A cerebellar-like terminal and postural tremor induced in normal man by transcranial magnetic stimulation.

Trains of repetitive transcranial magnetic stimulation (TMS) at 10-30 Hz and intensities of 90-120% motor threshold were delivered through a figure of eight coil over the motor cortex while normal subjects made either rapid, self-terminated (ballistic) wrist movements or maintained the position of their wrist at a fixed angle. Movement kinematics and EMG activity in antagonistic forearm muscles were analysed. In the ballistic task, repetitive TMS had little effect on the velocity or acceleration of the initial segment of the movement, although it induced large terminal oscillations (tremor) around the target position at frequencies between 4.4 and 7.2 Hz. The likelihood that tremor would occur increased with increasing stimulus intensities or frequencies. It was maximal with stimulation over the forearm area, and decreased with stimulation over the leg area, or over parietal sites; there was no tremor during stimulation of cervical nerve roots. The frequency of the induced tremor was independent of the rate of stimulation and did not depend on the presence of excitatory and inhibitory motor responses to the stimulus. Stimulation could also induce tremor of the same frequency in the fixed task, but only during co-contraction of forearm muscles. The amplitude of tremor was proportional to the level of co-contraction. Clinically, the tremor induced by repetitive TMS appeared very similar to cerebellar tremors. In order to confirm this we investigated two cerebellar patients, one with autosomal dominant cerebellar ataxia and the other with multiple sclerosis. Both of them had a terminal tremor of 6-7 Hz in the wrist movement task. In the holding task, the amplitude of their postural tremor increased with the level of co-contraction in forearm muscles. Since the frequency of repetitive TMS-induced tremor was independent of stimulus parameters, we conclude that it represents some intrinsic property of the CNS. We suggest that the tremor is caused by disruption of cortical processes involved in terminating a voluntary movement or maintaining a posture. Similarities to cerebellar patients suggest that repetitive TMS may cause tremor by interfering with adaptive cerebellar afferent inflow to motor cortex. Repetitive TMS-induced tremor, therefore, may represent a model of some forms of cerebellar tremor in man.

Bilateral segmental dystonia in a professional tennis player.

Dystonias occur frequently as repetitive movements, persistent elevations of muscle tone, or tonic contortions, whereby the cause is assumed to be an impairment of basal ganglia function. Focal dystonias are especially known in musicians, although little is reported on focal dystonias in athletic stress. The present case report describes the case of a 34-yr-old professional tennis player with bilateral segmental dystonia. The symptoms were expressed in involuntary movements when he intended to hit the ball and in a progredient tremor, initially in one hand, later in both, making him unable to write. The altered mobility during athletic stress was confirmed by video analysis, the altered innervation with excessive, uncoordinated impulse influx by means of electromyography during sport-type specific stress, and writing incapacity during a writing test. The symptoms abated under therapy with trihexyphenidyl-HCL, so that the patient has been able to work as a tennis coach with improved athletic performance for the past 3 yr. It is concluded that the various forms of dystonia should be included in the differential diagnosis of impaired coordinative movements under athletic exercise, especially of the upper extremities.

Deficits in phasic muscle force generation explain insufficient compensation for interaction torque in cerebellar patients.

A simple paradigm was used to investigate how patients with cerebellar lesions cope with the need to correct for joint interactions during a multi-joint movement. Normal subjects and patients with cerebellar degeneration performed fast unconstrained elbow flexions with the instruction to voluntarily fixate the shoulder joint. Angular kinematics and inverse dynamics analyses were performed. A susceptibility index quantified how strong-concomitant shoulder-motion depended on interactions from the elbow. Amplitudes of involuntary shoulder movements increased with elbow movement speed and were generally larger in patients. Susceptibility indices were smaller in patients, indicating a more variable compensatory response, however, increased with elbow movement speed. We conclude that patients were significantly less able to 'tune' their postural stabilizing response to match interaction torques. However, the velocity dependence of this effect points to a deficit in generating normal levels of phasic torque.

Long-term measurement of tremor.

To account for the fluctuating and context-dependent nature of tremor, the method of ambulatory long-term electromyography (EMG) was developed for quantification of this symptom. It is based on successive evaluation of 15-s intervals by using a fast Fourier transformation (FFT). The standard results obtained are (a) tremor occurrence, a measure of how many intervals contain tremor; (b) mean tremor intensity; and (v) mean tremor frequency. This new method fulfills the so-called "test criteria" such as reliability, validity, sensitivity, and specificity for tremor quantification in essential tremor (ET) and Parkinson's disease (PD). In addition, we developed a method of determining the antagonist activation pattern by using cross-correlation analysis, also based on the long-term approach. This allows differentiation between ET and PD with a high sensitivity and a high interrater reliability. We conclude that long-term EMG is useful for both quantification and differentiation of tremor.

Multijoint arm movements in cerebellar ataxia: abnormal control of movement dynamics.

In cerebellar ataxia, kinematic aberrations of multijoint movements are thought to originate from deficiencies in generating muscular torques that are adequate to control the mechanical consequences of dynamic interaction forces. At this point the exact mechanisms that lead to an abnormal control of interaction torques are not known. In principle, the generation of inadequate muscular torques may result from an impairment in generating sufficient levels of torques or from an inaccurate assessment and prediction of the mechanical consequences of movements of one limb segment on adjacent joints. We sought to differentiate the relative contribution of these two mechanisms and, therefore, analyzed intersegmental dynamics of multijoint pointing movements in healthy subjects and in patients with cerebellar degeneration. Unrestrained vertical arm movements were performed at three different target movement velocities and recorded using an optoelectronic tracking system. An inverse dynamics approach was employed to compute net joint torques, muscular torques, dynamic interaction torques and gravitational torques acting at the elbow and shoulder joint. In both groups, peak dynamic interaction forces and peak muscular forces were largest during fast movements. In contrast to normal subjects, patients produced hypermetric movements when executing fast movements. Hypermetric movements were associated with smaller peak muscular torques and smaller rates of torque change at elbow and shoulder joints. The patients' deficit in generating appropriate levels of muscular force were prominent during two different phases of the pointing movement. Peak muscular forces at the elbow were reduced during the initial phase of the movement when simultaneous shoulder joint flexion generated an extensor influence upon the elbow joint. When attempting to terminate the movement, gravitational and dynamic interaction forces caused overshooting extension at the elbow joint. In normal subjects, muscular torque patterns at shoulder and elbow joint were synchronized in that peak flexor and extensor muscular torques occurred simultaneously at both joints. This temporal pattern of muscular torque generation at shoulder and elbow joint was preserved in patients. Our data suggest that an impairment in generating sufficient levels of phasic muscular torques significantly contributes to the patients' difficulties in controlling the mechanical consequences of dynamic interaction forces during multijoint movements.

Validity of long-term electromyography in the quantification of tremor.

We previously developed a method of tremor quantification using long-term electromyography registration of antagonistic forearm muscles that is reliable, sensitive, and specific for pathologic tremors. The present study demonstrates that tremor occurrence as measured by this method correlates well with clinical parameters of tremor in idiopathic Parkinson's disease (PD) and essential tremor (ET) (subscores of the Unified Parkinson's Disease Rating Scale for PD, tremor rating according to Bain et al. for ET). We conclude that the method is a valid and objective means of tremor quantification in PD and ET.

Wrist tremor: investigation of agonist-antagonist interaction by means of long-term EMG recording and cross-spectral analysis.

We have developed a method to observe and quantify the phasic relationship between the burst patterns of antagonistic muscles in any roughly periodic movement, such as tremor, for up to 24 h. This paper describes our approach, in which long-term EMG recordings are evaluated by a procedure based on cross-spectral analysis. The method is then illustrated by data from 6 patients with essential tremor. Our data confirm earlier observations that a particular patient may show different burst patterns at different times. However, as opposed to tremor analysis based on short-term recording, our method allows quantitative statements on the relative frequency of the burst patterns, as they occur under everyday conditions. In addition, our data suggest that in ET (a) alternating tremor activity in one hand may occur simultaneously with synchronous activity in the other hand; (b) along with the classical alternating and co-contracting patterns there may be significant 'non-classical' activity, that cannot be called alternating or synchronous.

Reliability, specificity and sensitivity of long-term tremor recordings.

We have developed a method of long-term EMG recording that has proven suitable for the quantification of pathological tremor. In the present paper we show that the principal parameters of the method (tremor occurrence, tremor intensity, tremor frequency) are highly reproducible and that the method is specific and sensitive for detection of pathological tremor. Twelve patients with essential tremor (ET) and 13 patients with Parkinson's disease (PD) were recorded repeatedly on 3 successive days. For each patient group and for each parameter the intersubject variability was much larger than the intersubject variability. The intraclass correlation coefficient "R" was in the order of 0.9 for each parameter and the mean of Pearson's correlation coefficient between successive days was also approximately 0.9. Recordings from normal controls demonstrated that the method's specificity for pathological tremor is 94.1% and its sensitivity is 96%.

Tremorlytic activity of budipine: a quantitative study with long-term tremor recordings.

The tremorlytic activity of the novel antiparkinson agent budipine was quantified in an open trial. Eleven patients with Parkinson's disease (PD) were treated with individual doses of budipine added to stable conventional antiparkinsonian medication. Tremor activity was measured using long-term electromyogram (EMG) recordings. Tremor intensity was reduced by 25%, tremor occurrence by 34%, and conventional "Unified Parkinson's Disease Rating Scale" (UPDRS) scores improved by 20% with this medication. There were two dropouts because of side effects. One dropout appeared not to be related to budipine. Apart from those, the drug was well tolerated by all patients. We conclude that budipine is an effective and well-tolerated tremorlytic drug and that the method of long-term EMG recording is suitable for tremor quantification in clinical studies.

Variations on tremor parameters.

This paper describes our analysis procedure for long-term tremor EMG recordings, as well as three examples of applications. The description of the method focuses on how characteristics of the tremor (e.g. frequency, intensity, agonist-antagonist interaction) can be defined and calculated based on surface EMG data. The resulting quantitative characteristics are called "tremor parameters." We discuss sinusoidally modulated, band-limited white noise as a model for pathological tremor-EMG, and show how the basic parameters can be extracted from this class of signals. The method is then applied to (1) estimate tremor severity in clinical studies, (2) quantify agonist-antagonist interaction, and (3) investigate the variations of the tremor parameters using simple methods from time-series analysis. (c) 1995 American Institute of Physics.

Long-term tremor recordings in parkinsonian and essential tremor.

We have recently developed a method of long-term EMG recording (Bacher et al., 1989), which has proven suitable for the quantification of pathological tremor. In the present paper we show that (1) the principal parameters of the method (tremor occurrence, tremor intensity, tremor frequency) are highly reproducible with intraclass correlation coefficients in the order of 0.9, (2) that the method has both a high specificity (87.5%) and sensitivity (96%) for detection of pathological tremor, and (3) that it can be useful for examining agonist-antagonist muscle activation under everyday conditions.

[Growth hormone therapy and leukemia]. / Groeihormoon therapie en leukemie.

In this literature study the possible correlation between GH-therapy and leukemia has been critically evaluated. Two central questions have been studied: 'does leukemia occur more often in GH-deficient children in GH-therapy than in age-related normal individuals' and 'which influences of GH administration upon normal and leukemic leukocytes have been described?'. In some cases leukemia developed in GH-deficient children after GH-therapy. The data have shown a higher incidence of leukemia in the population of children treated with GH (5:100,000) than in the age-related normal population of children (2:100,000). However, hard evidence supporting the hypothesis that GH-therapy could induce leukemia has not yet been found. In vivo studies could not detect enhanced growth of blood cells influenced by GH-therapy. In vitro studies showed that GH either stimulated or did not affect the proliferation of unstimulated lymphocytes of GH-deficient children, normal individuals or leukemia-patients. The same effects occurred in leukemic cell lines. On PHA-stimulated lymphocytes of GH-deficient children and normal individuals both enhancing and inhibiting effects of GH have been found. It is suggested that GH-therapy could improve immunological resistance against tumors by improving Natural-Killer-cell activity. In mice GH seemed to influence lymphocyte-differentiation. In mice also an increase in the frequency of chromosomal aberrations related to GH has been observed. This evaluation suggests that patients, treated with GH-therapy should be carefully followed up. Also, the indication for GH-therapy has to be guarded critically.