Pathophysiology of Tremor-modulating Mechanisms of Propranolol and Primidone in Essential Tremor

Background: Although ET is the most common of movement disorders, its pathophysiology has not yet been fully explained. Central nervous system functional studies have shown that oscillatory activity within the cerebello-thalamo-cortical networks plays a key role in ET's pathophysiology. The origin of this oscillatory activity and the potential role of the primary motor cortex in its formation or modulation remains unknown. Neuropathological studies found degenerative structural changes in the cerebellum of ET patients. Propranolol and primidone are the first-line therapies for ET and the sole medications for treating ET with the level A recommendations according to the latest guidelines of the American Academy of Neurology. Propranolol is a beta-blocker class of medication and primidone is a barbiturate. In spite of solid evidence of their effectiveness in ET patients, the mechanisms of their central action are not yet fully understood. It is believed that propranolol mediates its therapeutic action through peripheral beta-2 adrenergic receptors of skeletal muscles and muscle spindles and through central beta-adrenergic and serotoninergic receptors. After oral intake, primidone is partially metabolized to phenylethylmalonamide (PEMA) and phenobarbital. Even though the studies have shown that PEMA does not have anti-tremor activity, primidone is much more effective in alleviating tremor than phenobarbital alone. In addition, it has been shown that the anti-tremor effect of primidone occurs sooner than its metabolite phenobarbital is produced. This may be due to the non-metabolized primidone compound having an anti-tremor activity or due to PEMA's and phenobarbital's synergistic activity. No association between anti-tremor activity and the concentration of primidone or phenobarbital in the serum has been found. While phenobarbital activity is well known to be mediated through binding to gamma-aminobutyric acid (GABA) A receptors, the mechanism of action of non-metabolized primidone is poorly understood.

Aims: To study the mechanisms of primidone and propranolol action in ET with the use of TMS. The investigators believe that studying mechanisms of action of medications that have been shown to reduce ET can further improve the understanding of ET pathophysiology. Since the cerebellum is thought to be involved in ET pathophysiology the EBCC paradigm will be used to evaluate cerebellar dysfunction in ET patients and to show whether cerebellar dysfunction influences the effectiveness of propranolol and primidone.

Patients and inclusion/exclusion criteria: Fifty patients will be recruited from the outpatient clinic for extrapyramidal disorders. Only patients with the diagnosis of ET made according to the newest consensus statement on the classification of tremors and only patients who will be initiated on propranolol or primidone will be included. Exclusion criteria for TMS will be used. Patients having a history of seizures or mental illness, patients with a cardiac pacemaker, metal material in the head (except dental material in the mouth), or with medication pumps and pregnant women will be excluded from the study.

Study protocol: Patients treated with propranolol or primidone will be studied prior to treatment and 3 - 6 months after treatment initiation. Patients will not be allowed to start any new medication with the action on the central nervous system, while included in the study. Tremor will be assessed clinically using the TETRAS scale and by EMG and accelerometry recordings. Positive treatment response will be defined as a 30% or more decrease in tremor amplitude. At baseline cerebellar function will be assessed clinically with the SARA scale and electrophysiologically using the EBCC paradigm. TMS will be used to study motor cortex excitability.

Methods:

Accelerometry with electromyography: Tremor (frequency and amplitude) will be objectively evaluated in the subjects with accelerometry. A triaxial accelerometer will be attached to the 3rd metacarpal bone bilaterally. Simultaneously EMG will be recorded. Bipolar Ag / AgCl surface EMG electrodes will be placed over the flexor carpi radialis and the extensor carpi radialis muscle bilaterally. Electromyography and accelerometry will be recorded while subjects will be sitting in an armchair/wheelchair or lying in a hospital bed (a) at rest position (b) with arms outstretched (postural condition) (c) at the postural condition with 500 g mass attached to the hand (weight loading) and (d) while performing a goal-directed task (action).

Transcranial magnetic stimulation (TMS) Single TMS pulses will be applied using Magstim 2002 magnetic stimulator with monophasic waveform (Magstim Company, Carmarthenshire, Wales, UK). For double TMS pulses, two Magstim 2002 stimulators connected with the Bistim module will be used. The stimulators will be connected to a standard figure 8 coil. The coil will be positioned tangentially to the skull and over the 'hotspot' point on the scalp, with the handle pointing backward at an angle of ~ 45 ° with respect to the sagittal plane. Hotspot point is defined as stimulation site resulting in the largest motor evoked potentials (MEPs) recorded over the contralateral abductor pollicis brevis (APB) muscle. A hotspot point will be found by visual inspection. The MEP amplitude in APB muscle will be measured with EMG.

The eyeblink classical conditioning (EBCC) paradigm is a protocol of associative motor learning in which paired presentation of a conditioned (CS) and unconditioned stimulus (US) leads to the production of a conditioned eyeblink response (CR) 10,42. The CS will be a tone with a frequency of 2000 Hz and a strength of 50-70 dB higher than the hearing threshold of the subject (but at least 80 dB) and a duration of 400 milliseconds that will be presented bilaterally via binaural headphones. The unconditioned stimulus will be delivered by percutaneous supraorbital nerve electrical stimulation through a pair of Ag-AgCl cup electrodes with the cathode over the supraorbital foramen and the anode 2 cm above. Percutaneous electrical stimulation of the supraorbital nerve will last 200 microseconds and will start 200 microseconds before the end of the CS so that the stimuli will co-terminate. Blinking will be recorded with EMG electrodes placed bilaterally over the orbicularis oculi muscles. The test will consist of seven sets. In the first six sets, there will be nine trials with paired conditioned-unconditioned stimuli, one trial with the only US, and one trial with only CS. In the seventh section, eleven trials of only CS will be given. Among the individual tests, there will be a random interval (from 10s to 30s), so that the habituation will be as small as possible.

Statistical analysis: Clinical and TMS measures before and after treatment will be compared using parametric or nonparametric two-related-samples T-test, depending on the data distribution or repeated-measures ANOVA. Regression analyses will be used to determine demographic, clinical, and electrophysiological predictors of response to treatment.

It is hypothesized by investigators that in ET patients, baseline electrophysiological parameters will differ between patients who will improve while taking propranolol or primidone (responders) and patients who will not improve while taking any of these medications (non-responders). Propranolol and primidone will cause a different pattern of change in electrophysiological parameters among responders. Since the intention component of action tremor usually responds to treatment to a lesser degree than other components of tremor and is reported to be associated with cerebellar dysfunction, the investigators hypothesize that cerebellar dysfunction will negatively correlate with the patient's response to treatment.