However, neither of these agents affected oscillations around 10 Hz. Clinically, the most powerful effects on physiological tremor are produced by beta-adrenergic agents.
The beta-adrenergic agonists enhance tremor adrenaline [23] ; isoprenaline [24] ; salbutamol [25] , whereas the antagonist propranolol reduces it [24]. If the effects of beta-adrenergic agents are solely peripheral, they will change the gain of peripheral feedback, which would inject oscillations into motoneuron firing. This might co-modulate oscillations at 10 Hz and 20 Hz [19]. In this paper, we test this idea directly.
These opposite effects on oscillations at 10 Hz and higher frequencies are similar to those seen in a computational model of recurrent feedback by Renshaw cells [29] , and are not expected if these agents only act peripherally. We speculate that beta-adrenergic agents also have a central action, allowing opposite effects on physiological tremor and beta-band corticomuscular coherence. Experiments were performed on 8 young healthy right-handed volunteer subjects 3 female; age range 21—32 years without a family history of essential tremor.
None of the subjects were taking prescription medication either regularly or as required. Subjects were not pre-selected based on their corticomuscular coherence. None of the subjects had received a prior diagnosis of enhanced physiological tremor or had evidence of enhanced physiological tremor when assessed by a clinical neurologist MRB at the time of experiments.
Informed written consent was obtained in accordance with the Declaration of Helsinki and all procedures were approved by the Cambridge Local Research Ethics Committee. Differential EEG was recorded from the left sensorimotor cortex using two adhesive scalp electrodes Neuroline S, Medicotest, St Ives, UK placed 30 mm lateral to the vertex and 20 mm anterior and posterior to the interaural line.
The anterior EEG electrode was connected to the non-inverting input of the amplifier; this is the same montage as used in our previous work [7] , [11] , [21] , [22] , [30]. Physiological tremor was quantified using accelerometry. A low mass splint was taped to the subject's right index finger, and restricted movements to the metacarpophalangeal joint.
Subjects gripped a fixed vertical pole with the thumb and digits 3—5, and extended the index finger. Recordings were made for 90 s. Measurement of corticomuscular coherence was carried out using an auxotonic precision grip task. Subjects held the two levers of a purpose-built manipulandum between thumb and index finger. At rest the levers were separated by 70 mm; a 1 N force was required to move the levers off their end-stops. The task see Figure 1 required subjects to maintain cursors representing each lever position within two moving target boxes on a computer screen.
Movement of the levers was resisted by the torque motors, which simulated an auxotonic spring-like load. The target boxes produced a hold-ramp-hold pattern, with the first hold requiring a rapid lever displacement of 12 mm from rest followed by a hold period of 3 s at a force level of 1.
The targets then produced a 2 s ramp movement to reach the second hold, with a displacement of 24 mm, 1. Postural tremor task. Example of postural physiological tremor in a single subject, recorded via an accelerometer. Auxotonic precision grip task. Drugs were prescribed and administered by one of the authors MRB , who is a clinical neurologist. Potential adverse reactions were minimised by using the lowest therapeutic dose recommended by the Joint Formulary Committee [31].
Propranolol experiments were conducted as a double blind randomised placebo-controlled trial. For each subject, placebo and propranolol 40 mg of active compound mixed with vehicle compound , which were indistinguishable in appearance, were randomly assigned a label A or B by an independent randomizer.
Each subject participated in experiments on two days, separated by a 2—3 week washout period. At the start of the morning session of each day, the subject was prepared for recording. A control experiment was then carried out, which consisted of 80 trials of the precision grip task and a measurement of tremor. After this, the electrode locations were marked on the skin with ink and the subject ingested experimental compound A first day or B second day.
Four hours later, when peak serum concentrations of the active agent should have been achieved [32] , the subject returned to the laboratory. Fresh adhesive electrodes were applied at the marked muscle and scalp locations, and further recordings were made.
The identities of compound A and B for each subject were only revealed by the randomizer once all experiments were complete and data were ready for analysis. By using a placebo, we were able to control for effects caused by the different time of day of the experimental and control recording sessions, which we have previously shown to be important [22].
The subjects who had participated in the propranolol experiments were also used in the salbutamol experiments, following a washout period of at least one week.
After the control recordings, 2. Inhaled aerosolised salbutamol is absorbed rapidly via the lungs into the bloodstream. The rapid absorption meant that control and test experiments were separated by only a short period, and we accordingly considered it unnecessary to carry out placebo experiments for salbutamol see paragraph 12 of the Results section for further justification. Electrocardiogram ECG was monitored throughout the salbutamol experiments.
Salbutamol at an average plasma concentration of 2. Prior to analysis EMG recordings were full wave rectified. Analysis of tremor power used 0. These were processed with a Fast Fourier Transform, yielding a tremor power spectrum with frequency resolution of 1. Accelerometer, EEG and EMG power spectra were first normalised to the total power in that signal across all frequencies.
For acceleration, the normalisation used the total power in the first recording of that day, allowing overall changes in tremor power to be measured. For EEG and EMG, each spectrum was normalised to its own total power, revealing the magnitude of spectral peaks relative to the total.
The spectra were then averaged across eight subjects for EEG or acceleration, and across eight subjects and five muscles for EMG. Coherence spectra were similarly averaged across subjects and muscles; significance limits for the averaged coherence were calculated according to the method described in Evans and Baker [35] and Baker et al [8].
Power was summed across a frequency band of interest 6. For propranolol, we needed to test not only whether propranolol produced a change, but whether this change was significantly different from that produced by placebo. For corticomuscular coherence, coherence was averaged across muscles and across bins within the The significance of the changes in coherence before and after substance administration was determined by finding 1 Where L is the number of disjoint sections used to calculate the coherence, and C After n,m f and C Before n,m f are the coherence calculated at frequency bin f for subject n , muscle m before and after substance administration.
On the null hypothesis that coherence is the same before and after substance administration, Z will be normally distributed with zero mean and unit variance [21] , [30]. The significance of changes in coherence was thus determined with reference to values of the standard normal probability distribution.
In experiments investigating the effects of propranolol, it was necessary to compare the changes caused by propranolol with those seen following placebo. We determined the effect of a drug or placebo on the coherence phase as follows. Firstly, frequency bins in the beta-band region The circular average of this difference was computed [36]. The shuffling procedure was repeated 10 5 times, allowing estimation of the distribution of the circular mean phase difference, on the null hypothesis that there was no change before and after substance administration.
Figure 2 illustrates the results obtained from a single subject in each experimental protocol tested. Figures 2A—C show the effect of the different substances administered on physiological tremor, measured from the acceleration power spectrum during finger extension. Each panel of Fig. There was little change in tremor following the placebo Fig. By contrast, salbutamol dramatically increased tremor Fig.
Tests may be done to rule out other reasons for the tremor. A tremor that occurs when the muscles are relaxed or that affects the legs or coordination may be a sign of another condition, such as Parkinson disease.
The speed of the tremor can be an important way to determine its cause. Blood tests and imaging studies such as a CT scan of the head, brain MRI , and x-rays are usually normal. Drug-induced tremor often goes away when you stop taking the medicine that is causing the shaking.
You may not need treatment or changes in the medicine if the tremor is mild and does not interfere with your daily activity. If the benefit of the medicine is greater than the problems caused by the tremor, your provider may have you try different dosages of the medicine.
Or, you may be prescribed another medicine to treat your condition. In rare cases, a drug such as propranolol may be added to help control the tremor. Severe tremor can interfere with daily activities, especially fine motor skills such as writing, and other activities such as eating or drinking. Call your provider if you are taking a medicine and a tremor develops that interferes with your activity or is accompanied by other symptoms. Always tell your provider about the medicines you take.
Up to half the variability between individuals to the response of beta 2 agonists , such as Salbutamol, has been suggested to be due to polymorphisms in the genome [7]. Jump to: navigation , search. Personal tools Log in. Namespaces Page Discussion. Views Read View source View history. This page was last modified on 20 October , at Objective: To study tremor side effects of salbutamol an easily applicable, quick and low-priced method is needed.
A new method using a commercially available, pen-shaped laser pointer was developed. Aim of the study was to determine sensitivity, reproducibility, reference values and the agreement with a questionnaire. Methods: Tremor was measured using a laser pointer technique.
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