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Neither simple nor sequential arm movements are bradykinetic in parkinsonian patients with peak-dose dyskinesias
Clinical Neurophysiology 116 (2005) 2077–2082 www.elsevier.com/locate/clinph
Neither simple nor sequential arm movements are bradykinetic in parkinsonian patients with peak-dose dyskinesias R. Agostino, S. Bagnato, L. Dinapoli, N. Modugno, A. Berardelli* Department of Neurological Sciences and Istituto Neurologico Mediterraneo Neuromed IRCCS, Pozzilli (IS), University of Rome ‘La Sapienza’, Italy
See Editorial, pages 1997–1998
Abstract Objective: To find out whether parkinsonian patients with levodopa-induced peak-dose dyskinesias are bradykinetic. Methods: The performance of a sequential internally determined arm movement and a simple externally triggered arm movement was studied in a group of dyskinetic parkinsonian patients during their best clinical condition and when they were OFF treatment. Patients’ performance was compared with that of an age-matched control group. Movements in the three-dimensional space were recorded by the ELITE motion analysis system. Kinematic variables analysed for the sequential motor task were total movement duration and total pause duration; for the simple motor task, movement duration and reaction time; and for both tasks, movement inaccuracy. Results: When patients were OFF therapy they performed sequential and simple movement tasks slower than healthy subjects whereas when they were dyskinetic they did not. During the sequential task, when the patients were dyskinetic total pause duration shortened and movement inaccuracy increased. Conclusions: Our kinematic finding indicates that parkinsonian patients’ with peak-dose dyskinesias are not bradykinetic. Significance: Parkinsonian patients with peak-dose dyskinesias are not bradykinetic, probably because dopamine at peak doses functionally normalizes the mechanisms controlling movement speed. q 2005 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Parkinson’s disease; Dyskinesias; Bradykinesia; Voluntary movement; Motor system
1. Introduction Bradykinesia (slowness of movement) is one of the cardinal signs of Parkinson’s disease. Neurophysiological studies show that bradykinesia is present during the performance of simple, single-joint rapid movements, but becomes more pronounced during complex, simultaneous or sequential motor acts and when movements are internally determined rather than externally triggered (Berardelli et al., 2001). Although patients ON antiparkinsonian therapy perform simple and complex arm movements faster than
* Corresponding author. Address: Dipartimento Scienze Neurologiche, Viale dell’Universita` 30, 00185 Roma, Italia. Tel.: C39 06 49914700; fax: C39 06 49914302. E-mail address: [email protected] (A. Berardelli).
patients OFF therapy they do so more slowly than normal subjects (Benecke et al., 1987a; Berardelli et al., 1986). The abnormal involuntary movements typically seen in patients with Parkinson’s disease under long-term treatment, levodopa-induced dyskinesias, can be differentiated by their onset time after levodopa intake (Berardelli and Curra`, 2003; Fahn, 2000; Hagell and Widner, 1999). Dyskinesias commonly appear when the clinical benefit peaks (peak-dose dyskinesia) but they can become manifest when the clinical benefit begins, or both when it begins and ends (Fahn, 2000). Although the onset of peak-dose dyskinesia coincides with a clinically apparent reduction in bradykinesia, to our knowledge, only one study has tried to quantify the effect of dopaminergic drugs on movement slowness in Parkinson’s disease with peak-dose dyskinesia (Caligiuri and Peterson, 1993). These investigators studied only simple movements
1388-2457/$30.00 q 2005 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2005.04.027
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R. Agostino et al. / Clinical Neurophysiology 116 (2005) 2077–2082
and found that dyskinetic patients were faster than OFF therapy patients. Yet because the study did not compare patients’ performance with that of normal subjects it provided no information on whether the movements in dyskinetic patients were normal or still bradykinetic. Nor does it give information on the performance of sequential internally determined movements in patients experiencing peak-dose dyskinesia. This question is not only of interest because bradykinesia worsens more during the execution of complex movements than during simple movements (Benecke et al., 1987b; Berardelli et al., 2001) but also because dopaminergic therapy improves movement speed more during complex than during simple motor tasks (Benecke et al., 1987a). In this study we investigated whether and to what extent parkinsonian patients experiencing peak-dose dyskinesias are bradykinetic. To study bradykinesia we assessed changes in kinematic variables during two motor tasks, sequential internally determined and simple externally triggered arm movements, in parkinsonian patients ON therapy experiencing dyskinesias, the same patients OFF dopaminergic therapy, and age-matched healthy subjects.
2. Methods 2.1. Subjects A total of 10 parkinsonian patients (mean age G1 SD 66. 6G8.3 years; 5 men and 5 women) and 8 healthy subjects (mean age 63.4G9.1 years; 4 men and 4 women) gave their informed consent to the study. The patients (Table 1) were studied on two different days: during the two experimental
sessions they were either OFF-therapy (‘OFF patients’) or on their usual daily medication regimen and experiencing hyperkinetic involuntary movements (dyskinetic patients). To be included in the study the patients had to be in the ON state and to have had dyskinesias for at least 45 min. When patients were tested OFF therapy, oral medications were stopped al least 12 h before the experimental session, while apomorphine subcutaneous infusion (Patients 4, 5, 7, 9 and 10 in the Table 1) was stopped 2 h before. Patients ON therapy experiencing dyskinesia were studied during their best clinical conditions, as judged by an expert neurologist. To score the patients’ clinical conditions we used the motor examination section of the UPDRS and the non defined Clinical Dyskinesia Rating Scale (CDRS) (Hagell and Widner, 1999). The motor examination section of the UPDRS comprised 14 items scored following a 5-grade severity code (0Zno abnormality; 4Zworst abnormality), and giving a maximal total score of 56. The non defined CDRS scored the dyskinesia observed in the face (including the tongue), neck, trunk, and right and left upper and lower limbs following a 5-grade severity code (0Zno dyskinesia; 4Zextreme dyskinesia), and giving a maximal total score of 28. Total CDRS scores ranged from 5 to 13 suggesting that all patients had mild-to-moderate dyskinesias (Table 1). Dyskinesia in the dominant arm was mild in 5 patients and moderate in the remaining 5. When studied no patients showed overt signs of depression or dementia. 2.2. Apparatus Movements in three-dimensional space were recorded by the ELITE motion analysis system. Two infrared ray cameras (100 Hz sampling rate) recorded the motion of a
Table 1 Patients’ clinical data Patient no.
Sex
Age (yr)
Disease duration (yr)
UPDRS-III OFF
UPDRS-III ON
CDRS
1
M
72
8
17
9
5
2
F
74
20
28
17
13
3 4
F F
73 47
30 12
30 23
21 9
7 5
5
M
64
14
24
8
13
6
M
59
8
23
8
8
7
F
73
12
28
13
5
8 9
F M
67 69
13 12
28 25
9 8
6 8
10
M
68
12
36
25
10
Medication Levodopa-benserazide selegiline pramipexole Levodopa-carbidopa levodopabenserazide methyl-levodopa pergolide cabergoline Levodopa-benserazide selegiline Apomorphine levodopa-carbidopa methyl-levodopa cabergoline Apomorphine levodopa-carbidopa cabergoline Levodopa-carbidopa methyl-levodopa pramipexole cabergoline Apomorphine levodopa-carbidopa methyl-levodopa cabergoline Levodopa-carbidopa pramipexole Apomorphine levodopa-carbidopa levodopa-benserazide Apomorphine levodopa-carbidopa
UPDRS-III refers to the motor examination score of the Unified Parkinson’s Disease Rating Scale. CDRS refers to the non defined Clinical Dyskinesia Rating Scale. Clinical conditions were rated immediately before patients did the motor task.
R. Agostino et al. / Clinical Neurophysiology 116 (2005) 2077–2082
passive marker placed on the distal phalanx of the second finger of the moving hand. A real-time TV imageconverting processor connected to the cameras digitalized the analog data and reconstructed the x, y, and z coordinated of the marker motion. Kinematic parameters were obtained from the mathematical arrangement of spatial coordinates and displayed in graphic form. 2.3. Tasks We studied the performance of two motor tasks, both executed in the free space. The sequential task consisted of an internally determined visually guided motor sequence comprising 5 steps. This task has been detailed elsewhere (Curra` et al., 1997). In brief, the subjects sat comfortably in front of a screen. For each subject, the position of the chair was adjusted to allow the index finger of the dominant hand to come close to the screen, without touching it. The subjects followed with their dominant arm a zig–zig vertical path marked by 6 targets (30 mm sided blank square; distance between the centre of two successive targets 28 cm) displayed on the screen. They were instructed to move at their will as fast as possible stopping anywhere inside the targets as briefly as possible. The simple task consisted of an externally triggered single vertical upward movement. Two blank targets similar to those for the sequential task were displayed on a screen and constituted the beginning and the end of the movement. The subjects sat comfortably on a chair and pointed with the index finger of their dominant arm at the initial target displayed on the screen. The initial target then became white and the subjects were instructed to keep pointing and to start moving immediately after the final target became white too, moving as fast as possible. The subjects were also told to stop anywhere inside the final target. To avoid a possible anticipation of the movement, during each trial the time elapsing after the two targets changed colour varied. For both tasks, the subjects first practiced the movements (5–10 trials) then 10 trials were recorded. Subjects rested for 30–45 s between each trial, and for 4–5 min between each task. In both groups, half of the subjects started the experiment by performing the sequential task, and the remaining half by performing the simple task. Tasks were presented in similar order when the patients were tested OFF therapy and when they were dyskinetic. 2.4. Analysis of kinematic variables Variables were measured off-line. Elite software plotted the displacement, velocity profiles of each movement and, for the simple task, a vertical line signalling the time when the targets changed colour. For the sequential task we first measured the duration of each step. Criteria for movement duration have been detailed elsewhere (Curra` et al., 1997). In brief, we used an arbitrary value of 50 mm per second as a threshold for hand motion. The start of each movement was
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taken when the velocity reached and stayed over 50 mm per second. The end of the movement was taken when the velocity fell below this value. The movement durations of the 5 sequential steps were summed to compute the total movement duration. We also measured the total pause duration, defined as the sum of the time elapsing between the end of one sequential step and the beginning of the next. For the simple task movement, duration was measured using the foregoing criteria. We also measured the reaction time, defined as the time elapsing after the final target changed colour and the hand movement began. Finally, for each step of the sequential task and the single stroke of the simple task we measured the spatial accuracy, i.e. we evaluated whether each movement ended inside the home target (accurate movements) or outside (inaccurate movements). The movements were considered accurate when the movement endpoint and the centre of the target were no more than 15 mm apart. We computed an inaccuracy index by dividing the total number of the accuracy errors in a block by the number of the trials measured in that block. The index ranged from 0 to 5 for the sequential task and from 0 to 1 for the simple task. Higher indexes indicated poorer performance. 2.5. Statistical analysis For the studied variables each data point was the average of the trials performed in each block. All data are expressed as meanG1 SE. Because the aim of the paper was to see whether dyskinetic patients were bradykinetic a one-way analysis of variance (ANOVA) was used to compare each variable between normal subjects, patients OFF therapy and the same patients when they were dyskinetic. When appropriate, Tukey’s honest significant difference (HSD) test was used for post hoc analysis. To analyse dopaminergic-induced changes in kinematic variables in greater detail, Student’s paired t-test was used to compare data for each variable in patients under the two conditions, OFF therapy and ON therapy with dyskinesias. Finally, we used Spearman rank correlation test to determine the correlation of movement variables (for the sequential task: total movement duration, total pause duration and inaccuracy index; for the simple task: movement duration, reaction time and inaccuracy index) with the severity of dyskinesias (total score of CDRS and the score of dyskinesias in the right arm). For each movement variable we also computed the difference between the data point during the dyskinetic state and that of the OFF state. We then determined the possible correlation between these differences and the severity of dyskinesias.
3. Results After a short period of practice, healthy subjects, and patients OFF therapy or dyskinetic were able to perform sequential and simple tasks proficiently, as judged clinically by the experimenters. In all 3 groups off-line visual inspection
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showed that arm displacement was roughly straight and velocity profiles for each movement were bell-shaped. 3.1. Comparison between healthy subjects and parkinsonian patients 3.1.1. Sequential task Total movement time differed between groups (F2,25Z6. 18; P!0.007) (Fig. 1). Post hoc analysis indicated that patients studied OFF therapy were slower than healthy subjects (P!0.02) and slower OFF therapy than when dyskinetic (P!0.01), while healthy subjects and dyskinetic patients had similar total movement duration. Total pause duration was similar in the 3 groups. Conversely, the inaccuracy index tended to differ (F2,25Z2.62; P!0.09). 3.1.2. Simple task Movement duration differed between groups (F2,25Z7. 62; P!0.003) (Fig. 2). Post hoc analysis indicated that
Fig. 2. Movement duration (panel A), reaction time (panel B) and movement inaccuracy (panel C) in control subjects, patients OFF therapy and the same patients ON therapy and dyskinetic, performing a simple externally triggered motor task. S means seconds.
patients OFF therapy were slower than normal subjects (P! 0.002) and tended to be slower when OFF therapy than when dyskinetic (P!0.07). By contrast, normal subjects and dyskinetic patients had similar movement duration. Reaction times tended to differ between groups (F2,25Z 2.91; P!0.07), whereas the inaccuracy index did not. 3.2. Comparison between patients who were dyskinetic and the same patients OFF therapy
Fig. 1. Total movement duration (panel A), total pause duration (panel B) and movement inaccuracy (panel C) in control subjects, patients OFF therapy, and the same patients ON therapy and dyskinetic, performing a sequential internally determined motor task. S means seconds.
3.2.1. Sequential task Total movement time and total pause duration were shorter when patients were dyskinetic than when they were OFF therapy (P!0.00002 and P!0.006). Again, patients were more inaccurate when dyskinetic than when OFF therapy (P!0.03).
R. Agostino et al. / Clinical Neurophysiology 116 (2005) 2077–2082
3.2.2. Simple task Movement duration was shorter when patients were dyskinetic than when OFF therapy (P!0.0001) whereas reaction times and accuracy were similar under both conditions. 3.3. Correlation between the severity of dyskinesia and movement variables for sequential and simple tasks No significant correlation was found between any movement variable in the sequential or simple tasks and the severity of dyskinesias.
4. Discussion When patients were OFF therapy they were bradykinetic whereas while ON therapy and experiencing peak-dose dyskinesias they were not. They lacked the bradykinesia typical of parkinsonian disease in both motor tasks we studied: the sequential internally determined and the simple, externally triggered arm movement. In the sequential motor task, not only did movement duration shorten but in patients with experiencing dyskinesias pause duration shortened and movement inaccuracy increased. Our finding that the improvement in movement speed and the presence of peak-dose dyskinesia were coincident in time suggests that these two phenomena share, at least in part, similar mechanisms. At the biochemical level, peak-dose dyskinesias probably appear when dopaminergic drugs overactivate the dopamine receptors in the striatum, especially the putamen (Fahn, 2000; Nutt, 2000). On the basis of neurophysiological data, Wichmann and DeLong (1996) have suggested that dyskinesias originate from reduced firing in the globus pallidus (internal segment) (GPi), which reduces thalamic inhibition thereby increasing excitatory thalamo-cortical drive. Apart from the quantitatively abnormal firing rates in the basal ganglia motor circuitry, the appearance of dyskinesias also reflects changes in the pattern, synchronization and somatosensory responsiveness of neural signalling in the pallidum and subthalamic nuclei (Obeso et al., 2000). Dyskinesias could therefore originate from an increased and qualitatively abnormal excitatory thalamo-cortical drive (Berardelli and Curra`, 2003; Obeso et al., 2000; Wichmann and DeLong, 1996). Accordingly, an imaging study in parkinsonian patients with peak-dose dyskinesias, performing a sequential finger-tothumb opposition movement (Rascol et al., 1998) showed in dyskinetic patients, but not in control subjects or medicated non dyskinetic parkinsonian patients, an excessive activation of the supplementary motor and sensorimotor primary areas—both areas belonging to the basal ganglia motor circuit (Wichmann and DeLong, 1996). The human sensorimotor primary area, together with basal ganglia and cerebellum, form part of the motor subcircuits, whose activation correlates with the speed of movement (Turner
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et al., 1998; 2003). Two other imaging studies have also observed velocity-related activation in the supplementary motor area (Blinkenberg et al., 1996; Van Meter et al., 1995). Although all these observations might singly or concurrently explain why we found that dyskinetic patients were not bradykinetic, our kinematic findings prompt further research. A mechanism we favour is that the increased firing accompanying the thalamo-cortical drive is related to the normal speed of voluntary movements whereas the quality of firing patterns is related to dyskinesia (Hallett, 2000). This conclusion is supported by the lack of correlation between the dyskinesia score and the movement variables in the sequential and simple tasks tested in this study. In performing the sequential task, patients were more inaccurate when they were dyskinetic than when they were OFF therapy. Some might argue that our data reflect a ‘speed-accuracy trade off’ (Fitts, 1954). Our finding that despite decreased movement duration in the simple task, accuracy failed to worsen nevertheless suggests that other factors played a role. For example, when moving at a normal speed, our dyskinetic patients possibly found sequential movements more difficult to perform than simple, single arm movements. This explanation accords with evidence that a group of non dyskinetic parkinsonian patients performing a sequence of reaching movements were faster and more inaccurate when ON treatment than when OFF treatment (Feigin et al., 2002). During the performance of the simple externally-triggered task, since movement extent and direction were fully specified before the go signal, we investigated the so-called simple reaction time. The comparison between patients OFF therapy and the same patients ON therapy and experiencing dyskinesias showed a similar simple reaction time under both conditions. This observation agrees with previous data demonstrating no changes in the simple reaction time in non dyskinetic parkinsonian patients OFF and ON therapy (Jahanshahi et al., 1992; Pulman et al., 1988). Hence movement initiation, as measured by the simple reaction time, is probably not a dopamine-dependent brain process. In conclusion, in this study, we show that during the performance of sequential and simple arm movements parkinsonian patients with peak-dose dyskinesia are not bradykinetic. In Parkinson’s disease, the presence of peakdose dyskinesia implies that the dopaminergic treatment functionally normalises the neural processes underlying movement speed.
References Benecke R, Rothwell JC, Dick JP, Day BL, Marsden CD. Simple and complex movements off and on treatment in patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry 1987a;50:296–303. Benecke R, Rothwell JC, Dick JP, Day BL, Marsden CD. Disturbance of sequential movements in patients with Parkinson’s disease. Brain 1987b;110:361–79.
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Berardelli A, Curra` A. Choreas, hemiballismus, dyskinesias, athetosis. In: Hallett M, editor. Handbook of clinical neurophysiology, vol. 1. Amsterdam: Elsevier; 2003. p. 571–82. Berardelli A, Dick JP, Rothwell JC, Day BL, Marsden CD. Scaling of the first agonist EMG burst during rapid wrist movements in patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry 1986;49:1273–9. Berardelli A, Rothwell JC, Thompson PD, Hallett M. Pathophysiology of bradykinesia in Parkinson’s disease. Brain 2001;124:2131–46. Blinkenberg M, Bonde C, Holm S, Svarer C, Andersen J, Paulson OB, et al. Rate dependence of regional cerebral activation during performance of a repetitive motor task: a PET study. J Cereb Blood Flow Metab 1996; 16:794–803. Caligiuri MP, Peterson S. A quantitative study of levodopa-induced dyskinesia in Parkinson’s disease. J Neural Trasm 1993;6:89–98. Curra` A, Berardelli B, Agostino R, Conti-Puerger, Manfredi M. Performance of sequential arm movements with and without advance knowledge of motor pathways in Parkinson’s disease. Mov Disord 1997;12:646–54. Fahn S. The spectrum of levodopa-induced dyskinesias. Ann Neurol 2000; 47(Suppl. 1):S2–S11. Feigin A, Ghilardi MF, Fukuda M, Mentis MJ, Dhawan V, Barnes A, Ghez CP, Eidelberg D. Effects of levodopa infusion on motor activation responses in Parkinson’s disease. Neurology 2002;59:220–6. Fitts PM. The information capacity of the human motor system in controlling the amplitude of the movement. J Exp Psychol 1954;47: 381–91. Jahanshahi M, Brown RG, Marsden CD. The effect of withdrawal of dopaminergic medication on simple and choice reaction time and the use of advance information in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1992;55:1168–76.
Hagell P, Widner H. Clinical rating of dyskinesias in Parkinson’s disease: use and reliability of a new rating scale. Mov Disord 1999; 14:448–55. Hallett M. Clinical physiology of dopa dyskinesia. Ann Neurol 2000; 47(Suppl. 1):S147–S50. Nutt JG. Clinical pharmacology of levodopa-induced dyskinesia. Ann Neurol 2000;47(Suppl. 1):S160–S6. Obeso JA, Rodriguez-Oroz MC, Rodriguez M, DeLong MR, Olanow CW. Pathophysiology of levodopa-induced dyskinesias in Parkinson’s disease: problems with the current model. Ann Neurol 2000; 47(Suppl. 1):S22–S32. Pulman SL, Watts RL, Juncos JL, Chase TN, Sanes JN. Dopaminergic effects on simple and choice reaction time performance in Parkinson’s disease. Neurology 1988;38:249–54. Rascol O, Sabatini U, Brefel C, Fabre N, Rai S, Senard JM, Celsis P, Viallard G, Montastruc JL, Chollet F. Cortical motor overactivation in parkinsonian patients with L-dopa-induced peak-dose dyskinesia. Brain 1998;121:527–33. Turner RS, Grafton ST, Votaw JR, DeLong MR, Hoffman JM. Motor subcircuits mediating the control of movement velocity: a PET study. J Neurophysiol 1998;80:2162–76. Turner RS, Desmurget M, Grethe J, Crutcher MD, Grafton ST. Motor subcircuits mediating the control of movement extent and speed. J Neurophysiol 2003;90:3958–66. Van Meter JW, Maisog JM, Zeffiro TA, Hallett M, Herscovitch P, Rapoport SI. Parametric analysis of functional neuroimages: application to a variable-rate motor task. Neuroimage 1995;2:273–83. Wichmann T, DeLong MR. Functional and pathophysiological models of the basal ganglia. Curr Opin Neurobiol 1996;6:751–8.
Neither simple nor sequential arm movements are bradykinetic in parkinsonian patients with peak-dose dyskinesias R. Agostino, S. Bagnato, L. Dinapoli, N. Modugno, A. Berardelli* Department of Neurological Sciences and Istituto Neurologico Mediterraneo Neuromed IRCCS, Pozzilli (IS), University of Rome ‘La Sapienza’, Italy
See Editorial, pages 1997–1998
Abstract Objective: To find out whether parkinsonian patients with levodopa-induced peak-dose dyskinesias are bradykinetic. Methods: The performance of a sequential internally determined arm movement and a simple externally triggered arm movement was studied in a group of dyskinetic parkinsonian patients during their best clinical condition and when they were OFF treatment. Patients’ performance was compared with that of an age-matched control group. Movements in the three-dimensional space were recorded by the ELITE motion analysis system. Kinematic variables analysed for the sequential motor task were total movement duration and total pause duration; for the simple motor task, movement duration and reaction time; and for both tasks, movement inaccuracy. Results: When patients were OFF therapy they performed sequential and simple movement tasks slower than healthy subjects whereas when they were dyskinetic they did not. During the sequential task, when the patients were dyskinetic total pause duration shortened and movement inaccuracy increased. Conclusions: Our kinematic finding indicates that parkinsonian patients’ with peak-dose dyskinesias are not bradykinetic. Significance: Parkinsonian patients with peak-dose dyskinesias are not bradykinetic, probably because dopamine at peak doses functionally normalizes the mechanisms controlling movement speed. q 2005 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Parkinson’s disease; Dyskinesias; Bradykinesia; Voluntary movement; Motor system
1. Introduction Bradykinesia (slowness of movement) is one of the cardinal signs of Parkinson’s disease. Neurophysiological studies show that bradykinesia is present during the performance of simple, single-joint rapid movements, but becomes more pronounced during complex, simultaneous or sequential motor acts and when movements are internally determined rather than externally triggered (Berardelli et al., 2001). Although patients ON antiparkinsonian therapy perform simple and complex arm movements faster than
* Corresponding author. Address: Dipartimento Scienze Neurologiche, Viale dell’Universita` 30, 00185 Roma, Italia. Tel.: C39 06 49914700; fax: C39 06 49914302. E-mail address: [email protected] (A. Berardelli).
patients OFF therapy they do so more slowly than normal subjects (Benecke et al., 1987a; Berardelli et al., 1986). The abnormal involuntary movements typically seen in patients with Parkinson’s disease under long-term treatment, levodopa-induced dyskinesias, can be differentiated by their onset time after levodopa intake (Berardelli and Curra`, 2003; Fahn, 2000; Hagell and Widner, 1999). Dyskinesias commonly appear when the clinical benefit peaks (peak-dose dyskinesia) but they can become manifest when the clinical benefit begins, or both when it begins and ends (Fahn, 2000). Although the onset of peak-dose dyskinesia coincides with a clinically apparent reduction in bradykinesia, to our knowledge, only one study has tried to quantify the effect of dopaminergic drugs on movement slowness in Parkinson’s disease with peak-dose dyskinesia (Caligiuri and Peterson, 1993). These investigators studied only simple movements
1388-2457/$30.00 q 2005 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2005.04.027
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R. Agostino et al. / Clinical Neurophysiology 116 (2005) 2077–2082
and found that dyskinetic patients were faster than OFF therapy patients. Yet because the study did not compare patients’ performance with that of normal subjects it provided no information on whether the movements in dyskinetic patients were normal or still bradykinetic. Nor does it give information on the performance of sequential internally determined movements in patients experiencing peak-dose dyskinesia. This question is not only of interest because bradykinesia worsens more during the execution of complex movements than during simple movements (Benecke et al., 1987b; Berardelli et al., 2001) but also because dopaminergic therapy improves movement speed more during complex than during simple motor tasks (Benecke et al., 1987a). In this study we investigated whether and to what extent parkinsonian patients experiencing peak-dose dyskinesias are bradykinetic. To study bradykinesia we assessed changes in kinematic variables during two motor tasks, sequential internally determined and simple externally triggered arm movements, in parkinsonian patients ON therapy experiencing dyskinesias, the same patients OFF dopaminergic therapy, and age-matched healthy subjects.
2. Methods 2.1. Subjects A total of 10 parkinsonian patients (mean age G1 SD 66. 6G8.3 years; 5 men and 5 women) and 8 healthy subjects (mean age 63.4G9.1 years; 4 men and 4 women) gave their informed consent to the study. The patients (Table 1) were studied on two different days: during the two experimental
sessions they were either OFF-therapy (‘OFF patients’) or on their usual daily medication regimen and experiencing hyperkinetic involuntary movements (dyskinetic patients). To be included in the study the patients had to be in the ON state and to have had dyskinesias for at least 45 min. When patients were tested OFF therapy, oral medications were stopped al least 12 h before the experimental session, while apomorphine subcutaneous infusion (Patients 4, 5, 7, 9 and 10 in the Table 1) was stopped 2 h before. Patients ON therapy experiencing dyskinesia were studied during their best clinical conditions, as judged by an expert neurologist. To score the patients’ clinical conditions we used the motor examination section of the UPDRS and the non defined Clinical Dyskinesia Rating Scale (CDRS) (Hagell and Widner, 1999). The motor examination section of the UPDRS comprised 14 items scored following a 5-grade severity code (0Zno abnormality; 4Zworst abnormality), and giving a maximal total score of 56. The non defined CDRS scored the dyskinesia observed in the face (including the tongue), neck, trunk, and right and left upper and lower limbs following a 5-grade severity code (0Zno dyskinesia; 4Zextreme dyskinesia), and giving a maximal total score of 28. Total CDRS scores ranged from 5 to 13 suggesting that all patients had mild-to-moderate dyskinesias (Table 1). Dyskinesia in the dominant arm was mild in 5 patients and moderate in the remaining 5. When studied no patients showed overt signs of depression or dementia. 2.2. Apparatus Movements in three-dimensional space were recorded by the ELITE motion analysis system. Two infrared ray cameras (100 Hz sampling rate) recorded the motion of a
Table 1 Patients’ clinical data Patient no.
Sex
Age (yr)
Disease duration (yr)
UPDRS-III OFF
UPDRS-III ON
CDRS
1
M
72
8
17
9
5
2
F
74
20
28
17
13
3 4
F F
73 47
30 12
30 23
21 9
7 5
5
M
64
14
24
8
13
6
M
59
8
23
8
8
7
F
73
12
28
13
5
8 9
F M
67 69
13 12
28 25
9 8
6 8
10
M
68
12
36
25
10
Medication Levodopa-benserazide selegiline pramipexole Levodopa-carbidopa levodopabenserazide methyl-levodopa pergolide cabergoline Levodopa-benserazide selegiline Apomorphine levodopa-carbidopa methyl-levodopa cabergoline Apomorphine levodopa-carbidopa cabergoline Levodopa-carbidopa methyl-levodopa pramipexole cabergoline Apomorphine levodopa-carbidopa methyl-levodopa cabergoline Levodopa-carbidopa pramipexole Apomorphine levodopa-carbidopa levodopa-benserazide Apomorphine levodopa-carbidopa
UPDRS-III refers to the motor examination score of the Unified Parkinson’s Disease Rating Scale. CDRS refers to the non defined Clinical Dyskinesia Rating Scale. Clinical conditions were rated immediately before patients did the motor task.
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passive marker placed on the distal phalanx of the second finger of the moving hand. A real-time TV imageconverting processor connected to the cameras digitalized the analog data and reconstructed the x, y, and z coordinated of the marker motion. Kinematic parameters were obtained from the mathematical arrangement of spatial coordinates and displayed in graphic form. 2.3. Tasks We studied the performance of two motor tasks, both executed in the free space. The sequential task consisted of an internally determined visually guided motor sequence comprising 5 steps. This task has been detailed elsewhere (Curra` et al., 1997). In brief, the subjects sat comfortably in front of a screen. For each subject, the position of the chair was adjusted to allow the index finger of the dominant hand to come close to the screen, without touching it. The subjects followed with their dominant arm a zig–zig vertical path marked by 6 targets (30 mm sided blank square; distance between the centre of two successive targets 28 cm) displayed on the screen. They were instructed to move at their will as fast as possible stopping anywhere inside the targets as briefly as possible. The simple task consisted of an externally triggered single vertical upward movement. Two blank targets similar to those for the sequential task were displayed on a screen and constituted the beginning and the end of the movement. The subjects sat comfortably on a chair and pointed with the index finger of their dominant arm at the initial target displayed on the screen. The initial target then became white and the subjects were instructed to keep pointing and to start moving immediately after the final target became white too, moving as fast as possible. The subjects were also told to stop anywhere inside the final target. To avoid a possible anticipation of the movement, during each trial the time elapsing after the two targets changed colour varied. For both tasks, the subjects first practiced the movements (5–10 trials) then 10 trials were recorded. Subjects rested for 30–45 s between each trial, and for 4–5 min between each task. In both groups, half of the subjects started the experiment by performing the sequential task, and the remaining half by performing the simple task. Tasks were presented in similar order when the patients were tested OFF therapy and when they were dyskinetic. 2.4. Analysis of kinematic variables Variables were measured off-line. Elite software plotted the displacement, velocity profiles of each movement and, for the simple task, a vertical line signalling the time when the targets changed colour. For the sequential task we first measured the duration of each step. Criteria for movement duration have been detailed elsewhere (Curra` et al., 1997). In brief, we used an arbitrary value of 50 mm per second as a threshold for hand motion. The start of each movement was
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taken when the velocity reached and stayed over 50 mm per second. The end of the movement was taken when the velocity fell below this value. The movement durations of the 5 sequential steps were summed to compute the total movement duration. We also measured the total pause duration, defined as the sum of the time elapsing between the end of one sequential step and the beginning of the next. For the simple task movement, duration was measured using the foregoing criteria. We also measured the reaction time, defined as the time elapsing after the final target changed colour and the hand movement began. Finally, for each step of the sequential task and the single stroke of the simple task we measured the spatial accuracy, i.e. we evaluated whether each movement ended inside the home target (accurate movements) or outside (inaccurate movements). The movements were considered accurate when the movement endpoint and the centre of the target were no more than 15 mm apart. We computed an inaccuracy index by dividing the total number of the accuracy errors in a block by the number of the trials measured in that block. The index ranged from 0 to 5 for the sequential task and from 0 to 1 for the simple task. Higher indexes indicated poorer performance. 2.5. Statistical analysis For the studied variables each data point was the average of the trials performed in each block. All data are expressed as meanG1 SE. Because the aim of the paper was to see whether dyskinetic patients were bradykinetic a one-way analysis of variance (ANOVA) was used to compare each variable between normal subjects, patients OFF therapy and the same patients when they were dyskinetic. When appropriate, Tukey’s honest significant difference (HSD) test was used for post hoc analysis. To analyse dopaminergic-induced changes in kinematic variables in greater detail, Student’s paired t-test was used to compare data for each variable in patients under the two conditions, OFF therapy and ON therapy with dyskinesias. Finally, we used Spearman rank correlation test to determine the correlation of movement variables (for the sequential task: total movement duration, total pause duration and inaccuracy index; for the simple task: movement duration, reaction time and inaccuracy index) with the severity of dyskinesias (total score of CDRS and the score of dyskinesias in the right arm). For each movement variable we also computed the difference between the data point during the dyskinetic state and that of the OFF state. We then determined the possible correlation between these differences and the severity of dyskinesias.
3. Results After a short period of practice, healthy subjects, and patients OFF therapy or dyskinetic were able to perform sequential and simple tasks proficiently, as judged clinically by the experimenters. In all 3 groups off-line visual inspection
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showed that arm displacement was roughly straight and velocity profiles for each movement were bell-shaped. 3.1. Comparison between healthy subjects and parkinsonian patients 3.1.1. Sequential task Total movement time differed between groups (F2,25Z6. 18; P!0.007) (Fig. 1). Post hoc analysis indicated that patients studied OFF therapy were slower than healthy subjects (P!0.02) and slower OFF therapy than when dyskinetic (P!0.01), while healthy subjects and dyskinetic patients had similar total movement duration. Total pause duration was similar in the 3 groups. Conversely, the inaccuracy index tended to differ (F2,25Z2.62; P!0.09). 3.1.2. Simple task Movement duration differed between groups (F2,25Z7. 62; P!0.003) (Fig. 2). Post hoc analysis indicated that
Fig. 2. Movement duration (panel A), reaction time (panel B) and movement inaccuracy (panel C) in control subjects, patients OFF therapy and the same patients ON therapy and dyskinetic, performing a simple externally triggered motor task. S means seconds.
patients OFF therapy were slower than normal subjects (P! 0.002) and tended to be slower when OFF therapy than when dyskinetic (P!0.07). By contrast, normal subjects and dyskinetic patients had similar movement duration. Reaction times tended to differ between groups (F2,25Z 2.91; P!0.07), whereas the inaccuracy index did not. 3.2. Comparison between patients who were dyskinetic and the same patients OFF therapy
Fig. 1. Total movement duration (panel A), total pause duration (panel B) and movement inaccuracy (panel C) in control subjects, patients OFF therapy, and the same patients ON therapy and dyskinetic, performing a sequential internally determined motor task. S means seconds.
3.2.1. Sequential task Total movement time and total pause duration were shorter when patients were dyskinetic than when they were OFF therapy (P!0.00002 and P!0.006). Again, patients were more inaccurate when dyskinetic than when OFF therapy (P!0.03).
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3.2.2. Simple task Movement duration was shorter when patients were dyskinetic than when OFF therapy (P!0.0001) whereas reaction times and accuracy were similar under both conditions. 3.3. Correlation between the severity of dyskinesia and movement variables for sequential and simple tasks No significant correlation was found between any movement variable in the sequential or simple tasks and the severity of dyskinesias.
4. Discussion When patients were OFF therapy they were bradykinetic whereas while ON therapy and experiencing peak-dose dyskinesias they were not. They lacked the bradykinesia typical of parkinsonian disease in both motor tasks we studied: the sequential internally determined and the simple, externally triggered arm movement. In the sequential motor task, not only did movement duration shorten but in patients with experiencing dyskinesias pause duration shortened and movement inaccuracy increased. Our finding that the improvement in movement speed and the presence of peak-dose dyskinesia were coincident in time suggests that these two phenomena share, at least in part, similar mechanisms. At the biochemical level, peak-dose dyskinesias probably appear when dopaminergic drugs overactivate the dopamine receptors in the striatum, especially the putamen (Fahn, 2000; Nutt, 2000). On the basis of neurophysiological data, Wichmann and DeLong (1996) have suggested that dyskinesias originate from reduced firing in the globus pallidus (internal segment) (GPi), which reduces thalamic inhibition thereby increasing excitatory thalamo-cortical drive. Apart from the quantitatively abnormal firing rates in the basal ganglia motor circuitry, the appearance of dyskinesias also reflects changes in the pattern, synchronization and somatosensory responsiveness of neural signalling in the pallidum and subthalamic nuclei (Obeso et al., 2000). Dyskinesias could therefore originate from an increased and qualitatively abnormal excitatory thalamo-cortical drive (Berardelli and Curra`, 2003; Obeso et al., 2000; Wichmann and DeLong, 1996). Accordingly, an imaging study in parkinsonian patients with peak-dose dyskinesias, performing a sequential finger-tothumb opposition movement (Rascol et al., 1998) showed in dyskinetic patients, but not in control subjects or medicated non dyskinetic parkinsonian patients, an excessive activation of the supplementary motor and sensorimotor primary areas—both areas belonging to the basal ganglia motor circuit (Wichmann and DeLong, 1996). The human sensorimotor primary area, together with basal ganglia and cerebellum, form part of the motor subcircuits, whose activation correlates with the speed of movement (Turner
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et al., 1998; 2003). Two other imaging studies have also observed velocity-related activation in the supplementary motor area (Blinkenberg et al., 1996; Van Meter et al., 1995). Although all these observations might singly or concurrently explain why we found that dyskinetic patients were not bradykinetic, our kinematic findings prompt further research. A mechanism we favour is that the increased firing accompanying the thalamo-cortical drive is related to the normal speed of voluntary movements whereas the quality of firing patterns is related to dyskinesia (Hallett, 2000). This conclusion is supported by the lack of correlation between the dyskinesia score and the movement variables in the sequential and simple tasks tested in this study. In performing the sequential task, patients were more inaccurate when they were dyskinetic than when they were OFF therapy. Some might argue that our data reflect a ‘speed-accuracy trade off’ (Fitts, 1954). Our finding that despite decreased movement duration in the simple task, accuracy failed to worsen nevertheless suggests that other factors played a role. For example, when moving at a normal speed, our dyskinetic patients possibly found sequential movements more difficult to perform than simple, single arm movements. This explanation accords with evidence that a group of non dyskinetic parkinsonian patients performing a sequence of reaching movements were faster and more inaccurate when ON treatment than when OFF treatment (Feigin et al., 2002). During the performance of the simple externally-triggered task, since movement extent and direction were fully specified before the go signal, we investigated the so-called simple reaction time. The comparison between patients OFF therapy and the same patients ON therapy and experiencing dyskinesias showed a similar simple reaction time under both conditions. This observation agrees with previous data demonstrating no changes in the simple reaction time in non dyskinetic parkinsonian patients OFF and ON therapy (Jahanshahi et al., 1992; Pulman et al., 1988). Hence movement initiation, as measured by the simple reaction time, is probably not a dopamine-dependent brain process. In conclusion, in this study, we show that during the performance of sequential and simple arm movements parkinsonian patients with peak-dose dyskinesia are not bradykinetic. In Parkinson’s disease, the presence of peakdose dyskinesia implies that the dopaminergic treatment functionally normalises the neural processes underlying movement speed.
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