2006; 21(Suppl. 14):S247–58.
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[5] Hermsdorfer J, Marquardt C, Wack S, Mai N. Comparative analysis of diadochokinetic movements. J Electromyogr Kinesiol 1999; 9:283–95. [6] Faist M, Xie J, Kurz D, Berger W, Maurer C, Pollak P, et al. Effect of bilateral subthalamic nucleus stimulation on gait in Parkinson’s disease. Brain 2001;124:1590–600. [7] Boraud T, Tison F, Gross C. Quantification of motor slowness in Parkinson’s disease: correlations between the tapping test and single joint ballistic movement parameters. Parkinsonism Relat Disord 1997;3:47–50. [8] Temperli P, Ghika J, Villemure JG, Burkhard PR, Bogousslavsky J, Vingerhoets FJ. How do Parkinsonian signs return after discontinuation of subthalamic DBS? Neurology 2003;60: 78–81.
[9] Meissner W, Paul G, Reum T, Reese R, Sohr R, Morgenstern R, et al. The influence of pallidal deep brain stimulation on striatal dopaminergic metabolism in the rat. Neurosci Lett 2000;296:149–52. [10] Agostino R, Berardelli A, Curra A, Accornero N, Manfredi M. Clinical impairment of sequential finger movements in Parkinson’s disease. Mov Disord 1998;13:418–21. [11] Schenk T, Baur B, Steude U, Bo¨tzel K. Effects of deep brain stimulation on prehensile movements in PD patients are less pronounced when external timing cues are provided. Neuropsychologia 2003;41:783–94. [12] Wenzelburger R, Kopper F, Zhang BR, Witt K, Hamel W, Weinert D, et al. Subthalamic nucleus stimulation for Parkinson’s disease preferentially improves akinesia of proximal arm movements compared to finger movements. Mov Disord 2003;18:1162–9.
Parkinsonism and Related Disorders 13 (2007) 438–442 www.elsevier.com/locate/parkreldis
Short communication
The time course of the return of upper limb bradykinesia after cessation of subthalamic stimulation in Parkinson’s disease Zoltan Keresztenyia,b,1, Peter Valkovicˇa,c,1, Thomas Eggerta, Ulrich Steuded, Joachim Hermsdo¨rfere, Jozsef Laczkob, Kai Bo¨tzela, a
Department of Neurology, Ludwig-Maximilians University, Munich, Germany b Department of Biomechanics, Semmelweis University, Budapest, Hungary c 2nd Department of Neurology, Comenius University, Bratislava, Slovakia d Department of Neurosurgery, Ludwig-Maximilians University, Munich, Germany e Clinical Neuropsychology Research Group, Hospital Mu¨nchen-Bogenhausen, Munich, Germany Received 22 March 2006; received in revised form 27 November 2006; accepted 10 December 2006
Abstract To investigate the time span within which bradykinesia re-occurs, we registered movement parameters immediately after the termination of deep brain stimulation of the subthalamic nucleus (STN) in nine Parkinson patients with chronically implanted bilateral STN electrodes. Two repetitive movements were investigated: finger-tapping and forearm pronation–supination. When stimulation was switched off, the amplitude and velocity of the investigated movements significantly declined, but the frequency did not. The time course of this decline was modeled by an exponential function that yielded time constants between 15 and 30 s. The effect of stimulation had completely disappeared within 1 min. These results suggest that it is necessary to wait at least for 1 min after the end of stimulation before performing further assessments. r 2007 Elsevier Ltd. All rights reserved. Keywords: Parkinson’s disease; Subthalamic stimulation; Bradykinesia
1. Introduction High-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for levodopa-responsive motor symptoms in advanced Parkinson’s disease (PD) [1]. To position the electrode during surgery, and to optimize stimulation parameters postoperatively, stimulation is frequently switched on and off. After switching the stimulator off, Parkinsonian symptoms usually recur within minutes and gradually worsen over 30 min, whereas clinical improvement after activating the stimulator takes less time [2]. Thus, it would be of considerable clinical relevance to determine the ‘‘immediate’’ effect of the termination of DBS on bradykinesia. Our study had three aims. First, to investigate two simple Corresponding author. Tel.: +49 89 70953673; fax: +49 89 70953677. 1
E-mail address: [email protected] (K. Bo¨tzel). Both authors contributed equally to this paper.
1353-8020/$ - see front matter r 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.parkreldis.2006.12.003
sequential movements, routinely used in the clinical assessment and also included in the unified PD rating scale (UPDRS) [3]: thumb-index tapping (TIT; item 23) and alternate forearm pronation–supination (PS; item 25). Second, the impact of physical fatigue (during continuous stimulation) on the performance in both tasks was determined. Third, because distal and more proximal muscles were differently engaged in both movements, we also investigated whether STN–DBS has a different effect on distal than on more proximal muscle groups. 2. Methods 2.1. Subjects Nine male patients with advanced-stage PD, a mean age of 61.3 years (range, 49–69), and mean duration of PD of 15.4 years (range, 10–20) took part. The subjects gave their written informed consent to participate in the study in agreement with the Declaration of Helsinki and the study was approved by the local ethics committee. Patients with tremor, which could
ARTICLE IN PRESS Z. Keresztenyi et al. / Parkinsonism and Related Disorders 13 (2007) 438–442 possibly influence the results of the tests, were not included. All had had bilateral STN-stimulating electrodes chronically implanted for an average of 16.7 months before assessment (range, 5–42). Implantation was performed using MRI-guided stereotaxy, microelectrode registration and macrostimulation [4]. Postoperative testing was during the week following the implantation and lasted for 4 days. A standardized protocol was used to assess several aspects of bradykinesia as well as rigidity and tremor at all electrodes and at increasing voltages. Then medication was reintroduced, as necessary. All patients had an enduring and clinically significant benefit from DBS (Table 1). To avoid any possible interference between medication and DBS, the patients were tested after their medication had been withdrawn for at least 12 h. The motor scores of the UPDRS were determined in the offmedication, on-stimulation setting immediately before the tests began. Thereafter, the stimulator ipsilateral to the tested arm was switched off, to rule out confounding effects of the stimulation of the not tested half of the body. Then approximately 15 min passed before the movement registration began. The UPDRS assessment was repeated in the off-stimulation state immediately after the first ‘‘stimulation-off’’ trial was completed (see below; Table 1).
2.2. Movement registration Movement registration was based on a method developed in a previous study with healthy adults [5]. Two alternating movements were studied: (1) TIT and (2) alternate forearm PS. Only the most severely affected arm was examined in this study. These movements were recorded using an ultrasonic device that continuously calculated the three-dimensional spatial positions of tiny markers (diameter height: 7 6 mm, weight: 1 g) attached by flexible cables to moving body parts (CMS 20S, Zebris, Isny, Germany). Two markers were used in each task, and their threedimensional coordinates were sampled with a frequency of 100 Hz each. The subject sat at a table in a comfortable position. During TIT, two markers were taped to the distal phalanxes of the thumb and index fingers and the forearm rested in a stationary position on the table. During alternate forearm PS, the elbow rested on the table and was flexed approximately 901. One marker was fixed to each end of a paperboard cylinder (length diameter: 21 4 cm, weight: 16 g), which was held by the subject. PS then appeared as a rotation of the line connecting the two markers. Subjects were instructed to perform the required movements as fast as possible and with the largest amplitude. The trials lasted 5 min and consisted of the repetition of a 4-s active movement with a pause of 6 s between the movement epochs. This design was chosen because continuous movement for several minutes was considered too exhausting for the subjects. The start and stop commands for each 4-s movement
439
epoch were presented on a computer screen in front of the subject together with a short acoustic signal at the beginning of each command; the reaction time was not taken into account. Before recording began, the examiner demonstrated the requested movement and subjects practiced for a few short trials.
2.3. Test sequence Four tests were always performed in the same sequence: TIT stim-off, TIT stim-on, PS stim-on, PS stim-off with pauses of 10–20 min between these trials. In stim-off trials, the stimulator was switched off exactly after the second 4-s movement epoch finished. This instance was denoted as T0. The receiver of the Medtronic N’Vision programmer had been fixed to the skin over the stimulator, and the experimenter operated this device without patient’s awareness.
2.4. Data analysis and statistics Data were analyzed off-line using software programmed in MATLABs (The MathWorks, Inc., Natick, MA). For the TIT movement, the distance between the two markers was calculated, and amplitude, frequency, and peak velocity of each individual movement were determined. These data were averaged for each 4-s movement epoch, and a value corresponding to the time elapsed between T0 and the middle of the movement epoch was assigned to them. For each 4-s movement epoch of the PS movement, the three-dimensional data were transformed so that the variance in the x–y plane of rotation was maximized and minimized in the z-dimension (main axis transformation after eigenvector-determination). By this procedure any tilt of the plane of the microphones and the movement plane was compensated for. Thereafter the angle between a line connecting the two markers and the horizontal was determined, and the angular amplitude, frequency, and peak velocity were calculated for each movement and averaged for each 4s movement cycle. The corresponding time value was assigned. The amplitude, peak velocity, and frequency of the second movement epoch were taken as the baseline (i.e., 100%) and all values were normalized. The normalized parameters were indicated by the abbreviations AMP, VEL, and FRE. To detect differences between the tests with and without stimulation, the mean and confidence intervals for all normalized parameters were computed and displayed. To analyze whether a systematic change over time occurred in any of the normalized parameters during the different conditions, they were analyzed using Friedman’s ANOVA for repeated measures (STATISTICA, StatSoft Inc., Tulsa, OK; po0.05). A significance below 0.05 indicated that a change over time occurred during this
Table 1 Clinical and deep brain stimulation characteristics of the patients Patient no.
1 2 3 4 5 6 7 8 9
Stimulation parameters Pulse width R/L (ms)
Rate R/L (Hz)
Amplitude R/L (V)
60/60 60/60 60/60 60/60 60/60 60/60 60/60 60/60 60/60
130/130 130/130 160/160 130/160 130/130 130/130 130/130 130/130 130/130
2.5/3.5 3.5/3.3 3.0/3.0 3.0/3.0 3.1/3.1 2.9/3.1 2.8/3.0 3.8/3.5 2.3/3.0
UPDRS ON/OFF
Side tested
Daily medication (mg)
22/50 34/67 33/50 26/53 23/39 26/57 31/46 28/51 37/56
R L R R L R L L R
L 400, AMA 200 L 300 L 600 L 400, PER 0.75 L 400 L 500 — L 500 L 300
R/L—right/left; L—levodopa; AMA—amantadine; PER—pergolide. UPDRS ON/OFF refers to the effect of stimulation only, since medication was withdrawn at least 12 h before the UPDRS assessment. UPDRS: unified Parkinson’s Disease Rating Scale.
ARTICLE IN PRESS Z. Keresztenyi et al. / Parkinsonism and Related Disorders 13 (2007) 438–442
Amp ¼ 100 DAmp expðt=tÞ. In the third step, to detect any significant influences of the factors ‘‘test’’ and ‘‘parameter’’ on D and t, one repeated measures ANOVA was computed for each (see Section 3). The significance levels in these repeated measures ANOVAs were computed using the so-called MANOVA approach to repeated measures, which is insensitive to potential violations of the ‘‘compound symmetry’’ or ‘‘sphericity’’ assumption of the ordinary repeated measures approach. The corresponding multivariate F-tests were based on Wilk’s lambda (l). Post-hoc comparisons were performed using the Scheffe´ test.
3. Results
140 120 100 80 60 40 20 0
0
50
100 150 200 250 Time [s]
Normalized Amplitude [%]
B
140 120 100 80 60 40 20 0
0
20
40 60 80 100 120 Time [s]
Normalized Amplitude [%]
Normalized Amplitude [%]
A
140
Normalized Amplitude [%]
The average UPDRS motor score increased from 28 to 52 (increase of 80%) after the DBS was switched off (Table 1; Wilcoxon test: po0.008). The analysis of the experimental outcome parameters revealed the following results. The curves of tests with and without stimulation significantly differed on the basis of non-overlapping confidence intervals for AMP and VEL, but not for FRE (Fig. 1). MANOVA revealed a significant change over time of AMP and VEL for all stim-off tests but also for PS stim-on. In contrast, FRE showed an inconclusive pattern: significant temporal changes were observed for PS stim-off as well as for TIT stim-on.
140
On the basis of these results, coefficients D and t were fitted for AMP, VEL, and FRE in the tests with significant temporal changes (Table 2). The decay of performance (D) was in the range of 60–80% for AMP and VEL values in the stim-off tests. The corresponding time constants in these tests were approx. 30 s for TIT and 15–18 s for PS tests (Table 2, Fig. 1). The two repeated measures ANOVAs, which were computed to define the effect that the two within-subjects factors test (TIT stim off/PS stim off/PS stim on) and parameter (AMP vs. VEL) had on the two coefficients (t, D) as dependent variables gave the following results. There was a main effect of test on D (l ¼ 0.298, F(2,7) ¼ 8.247; po0.02), showing that D was larger during PS stim-on than under TIT stim-off or PS stim-off (Scheffe´ test: po0.003). D only tended to be somewhat higher for VEL than for AMP but this effect was not significant. The repeated measures ANOVA of the dependent variable t only showed a marginally significant effect of the factor parameter (l ¼ 0.619, F(1,8) ¼ 4.927; po0.057). There was no significant main effect of the factor test (l ¼ 0.563, F(2,7) ¼ 2.720; po0.134). 4. Discussion Our findings demonstrate that the performance of repetitive upper limb movements deteriorates by 60–80% within a minute after switching the stimulator off. This decline can be modeled by an exponential decay function with time constants in the range of 15–30 s. Physical fatigue
120 100 80 60 40 20 0
0
50
100 150 200 250 Time [s]
120 100 80 60 40 20 0
0
20
40 60 80 100 120 Time [s]
Normalized Amplitude [%]
condition and in this case the data of individual patients were approximated by an exponential decay model, characterized by the time constant t and the percent decay (D). The constant D is the difference between the baseline and the asymptotic value of the exponential fit. The constant t is the time after which the exponential function has dropped to 36.8% of the difference between baseline and D. The fitted decay function for the normalized amplitude was
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440
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0
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0
20
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Fig. 1. Group average time courses and confidence intervals of the means AMP (left column), VEL (middle column), and FRE (right column) during performance of thumb-index tapping (upper row A) and pronation–supination (lower row B). Solid line: stim-off trials; dashed line: stim-on. Different time scaling between A and B was used because of the inability of 6 of 9 patients to continue the performance of pro-sup movements for approx. 120 s after discontinuation of DBS. A clear difference between the performance in on and off trials is evident only for the parameters AMP and VEL, but not for FRE.
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Table 2 Constants characterizing the decline in patient performance Amplitude
TIT stim-off TIT stim-on PS stim-off PS stim-on
Peak velocity
Frequency
D (%)
t (s)
Error
D (%)
t (s)
Error
D (%)
t (s)
Error
65.9718.5 / 68.5722.3 29.8728.6
32.0723.7 / 18.2724.6 114.37115.0
6.1 / 6.3 11.9
72.8715.2 / 80.178.5 31.0728.3
30.4722.2 / 15.2714.4 54.0754.6
5.6 / 5.8 12.1
/ 12.7714.2 45.9742.5 /
/ 69.87100.3 64.57100.5 /
/ 6.5 9.6 /
Constants D and t are given separately for each normalized parameter (AMP, VEL, FRE) after approximation by an exponential decay model for each curve with significant decay of the corresponding normalized parameter. t—time constant; ‘‘error’’ describes mean squared error between the experimental data and the model fit.
during stim-on trials resulted in a decay of about 30% and was significantly less than in the tests after the termination of stimulation. Of the parameters used for evaluation, we found that amplitude and velocity of repetitive movements are reliable values, whereas frequency is not. Frequency decays less and more slowly than the other two parameters. This is similar for lower limb movements in PD patients: stepping frequency may even increase in bradykinetic phases when stride length decreases [6]. The advantage of measuring movement frequency is that it is easy to determine in the clinical setting, whereas amplitude and velocity measurements require certain technical devices. This problem can be solved by using a task in which the distance (amplitude) between sequential movements is fixed; for example, the hand-tapping test can be assessed by a device with two manual counters or the finger-tapping test can use the keyboard of the computer. Such an approach showed excellent correlation with therapeutic interventions and was also feasible for follow-up studies [7]. It would be useful to develop recording devices that can determine amplitude and velocity of simple repetitive limb movements on-line. It is worth noting, however, that these results are valid only for the evaluation of patients after anti-Parkinson medication washout and cannot be generalized for patients on medication. Whereas our experiments focused on the decay of performance within the first minutes, others have investigated the performance over longer intervals. When the UPDRS motor score was assessed over 4 h following cancellation of STN–DBS, bradykinesia and rigidity showed a dramatic return during the first minutes [8]. However, UPDRS scores continued to worsen during the following hours. In another study, investigating the movement time in a reaction time task, the strongest increase also occurred within the first minutes, and a plateau was reached within 30 min [2]. Despite use of different methods, this indicates that several mechanisms with different time constants constitute the benefit of STN stimulation on motor parameters. One of these mechanisms may be a desinhibition of substantia nigra compacta neurons by STN stimulation, which then causes an increase of striatal
dopa metabolites during the following 40 min [9]. These long-term effects cannot be investigated during the implantation or during post-operative tests. In view of this situation our data suggest it is best to wait at least 1 min after the stimulator has been switched off before further assessments are made, when the short-term effect of stimulation can be safely assumed to have completely vanished. It should be noted that the tasks we used made unequal force demands and required the engagement of different muscles. PD patients normally tend to have more difficulty with impaired finger movements than with more proximal bradykinesia [10]. The literature disagrees as to which muscles are most affected by STN stimulation. In our present study the decay and time constants were not significantly different in the more proximal vs. the more distal task. This finding corresponds to our previous results, which showed that both a concomitant reaching and grasping task can be equally accelerated by the presence of DBS (in that case globus pallidus stimulation) when the object to be grasped is stationary [11]. In contrast, another study showed that more proximal arm movements rely more on the effect of STN–DBS than finger movements [12]. Further studies, which are directly addressing this aspect, will have to clarify this discrepancy. References [1] Deuschl G, Schade-Brittinger C, Krack P, Volkmann J, Schafer H, Bo¨tzel K, et al. A randomized trial of deep-brain stimulation for Parkinson’s disease. N Engl J Med 2006;355:896–908. [2] Lopiano L, Torre E, Benedetti F, Bergamasco B, Perozzo P, Pollo A, et al. Temporal changes in movement time during the switch of the stimulators in Parkinson’s disease patients treated by subthalamic nucleus stimulation. Eur Neurol 2003;50:94–9. [3] Fahn S, Elton RL. Committee MotUD: unified Parkinson’s Disease Rating Scale. In: Fahn S, Marsden CD, Calne D, Goldstein M, editors. Recent developments in Parkinson’s disease. Florham Park, NJ: MacMillan Health Care Information; 1987. p. 153–63. [4] Machado A, Rezai AR, Kopell BH, Gross RE, Sharan AD, Benabid AL. Deep brain stimulation for Parkinson’s disease: surgical technique and perioperative management. Mov Disord 2006; 21(Suppl. 14):S247–58.
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