Clinical and Physiological Studies of Tremor Syndromes
Clinical and Physiological Studies of Tremor Syndromes
Background:

 Researchers have some data on how the brain controls movement and why some people have
 tremor. But the causes of tremor are not fully known. Researchers want to study people with
 tremor to learn about changes in the brain and possible causes of tremor.

 Objective:

 To better understand how the brain controls movement, learn more about tremor, and train
 movement disorder specialists.

 Eligibility:

 People ages 18 and older with a diagnosed tremor syndrome

 Healthy volunteers ages 18 and older

 Design:

 Participants will be screened with:

 -  Medical history

 -  Physical exam

 -  Urine tests

 -  Clinical rating scales

 -  Health questions

 -  They may have electromyography (EMG) or accelerometry. Sensors or electrodes taped to
 the skin measure movement.

 Participation lasts up to 1 year.

 Some participants will have a visit to examine their tremor more. They may have rating
 scales, EMG, and drawing and writing tests.

 Participants will be in 1 or more substudies. These will require up to 7 visits. Visits could
 include the following:

 -  EMG with accelerometry

 -  Small electrodes taped on the body give small electric shocks that stimulate nerves.

 -  MRI: Participants lie on a table that slides into a cylinder that takes pictures of the
 body while they do simple tasks.

 -  Small electrodes on the scalp record brain waves.

 -  A cone with detectors on the head measures brain activity while participants do tasks.

 -  A wire coil held on the scalp gives an electrical current that affects brain activity.

 -  Tests for thinking, memory, smell, hearing, or vision

 -  Electrodes on the head give a weak electrical current that affects brain activity.

 -  Photographs or videos of movement

 Participant data may be shared with other researchers.
Objectives

 The purpose of this protocol is to study the phenotypic spectrum and the pathophysiology of
 tremor syndromes by performing small behavioral, electrophysiological and neuroimaging
 sub-studies. The protocol includes techniques with minimal risk (standard clinical
 evaluation, MRI, EEG, peripheral nerve stimulation, single and paired pulse TMS) and certain
 sub-studies may involve healthy volunteers. This protocol aims to study neurophysiological
 and behavioral outcomes in defined groups of patients with tremor syndromes, to inform future
 hypothesis-driven and confirmatory studies, which will be developed and submitted as separate
 protocols. For this purpose, we aim to conduct 1) pilot sub-studies, 2) individual patient
 investigations, 3) technical development studies.

 Study population

 We intend to enroll up to 300 patients with essential tremor and other isolated action tremor
 syndromes, as well as 150 healthy volunteers.

 Design

 This is a non-hypothesis driven study involving standardized phenotyping After patients and
 healthy volunteers complete a screening visit, patients will undergo a standardized
 phenotyping visit including clinical rating scales as well as electrophysiological
 tremorworkup. Patient and healthy controls may then be enrolled in sub-studies, and if a
 substudy leads to results of interest, a separate protocol will be submitted with a priori
 hypotheses, specific study design and power analysis adapted from the pilot or exploratory
 sub-studies performed in the present protocol.

 Outcome measures

 Outcome measures applied in this protocol involve methods for tremor phenotyping such as
 clinical rating scales and questionnaires, electrophysiological tremor studies, videotaped
 exam, as well as digitizing based tasks. During the sub-studies focused on the
 neurophysiological characterization of tremor syndromes, the following outcome measures will
 be applied: EMG: we will analyze tremor signals using spectral analyses, coherence analyses,
 and in combination with accelerometry, EEG, MEG, and TMS to explore tremor-networks. MRI: we
 will analyze measures such as the amplitude of the BOLD signal (fMRI); tractography between
 seed and target regions of interest (using DTI); morphometry of brain regions (using VBM);
 and different neurotransmitter levels in brain regions of interest (using MRS). EEG and MEG:
 we will quantify measures such as corticomuscular coherence, event- or task-related
 potentials, synchronization/desynchronization, and coherence between sensors or sources
 located close to the brain areas of interest. TMS: we will analyze measures such as MEP
 amplitude and central conduction time, as well as measures of cortical excitability and
 inhibition paradigms. Behavioral measures: we will quantify measures of voluntary movement
 involving tremor, reaction times to initiate movements, EMG patterns, movement kinematics
 (position, velocity, acceleration, curvature), eye movement. Actigraphy: We will quantify
 continuous recordings of motion sensors involving multiaxial accelerometers and gyroscopes.
 Furthermore, we may measure autonomic data during the course of experiments (such as blood
 pressure, skin co ductance, and respiratory rate) which would correlate to the outcome
 measures.
-  INCLUSION CRITERIA FOR TREMOR PATIENTS:

 -  Patients diagnosed with a tremor syndrome, including, but not limited to

 -  Essential tremor (per definition of the Tremor Research Group)

 -  Parkinson disease (per UK Brain Bank criteria)

 -  Focal tremor such as isolated head tremor, voice tremor

 -  Task-specific tremor such as primary writing tremor

 -  Orthostatic tremor

 -  Patients with other tremor syndromes such as dystonic tremor, intention tremor,
 etc.

 -  Age 18 or older

 -  Able to give informed consent

 -  Agree to not drink caffeine or alcohol for 12 hours before phenotyping and selected
 sub-study visits because both agents can modify brain activity and may confound
 outcome measures.

 INCLUSION CRITERIA FOR HEALTHY VOLUNTEERS:

 -  Age 18 or older.

 -  Able to give informed consent.

 -  Agree to not consume caffeine or alcohol for 12 hours before selected sub-study visits
 because both agents may modify the activity of the brain during the study.

 EXCLUSION CRITERIA FOR TREMOR PATIENTS:

 -  Problematic alcohol use, as defined by a score of 8 or higher on the WHO Alcohol Use
 Disorders Identification Test (AUDIT).

 -  History of a brain tumor, a stroke, traumatic brain injury, epilepsy or a history of
 seizures.

 -  History of psychotic disorder, Bipolar Disorder or a current depressive episode.

 -  History or clinical evidence of another neurologic disorder than a tremor syndrome as
 defined above, which may interfere with the ability to comply with protocol
 requirements or interpret the obtained results.

 EXCLUSION CRITERIA FOR HEALTHY VOLUNTEERS:

 -  Have abnormal findings of clinical significance on the neurological examination that
 may affect the scientific integrity of the study

 -  Problematic alcohol use, as defined by a score of 8 or higher on the WHO Alcohol Use
 Disorders Identification Test (AUDIT)

 -  History of a brain tumor, a stroke, traumatic brain injury, epilepsy or a history of
 seizures.

 -  History of psychotic disorder, Bipolar Disorder or a current depressive episode.

 ADDITIONAL EXCLUSION CRITERIA FOR MOVEMENT DISORDER PATIENTS AND HEALTHY VOLUNTEERS
 SPECIFICALLY FOR MRI:

 We will follow the NMR Center guidelines for MR safety.

 Some of the exclusions are:

 -  Have non-MRI compatible metal in the body, such as a cardiac pacemaker, brain
 stimulator, shrapnel, surgical metal, clips in the brain or on blood vessels, cochlear
 implants, artificial heart valves or ferromagnetic fragments in the eye or oral cavity
 as these make having an MRI unsafe.

 -  Unable to lie flat on the back for the expected length of the experiment.

 -  Have uncontrolled movements of the head.

 -  Have an abnormality on the brain imaging or neurologic examination not related to the
 diagnosis.

 -  Uncomfortable being in a small space for the expected length of the experiment.

 -  Non-removable body piercing or tattoo posing MRI risk

 -  Pregnancy.

 ADDITIONAL EXCLUSION CRITERIA FOR TREMOR PATIENTS AND HEALTHY VOLUNTEERS FOR TMS AND MRI:

 -  Ferromagnetic metal in the cranial cavity or eye, e.g. aneurysm clip or ocular foreign
 body.

 -  Implanted electronic device including deep brain stimulation systems.