Eur. J. Appl. Physiol. 39, 203-207 (1978) European Journal of

Applied Physiology and Occupational Physiology �9 Springer-Verlag 1978

A Method for the Measurement of Tremor, and a Comparison of the Effects of Tocolytic /3-Mimetics

K. Behling, A. Bleichert, and M. Scarperi

Abteilung ffir angewandte Physiologic, Physiologisches Institut der Universit/it Hamburg, Martinistral3e 52, D-2000 Hamburg 20, Federal Republic of Germany

Summary. A method permitting measurement of finger tremor as a displace- ment-time curve is described, using a test system with simple amplitude calibra- tion.

The coordinates of the inversion points of the displacement-time curves were transferred through graphical input equipment to punched tape. By means of a computer program, periods and amplitudes of tremor oscillations were calcu- lated and classified. The event frequency for each class of periods and ampli- tudes was determined. The actions of fenoterol-hydrobromide, ritodrin-HC1 and placebo given to 10 healthy subjects by intravenous infusion in a double-blind crossover study were tested by this method.

At therapeutic doses, both substances raised the mean tremor amplitude to about three times the control level. At the same time, the mean period within each class of amplitudes shortened by 10-20 ms, whereas the mean periods calculated from all oscillations together did not change significantly. After the end of fenoterol-hydrobromide infusion, tremor amplitudes decreased signifi- cantly faster than those following ritodrin-HCl infusion.

Key words: Tremor -- /3-mimetics -- Tocolytics.

Studies on tremor have become important in pharmacology with the increasing use of drugs with tremor enhancing side-effects, such as the frequently used/5-mimetic substances (Marsden et al., 1967). Simple observation of tremor is as inadequate for comparing various drugs as the recording of tremor with uncalibrated test devices. For complete tremor analysis, both frequency and amplitude of tremor should be measured quantitatively. The most frequently used accelerometers are suitable for frequency measurements on free moving limbs. Calibration of amplitudes, however, is only possible on an adjustable jarring table if the accelerometer itself is a true acceleration transducer (Herz and Nusselt, 1973). Exact amplitude calibration is

Offprint requests to: Dr. K. Behling (address see above)

0301-5548/78/0039/0203/$ 01.00

204 K. Behling et al.

imposs ib l e if devices are u sed w h i c h b e c o m e a c c e l e r o m e t e r s b y elast ic c o n n e c t i o n o f

a fo rce t r a n s d u c e r to the l imb to be i nves t i ga t ed (e.g., F i n k a n d B a c k h a u s e n , 1975;

K l a u s et al., 1974; M a r s d e n et al., 1967; P o t v i n et al., 1975). O u r device a l lows a

d i rec t r e c o r d i n g o f d i s p l a c e m e n t - t i m e curves . T h e usefu lness o f this m e t h o d espe-

cial ly wi th r e g a r d to t r e m o r a m p l i t u d e s is d e m o n s t r a t e d b y c o m p a r i s o n o f the t r em-

o r - e n h a n c i n g effect o f t w o t o c o l y t i c / 3 - m i m e t i c s , f e n o t e r o l - h y d r o b r o m i d e (Pa r tus i s -

ten | a n d r i t o d r i n - h y d r o c h l o r i d e (Pre -Par |

Methods

The supinated right forearm of the subject was rested comfortably on a sloping support. The forefinger was fixed by means of an adhesive (Histoacryl | to the end of the force-transducer lever (Shinkoh VI- 20-120, natural frequency 210 Hz). The other fingers and the palm remained free. The force transducer was connected to a carrier-wave bridge-amplifier (Hellige TF 19). The output signal from the amplifier was supplied by DC coupling to a cathode-ray oscilloscope and in parallel to an ECG recorder (Siemens Cardirex 3 T). The subject was instructed to maintain the lever of the force transducer precisely in the null position. This was possible after a little practice by checking the band of the tremor oscillations on the oscilloscope. In order to utilize fully the width of the recording paper, we used an AC-input to the ECG apparatus to avoid registration of slow correction movements. For calibration, defined changes in displacement of the transducer lever were obtained using a dial gauge. The corre- sponding deflections on the oscilloscope were measured. The frequency characteristic of the ECG recorder was estimated using a sine-wave generator. The stiffness of the force transducer was 590 N/re. The maximum deflection was 0.4 mm, corresponding to a force of 0.24 N.

Experimental Procedure and Subjects

The experiments were carried out on 10 healthy volunteers of either sex (six male, four female), aged between 23 and 39 years. In a double-blind, crossover arrangement, each subject received placebo (isotonic NaC1 solution), ritodrin-HC1 or fenoterol-hydrobromide in isotonic NaC1 solution by intrave- nous infusion (Braun perfusor) in a randomized sequence. After a rest period of 10 min, the infusion was delivered as follows: 7.5 min at 11 ml/min, 7.5 min at 27 ml/min, 20 min at 55 ml/min. Thereafter the subjects rested for 20 min. Tremor measurements were performed after 5 and 10 min in the first rest period, 5, 10, 15, and 20 rain after switching to 55 ml/h in the main period and 10 and 20 min after the end of infusion. Each period of measurement lasted 7--10 s. In the main period the subjects received 0.3 mg/min of ritodrin-HC1 or 0.003 mg/min of fenoterol-hydrobromide, corresponding to the therapeutic dose. There was an interval of at least 2 days between individual experiments. All experiments were performed at the same time of the day.

Analysis of the Records

A range of 5 s taken from the central part of each tremor recording was analyzed. The coordinates of the inversion points on the recordings were obtained by means of a semi-automatic curve digitizer (WDV, type 2860). The resolution was 0.5 mm in both axes. For all oscillations, the distance between two adjacent maxima was used to determine the period of oscillation. The difference between the mean value of two adjacent maxima and the minimum between them was used for all oscillations to deter- mine the amplitude (corrected according to the non-llnearity of the ECG-recorder).

The test data were arranged in classes of 0.005 mm for amplitudes and 10 ms for periods of oscillation. All calculations were done on an IBM 360.

The Effects of Tocolytic /3-Mimetics

Results

205

Figure 1 shows a typical section of an original recording. Before infusion of the drug, only oscillations with small amplitudes occur. At the end of the infusion of ritodrin-HC1, the number of large oscillations has increased considerably while the peridiocity does not appear to have changed.

In Figure 2, the data obtained from all 10 subjects are shown before (control period, Fig. 2a) and during infusion of ritodrin-HC1 (Fig. 2b). During the control period, oscillations with small amplitudes prevail. They are distributed over a wide range of periods, the maximal event frequencies lying at relatively short periods. In the classes of higher amplitudes, the distribution becomes narrower and the maximal event frequencies are shifted to longer periods. During infusion of ritodrin-HC1 (Fig. 2b) oscillations with amplitudes higher than those observed during the control period occur frequently. The mean period within each amplitude class is slightly shorter (10-20 ms) than before infusion. This difference is statistically significant (Wilco- xon-test, p < 1%). A very similar distribution of amplitudes and periods was ob- served during infusion of fenoterol-hydrobromide (not shown here).

In Figure 3 the mean amplitudes (calculated from all oscillations of each ana- lyzed 5 s-period of all 10 subjects) are shown for the three different experimental runs. The mean amplitudes scarcely differ in the first control period. During the infusion of ritodrin-HC1 or fenoterol-hydrobromide they are about three times higher than those during the placebo infusion. The slight increase of the mean during place- bo infusion is not significant. During recovery, the mean amplitude falls more steep- ly in the case of fenoterol-hydrobromide than in the case of ritodrin-HC1. This difference is significant (p < 5%). It is obvious also in the individual experiments: in nine out of 10 subjects the mean amplitude at the end of the experiment is lower following infusion of fenoterol-hydrobromide than after infusion of ritodrin-HC1.

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Fig. 1. Portion of an original recording. Above: before the start of the infusion. Below: 45th rain of the experiment (just prior to ending the period of infusion) with infusion of ritodrin-HC1 (0.3 mg/min). Subject: M.S., male, 34 years. Amplitude calibration is valid for 10 Hz

206 K. Behling et al.

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The Effects of Tocolytic /3-Mimetics 207

Despite the change in distribution of periods within the classes of amplitudes as an effect of t3-mimetics, the mean period of all oscillations (75 ms) shows no statistically significant difference between the three runs at any time of the experiments.

Discussion

The recordings of finger tremor obtained by means of a force-transducer as de- scribed here can be interpreted directly as recordings of displacement since the force necessary to move the transducer lever is negligibly small even at the largest ampli- tude. Our results are in agreement with the more global findings of Marsden et al. (1967) that/3-adrenergic drugs increase the amplitude of physiological tremor.

In addition, we have observed a change in the frequency pattern of the tremor under/3-adrenergic stimulation: the mean period of oscillations within all classes of amplitudes shortens. Nevertheless, the mean period of all oscillations together keeps nearly constant, because the shortening of periods within each class of amplitudes is compensated by the decrease in the number of oscillations with small amplitudes and corresponding short periods, and the increase in number of oscillations with high amplitudes and corresponding long periods. These changes in tremor could only be established by means of calibrated measurement of frequency and ampli- tude.

References

Finke, J., Bachhausen, D.: Tremorregistrierung mittels Infraton-Pulsabnehmer. Nervenarzt 46, 272--273 (1975)

Herz, H., Nusselt, L.: Ein einfaches Geriit zur Tremorregistrierung. Biomed. Tech. 18, 240-241 (1973)

Klaus, D., Finke, J., Fahlbusch, W., Bachhausen, D.: Reflexzeitmessung sowie Tremor-Registrierung mittels Infraton-Pulsabnehmer. Med. Welt, 25, 698-701 (1974)

Marsden, C. D., Foley, T. H., Owen, D. A. L., McAllister, R. G.: Peripheral fi-adrenergic receptors concerned with tremor. Clin. Sci. 33, 53-65 (1967)

Potvin, A. R., Tourtelotte, W. W., Snyder, D. N., Henderson, W. G., Albers, J. W.: Validity of quantitative test measuring tremor. Amer. J. Phys. Med. 54, 243--252 (1975)

Accepted January 20, 1978