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Modulation of tremor amplitude during deep brain stimulation at different frequencies
Brain and Cognition 53 (2003) 190–192 www.elsevier.com/locate/b&c
Modulation of tremor amplitude during deep brain stimulation at different frequencies Anne Beuter and Michele S. Titcombe Centre de Neuroscience de la Cognition, Universit e du Qu ebec a Montr eal, Canada Centre for Nonlinear Dynamics in Physiology and Medicine, McGill University, Montreal, Que., Canada Accepted 7 May 2003
Abstract Rest tremor was quantified in the index finger tip of 16 patients with ParkinsonÕs disease (PD) receiving deep brain stimulation (DBS) of the ventro-intermediate nucleus (Vim) of the thalamus, the subthalamic nucleus (STN), or the internal part of the globus pallidus (GPi) while being off L -dopa for 12 h. Clinically, without DBS, tremor amplitude varied from absent to high. Tremor was recorded continuously for about 5 min under three conditions of DBS repeated twice, namely, effective frequency (E), ineffective frequency (I), and no DBS (O). No changes in tremor were observed across conditions in subjects with little or no tremor. However, in subjects with moderate to large amplitude tremor, DBS decreased tremor amplitude to near normal values within a few seconds. Generally, transitions were progressive and occurred with a varying time delay. Occasionally, tremor escaped from control regardless of the stimulation condition considered. In some cases tremor amplitude in one condition appeared to depend on the preceding condition. Finally, the results were reproducible on two consecutive days. We conclude that tremor control with DBS follows specific dynamical rules, which must be compatible with the hypotheses proposed regarding the underlying mechanisms of DBS. Ó 2003 Elsevier Inc. All rights reserved.
1. Introduction A growing number of patients with ParkinsonÕs disease (PD) receive chronic bilateral deep brain stimulation (DBS) of subcortical structures to attenuate symptoms such as tremor, rigidity, or dyskinesia. The attenuation of symptoms is now well documented (Limousin-Dowsey et al., 1999) and the clinical effects are equivalent to lesions (Benabid et al., 1991; The Deep Brain Stimulation for ParkinsonÕs Disease Study Group, 2001). However, the physiological mechanisms underlying the action of DBS still remain unknown and are the focus of intense research efforts (Benazzouz & Hallett, 2000). In this short paper we examined the qualitative changes occurring in tremor amplitude while stimulation frequency was manipulated. It is now well known that stimulation frequency must be higher than 100 Hz for symptoms to be attenuated or suppressed. Thus tremor amplitude recorded continuously at the periphery while stimulation frequency is above or below 100 Hz reflects the effect of central stimulation on the 0278-2626/$ - see front matter Ó 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0278-2626(03)00107-6
neural network controlling tremor. Particular attention was paid to tremor amplitude during the transitions between stimulating conditions. These observations should be useful not only in the development or improvement of theoretical models attempting to explain the mechanisms of action of DBS in patients with PD (Titcombe, Glass, Guehl, & Beuter, 2001) but also in the development of future prospects of brain stimulation (Benabid et al., 2000).
2. Methods Sixteen subjects with PD receiving chronic uni- or bilateral stimulation for the relief of tremor, dyskinesia, or rigidity were tested while being off medication for 12 h. They were under 70 years of age and included 11 males and 5 females receiving stimulation of the GPi, the STN, or the Vim. All participants were clinically stable at the moment of the tests and were right handed except for one of them. In the sequence recorded
A. Beuter, M.S. Titcombe / Brain and Cognition 53 (2003) 190–192
(i.e., EOEIOI), ‘‘E’’ means effective frequency (between 135 and 185 Hz), ‘‘O’’ means no stimulation, and ‘‘I’’ means ineffective stimulation (effective stimulation divided by 2 or 3). Rest tremor was recorded continuously for about 5 min with each condition lasting 45–50 s and being repeated twice. Thus each test lasted about 270 s. Rest tremor was recorded with a safe (Class II) velocity-transducing helium–neon laser (Norman, Edwards, & Beuter, 1999) from Bruel and Kjaer (Naerum, Denmark). Finger tremor was detected and converted into a calibrated voltage output proportional to finger velocity. Each tremor test was preceded by a clinical examination using part III, item 20, of the UPDRS (Fahn & Elton, 1987). Data were collected using the MacLab data acquisition system (V 3.5.6/S, AD Instruments, Castle Hill, Australia), sampled at 100 Hz, and filtered (median filter).
3. Results In subjects with little or no clinical signs of tremor on the UPDRS, DBS appeared to have very little effect, if any. The signal looked qualitatively similar during the entire sequence recorded (EOEIOI) (not shown). The tremor of these participants looked like normal physiological tremor. It was irregular (i.e., noisy) and had little fluctuation in its amplitude. We now consider the results obtained with subjects having a large amplitude tremor on the UPDRS. Under effective stimulation (E). In subjects with large amplitude tremor DBS decreased tremor amplitude drastically (Figs. 1a–c). The effect was visible within a
Fig. 1. Data recorded in three participants illustrating the transitions occurring during the sequence (i.e., EOEIOI). See text for explanations and details. (a) Subject with DBS of the GPi; (b) subject with DBS of the STN; (c) subject with DBS of the Vim. In (c) the sequence presented corresponds to EOE only. Note that the recording started after a minimum of 5 min of continuous DBS.
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couple seconds (Figs. 1a–c). Tremor amplitude was reduced to near normal values. Bursts of tremor escaping control were noted during this condition (Fig. 1c). There was no obvious difference between the first ‘‘effective’’ and the second ‘‘effective’’ conditions (i.e., the two ‘‘E’’ in Fig. 1). Under no stimulation (O). Regular oscillations tended to grow back with a delay varying between 1 and 10 s (Figs. 1a–c). The growth of the oscillation was progressive (Fig. 1b), rapid (Fig. 1c), or delayed and rapid (Fig. 1a). In Fig. 1b, both ‘‘off’’ conditions were very similar and the transitions were progressive. In Fig. 1a, tremor amplitude fluctuated during the second ‘‘off’’ condition and the transition was not clearly defined. Under the ineffective condition (I). Under this condition, tremor amplitude appeared to depend on the preceding condition. In Fig. 1a, for example, the first ‘‘ineffective’’ condition followed an ‘‘effective’’ episode and was characterized by a long delay without tremor and a return of the oscillation after about 20–25 s. The second ‘‘ineffective’’ condition followed an ‘‘off’’ condition and tremor remained minimal for the entire period (about 45 s). In Fig. 1b, the situation was different. The first ‘‘ineffective’’ condition could not be distinguished from the preceding condition (i.e., the ‘‘effective’’ condition), while the second ‘‘ineffective’’ condition was characterized by a progressive decay of the oscillation following an ‘‘off’’ condition. As was suggested above for the ‘‘ineffective’’ condition, the order of the conditions appeared to be important. However, as shown in Fig. 2, the mean values for identical conditions (i.e., ‘‘E’’ and ‘‘E’’ or ‘‘I’’ and ‘‘I’’) does not appear to be significantly different when the dispersion of the results is considered.
Fig. 2. Summary of the fluctuations in amplitude for 9 trials and 6 subjects with high amplitude tremor (above). Means for the percentage of maximal amplitude with standard deviations for each condition of the sequence (below).
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A. Beuter, M.S. Titcombe / Brain and Cognition 53 (2003) 190–192
4. Discussion Subjects with no clinical signs of tremor and receiving DBS for other PD symptoms (mainly for dyskinesia or rigidity) had a tremor, which looked like physiological tremor. In fact DBS seems to have no effect on tremor when its amplitude is within normal values (Beuter, Titcombe, Richer, Gross, & Guehl, 2001). This suggests that either the network controlling tremor is not sensitive to DBS when tremor has a small amplitude, or that the effect cannot be detected despite the precision of the recording instrument used. Tremor can escape from its control mechanisms during ‘‘effective’’ conditions and fluctuate during ‘‘off’’ conditions. This is probably not a consequence of DBS itself but rather a sign of the disease, as bursts of tremor have been reported before in patients with PD (Beuter & Vasilakos, 1995). Given the small number of subjects, the variety of targets stimulated and the difference in the adjustment of the stimulation parameters (Beuter et al., 2001), it is difficult to draw definite conclusions regarding the modulation of amplitude by DBS. However, the results have been reproduced on consecutive days and can be considered as reliable. Furthermore, these results could not have been obtained with the clinical rating scales that are typically used by clinicians to evaluate their patients. The progressive nature of the transitions and the presence of a varying time delay in the growth or decay of tremor oscillations have been explored recently from a theoretical perspective (Titcombe et al., 2001). However, the tendency for tremor amplitude to escape from its control mechanisms regardless of the stimulation condition considered must now be considered in further models of tremor control. The same thing can be said about the fact that tremor amplitude in one condition appeared to depend on the preceding condition. Fundamental questions concerning the dynamics of tremor abound (see Glass, 2001 for more general examples about rhythmic processes in physiology). For example, what is the origin of physiological tremor? How do physiological and pathological tremors interact with each other and with peripheral influences? By exploring fluctuations and escape during tremor control by DBS
in greater details we hope to be able to develop better methods to control tremor in PD.
Acknowledgments The authors wish to thank all the participants and Dr. Dominique Guehl who performed the clinical examinations. The first author received support from NSERC (Canada) and FCAR (Quebec).
References Benabid, A. L., Pollak, P., Gervason, C., Hoffmann, D., Gao, D. M., Hommel, M., Perret, J. E., & de Rougemont, J. (1991). Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. The Lancet, 337, 403–406. Benabid, A. L., Koudsie, A., Pollak, P., Kahane, P., Chabardes, S., Hirsch, E., Marescaux, C., & Benazzouz, A. (2000). Future prospects of brain stimulation. Neurological Research, 22, 237–246. Benazzouz, A., & Hallett, M. (2000). Mechanism of action of deep brain stimulation. Neurology, 55(6), s13–s16. Beuter, A., Titcombe, M., Richer, F., Gross, C., & Guehl, D. (2001). Effect of deep brain stimulation on amplitude and frequency characteristics of rest tremor in ParkinsonÕs disease. Thalamus and Related Systems, 1, 203–211. Beuter, A., & Vasilakos, K. (1995). Fluctuations in tremor and respiration in patients with ParkinsonÕs disease. Parkinsonism and Related Disorders, 1(2), 103–111. Fahn, S., & Elton, R. L. (1987). Unified ParkinsonÕs disease rating scale. In S. Fahn, C. D. Marsden, D. B. Calne, & Goldstein (Eds.), Recent developments in ParkinsonÕs disease (pp. 153–164). Florham Park, New Jersey: Macmillan Health Care. Glass, L. (2001). Synchronization and rhythmic processes in physiology. Nature, 410, 277–284. Limousin-Dowsey, P., Pollak, P., Van Blercom, N., Krack, P., Benazzouz, A., & Benabid, A. L. (1999). Thalamic, subthalamic nucleus and internal pallidum stimulation in ParkinsonÕs disease. Journal of Neurology, 246(14), 542–545. Norman, K. E., Edwards, R., & Beuter, A. (1999). The measurement of tremor using a velocity transducer: Comparison to simultaneous recordings using transducers of displacement, acceleration and muscle activity. Journal of Neuroscience Methods, 92, 41–54. The Deep-Brain Stimulation for ParkinsonÕs Disease Study Group (2001). Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in ParkinsonÕs disease. The New England Journal of Medicine 345(13), 956–963. Titcombe, M., Glass, L., Guehl, D., & Beuter, A. (2001). Dynamics of Parkinsonian tremor during deep brain stimulation. Chaos, 11(4), 766–773.
Modulation of tremor amplitude during deep brain stimulation at different frequencies Anne Beuter and Michele S. Titcombe Centre de Neuroscience de la Cognition, Universit e du Qu ebec a Montr eal, Canada Centre for Nonlinear Dynamics in Physiology and Medicine, McGill University, Montreal, Que., Canada Accepted 7 May 2003
Abstract Rest tremor was quantified in the index finger tip of 16 patients with ParkinsonÕs disease (PD) receiving deep brain stimulation (DBS) of the ventro-intermediate nucleus (Vim) of the thalamus, the subthalamic nucleus (STN), or the internal part of the globus pallidus (GPi) while being off L -dopa for 12 h. Clinically, without DBS, tremor amplitude varied from absent to high. Tremor was recorded continuously for about 5 min under three conditions of DBS repeated twice, namely, effective frequency (E), ineffective frequency (I), and no DBS (O). No changes in tremor were observed across conditions in subjects with little or no tremor. However, in subjects with moderate to large amplitude tremor, DBS decreased tremor amplitude to near normal values within a few seconds. Generally, transitions were progressive and occurred with a varying time delay. Occasionally, tremor escaped from control regardless of the stimulation condition considered. In some cases tremor amplitude in one condition appeared to depend on the preceding condition. Finally, the results were reproducible on two consecutive days. We conclude that tremor control with DBS follows specific dynamical rules, which must be compatible with the hypotheses proposed regarding the underlying mechanisms of DBS. Ó 2003 Elsevier Inc. All rights reserved.
1. Introduction A growing number of patients with ParkinsonÕs disease (PD) receive chronic bilateral deep brain stimulation (DBS) of subcortical structures to attenuate symptoms such as tremor, rigidity, or dyskinesia. The attenuation of symptoms is now well documented (Limousin-Dowsey et al., 1999) and the clinical effects are equivalent to lesions (Benabid et al., 1991; The Deep Brain Stimulation for ParkinsonÕs Disease Study Group, 2001). However, the physiological mechanisms underlying the action of DBS still remain unknown and are the focus of intense research efforts (Benazzouz & Hallett, 2000). In this short paper we examined the qualitative changes occurring in tremor amplitude while stimulation frequency was manipulated. It is now well known that stimulation frequency must be higher than 100 Hz for symptoms to be attenuated or suppressed. Thus tremor amplitude recorded continuously at the periphery while stimulation frequency is above or below 100 Hz reflects the effect of central stimulation on the 0278-2626/$ - see front matter Ó 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0278-2626(03)00107-6
neural network controlling tremor. Particular attention was paid to tremor amplitude during the transitions between stimulating conditions. These observations should be useful not only in the development or improvement of theoretical models attempting to explain the mechanisms of action of DBS in patients with PD (Titcombe, Glass, Guehl, & Beuter, 2001) but also in the development of future prospects of brain stimulation (Benabid et al., 2000).
2. Methods Sixteen subjects with PD receiving chronic uni- or bilateral stimulation for the relief of tremor, dyskinesia, or rigidity were tested while being off medication for 12 h. They were under 70 years of age and included 11 males and 5 females receiving stimulation of the GPi, the STN, or the Vim. All participants were clinically stable at the moment of the tests and were right handed except for one of them. In the sequence recorded
A. Beuter, M.S. Titcombe / Brain and Cognition 53 (2003) 190–192
(i.e., EOEIOI), ‘‘E’’ means effective frequency (between 135 and 185 Hz), ‘‘O’’ means no stimulation, and ‘‘I’’ means ineffective stimulation (effective stimulation divided by 2 or 3). Rest tremor was recorded continuously for about 5 min with each condition lasting 45–50 s and being repeated twice. Thus each test lasted about 270 s. Rest tremor was recorded with a safe (Class II) velocity-transducing helium–neon laser (Norman, Edwards, & Beuter, 1999) from Bruel and Kjaer (Naerum, Denmark). Finger tremor was detected and converted into a calibrated voltage output proportional to finger velocity. Each tremor test was preceded by a clinical examination using part III, item 20, of the UPDRS (Fahn & Elton, 1987). Data were collected using the MacLab data acquisition system (V 3.5.6/S, AD Instruments, Castle Hill, Australia), sampled at 100 Hz, and filtered (median filter).
3. Results In subjects with little or no clinical signs of tremor on the UPDRS, DBS appeared to have very little effect, if any. The signal looked qualitatively similar during the entire sequence recorded (EOEIOI) (not shown). The tremor of these participants looked like normal physiological tremor. It was irregular (i.e., noisy) and had little fluctuation in its amplitude. We now consider the results obtained with subjects having a large amplitude tremor on the UPDRS. Under effective stimulation (E). In subjects with large amplitude tremor DBS decreased tremor amplitude drastically (Figs. 1a–c). The effect was visible within a
Fig. 1. Data recorded in three participants illustrating the transitions occurring during the sequence (i.e., EOEIOI). See text for explanations and details. (a) Subject with DBS of the GPi; (b) subject with DBS of the STN; (c) subject with DBS of the Vim. In (c) the sequence presented corresponds to EOE only. Note that the recording started after a minimum of 5 min of continuous DBS.
191
couple seconds (Figs. 1a–c). Tremor amplitude was reduced to near normal values. Bursts of tremor escaping control were noted during this condition (Fig. 1c). There was no obvious difference between the first ‘‘effective’’ and the second ‘‘effective’’ conditions (i.e., the two ‘‘E’’ in Fig. 1). Under no stimulation (O). Regular oscillations tended to grow back with a delay varying between 1 and 10 s (Figs. 1a–c). The growth of the oscillation was progressive (Fig. 1b), rapid (Fig. 1c), or delayed and rapid (Fig. 1a). In Fig. 1b, both ‘‘off’’ conditions were very similar and the transitions were progressive. In Fig. 1a, tremor amplitude fluctuated during the second ‘‘off’’ condition and the transition was not clearly defined. Under the ineffective condition (I). Under this condition, tremor amplitude appeared to depend on the preceding condition. In Fig. 1a, for example, the first ‘‘ineffective’’ condition followed an ‘‘effective’’ episode and was characterized by a long delay without tremor and a return of the oscillation after about 20–25 s. The second ‘‘ineffective’’ condition followed an ‘‘off’’ condition and tremor remained minimal for the entire period (about 45 s). In Fig. 1b, the situation was different. The first ‘‘ineffective’’ condition could not be distinguished from the preceding condition (i.e., the ‘‘effective’’ condition), while the second ‘‘ineffective’’ condition was characterized by a progressive decay of the oscillation following an ‘‘off’’ condition. As was suggested above for the ‘‘ineffective’’ condition, the order of the conditions appeared to be important. However, as shown in Fig. 2, the mean values for identical conditions (i.e., ‘‘E’’ and ‘‘E’’ or ‘‘I’’ and ‘‘I’’) does not appear to be significantly different when the dispersion of the results is considered.
Fig. 2. Summary of the fluctuations in amplitude for 9 trials and 6 subjects with high amplitude tremor (above). Means for the percentage of maximal amplitude with standard deviations for each condition of the sequence (below).
192
A. Beuter, M.S. Titcombe / Brain and Cognition 53 (2003) 190–192
4. Discussion Subjects with no clinical signs of tremor and receiving DBS for other PD symptoms (mainly for dyskinesia or rigidity) had a tremor, which looked like physiological tremor. In fact DBS seems to have no effect on tremor when its amplitude is within normal values (Beuter, Titcombe, Richer, Gross, & Guehl, 2001). This suggests that either the network controlling tremor is not sensitive to DBS when tremor has a small amplitude, or that the effect cannot be detected despite the precision of the recording instrument used. Tremor can escape from its control mechanisms during ‘‘effective’’ conditions and fluctuate during ‘‘off’’ conditions. This is probably not a consequence of DBS itself but rather a sign of the disease, as bursts of tremor have been reported before in patients with PD (Beuter & Vasilakos, 1995). Given the small number of subjects, the variety of targets stimulated and the difference in the adjustment of the stimulation parameters (Beuter et al., 2001), it is difficult to draw definite conclusions regarding the modulation of amplitude by DBS. However, the results have been reproduced on consecutive days and can be considered as reliable. Furthermore, these results could not have been obtained with the clinical rating scales that are typically used by clinicians to evaluate their patients. The progressive nature of the transitions and the presence of a varying time delay in the growth or decay of tremor oscillations have been explored recently from a theoretical perspective (Titcombe et al., 2001). However, the tendency for tremor amplitude to escape from its control mechanisms regardless of the stimulation condition considered must now be considered in further models of tremor control. The same thing can be said about the fact that tremor amplitude in one condition appeared to depend on the preceding condition. Fundamental questions concerning the dynamics of tremor abound (see Glass, 2001 for more general examples about rhythmic processes in physiology). For example, what is the origin of physiological tremor? How do physiological and pathological tremors interact with each other and with peripheral influences? By exploring fluctuations and escape during tremor control by DBS
in greater details we hope to be able to develop better methods to control tremor in PD.
Acknowledgments The authors wish to thank all the participants and Dr. Dominique Guehl who performed the clinical examinations. The first author received support from NSERC (Canada) and FCAR (Quebec).
References Benabid, A. L., Pollak, P., Gervason, C., Hoffmann, D., Gao, D. M., Hommel, M., Perret, J. E., & de Rougemont, J. (1991). Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. The Lancet, 337, 403–406. Benabid, A. L., Koudsie, A., Pollak, P., Kahane, P., Chabardes, S., Hirsch, E., Marescaux, C., & Benazzouz, A. (2000). Future prospects of brain stimulation. Neurological Research, 22, 237–246. Benazzouz, A., & Hallett, M. (2000). Mechanism of action of deep brain stimulation. Neurology, 55(6), s13–s16. Beuter, A., Titcombe, M., Richer, F., Gross, C., & Guehl, D. (2001). Effect of deep brain stimulation on amplitude and frequency characteristics of rest tremor in ParkinsonÕs disease. Thalamus and Related Systems, 1, 203–211. Beuter, A., & Vasilakos, K. (1995). Fluctuations in tremor and respiration in patients with ParkinsonÕs disease. Parkinsonism and Related Disorders, 1(2), 103–111. Fahn, S., & Elton, R. L. (1987). Unified ParkinsonÕs disease rating scale. In S. Fahn, C. D. Marsden, D. B. Calne, & Goldstein (Eds.), Recent developments in ParkinsonÕs disease (pp. 153–164). Florham Park, New Jersey: Macmillan Health Care. Glass, L. (2001). Synchronization and rhythmic processes in physiology. Nature, 410, 277–284. Limousin-Dowsey, P., Pollak, P., Van Blercom, N., Krack, P., Benazzouz, A., & Benabid, A. L. (1999). Thalamic, subthalamic nucleus and internal pallidum stimulation in ParkinsonÕs disease. Journal of Neurology, 246(14), 542–545. Norman, K. E., Edwards, R., & Beuter, A. (1999). The measurement of tremor using a velocity transducer: Comparison to simultaneous recordings using transducers of displacement, acceleration and muscle activity. Journal of Neuroscience Methods, 92, 41–54. The Deep-Brain Stimulation for ParkinsonÕs Disease Study Group (2001). Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in ParkinsonÕs disease. The New England Journal of Medicine 345(13), 956–963. Titcombe, M., Glass, L., Guehl, D., & Beuter, A. (2001). Dynamics of Parkinsonian tremor during deep brain stimulation. Chaos, 11(4), 766–773.