Pathophysiology of Tremor-modulating Mechanisms of Propranolol and Primidone in Essential Tremor
Pathophysiology of Tremor-modulating Mechanisms of Propranolol and Primidone in Essential Tremor
Pathophysiology of tremor-modulating mechanisms of propranolol and primidone in essential
 tremor (ET) will be studied using accelerometry with electromyography (EMG), transcranial
 magnetic stimulation (TMS), and eyeblink conditioning paradigm (EBCC). TMS is a
 well-established experimental method for studying the effects of drugs on motor cortex
 excitability. EBCC is a learning paradigm that can be used for studying cerebellar
 dysfunction since only brainstem and cerebellar functions seem to be needed for this
 paradigm. The investigators will use TMS to study the mechanisms of primidone and propranolol
 action in ET, EBCC paradigm to evaluate cerebellar dysfunction in ET patients and to show
 whether cerebellar dysfunction influences the effectiveness of propranolol and primidone. The
 investigators will clinically assess patients using The Essential Tremor Rating Assessment
 Scale (TETRAS) and the Scale for the Assessment and Rating of Ataxia (SARA) scales. Patients
 with ET will be studied prior to treatment with propranolol or primidone and re-tested 3-6
 months after treatment initiation. On each visit, the investigators will clinically assess
 the patients and perform accelerometry, TMS measurements, and the eyeblink classical
 conditioning (EBCC) paradigm. The investigators hypothesize that in ET patients, baseline
 electrophysiological parameters will differ between responders and non-responders to
 propranolol and primidone and that propranolol and primidone will cause a different pattern
 of change in electrophysiological parameters among responders. It is hypothesized that
 cerebellar dysfunction will negatively correlate with patients' response to treatment.
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.
Inclusion Criteria:

 -  diagnosis of essential tremor made according to the newest consensus statement on the
 classification of tremors

 -  patients initiated on propranolol or primidone

 Exclusion Criteria:

 -  a history of seizures

 -  a history of mental illness,

 -  having a cardiac pacemaker

 -  having metal material in the head (except dental material in the mouth)

 -  having a medication pump

 -  pregnancy