Changes in Cortical Oscillations Induced by Repetitive Transcranial Magnetic Stimulation (rTMS) Therapy in Patient Populations With Tremor
Phase: NA
Conditions: Dystonia, Tremor
Sponsor: University of Florida

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Protocol 
 
 
Title:  Changes in Cortical Oscillations Induced by rTMS Therapy in Patient Populations 
with Tremor 
 
Principal Investigator: David E. Vaillancourt, PhD 
Principal Co-Investigator: Aparna Wagle Shukla, MD 
Sub-Investigator: Felix-Antoine Savoie, PhD 
Sub-Investigator: Marissa Schauder 
Sub-Investigator: David Arpin, PhD 
 
Dystonia is a movement disorder characterized by sustained or intermittent muscle 
contractions causing abnormal movements and/or postures [1]. In some patients, they 
experience both the dystonic symptoms and also an oscillating tremor and these 
patients are referred to as having dystonic tremor (DT). Here, the contractions are 
intermittent and oscillatory, and movement can appear rhythmical. When DT appears in 
the arms, it is similar to symptoms of another movement disorder called essential tremor 
(ET). Sometimes, DT and ET can be misdiagnosed. These disorders are associated 
with a loss of inhibition along different levels of the central nervous system. Non-
invasive modalities of brain stimulation that can modulate cortical excitability, such as 
repetitive Transcranial Magnetic Stimulation (rTMS), have been proposed as an 
alternative therapeutic opportunity to correct the loss of inhibition. However, studies 
analyzing the effects of rTMS on dystonia populations have shown contradictory results 
[2], ranging from mild to non-detectable clinical benefit over short periods of time. Many 
of these studies use clinical scales as the only outcome measure, which may not be 
sensitive enough to capture minor changes in cortical activity. These inconclusive 
findings have complicated what future directions to take with this approach. Therefore, 
there is merit in assessing whether any therapeutic change is occurring in the cerebral 
cortex using more sensitive measures of the physiology.  
In prior work [3][4], we have used high-density electroencephalography (EEG) to study 
DT and ET.  We have found that in both groups, patients exhibit attenuated changes in 
alpha (7-12 Hz) and beta (12-30 Hz) band activity over the motor cortices during a force 
control task. Irregular activation of the motor cortices has also been confirmed in fMRI 
studies [5]. We propose using EEG as an outcome measure to detect changes in 
cortical oscillations caused by rTMS in patient populations with tremor. The near 
millisecond resolution of EEG will allow us to detect changes in distinct frequency bands 
in signals recorded from the cortex. 
 
The primary goal of this study is to compare differences in cortical activity of patients 
with dystonia and/or tremor before and after applying a session of rTMS. Specifically, 
we will apply rTMS to the primary motor cortex (M1) as our group and others have 
shown abnormal function of the region. Moreover, a study [6] shows that targeting of M1 
and the dorsal premotor cortex (dPMC) with rTMS results in a trend towards improved 
clinical outcome in patients with focal hand dystonia and cervical dystonia.  
 

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The central hypothesis of this study is that rTMS can modify cortical oscillations in 
patient populations with dystonia and/or tremor and that we will be able to detect these 
changes with the use of EEG. By applying inhibitory rTMS to the motor cortices, we may 
expect a shift in cortical oscillations towards normal activity. 
 
Specific Aim 1: Determine therapeutic effect of rTMS on the cortex of patients with 
Dystonia  
 
We will determine any therapeutic effect of a 1-Hz rTMS session on the primary motor 
cortex of patients with dystonia by comparing the differences in cortical activity of 
healthy controls and patients with dystonia pre-rTMS session to the differences in 
cortical activity of healthy controls and patients with dystonia post-rTMS session. We 
hypothesize that after the rTMS session, the cortical activity of patients with dystonia will 
shift towards the cortical activity of healthy controls. 
 
Specific Aim 2: Determine therapeutic effect of rTMS on the cortex of patients with 
tremor 
 
We will determine any therapeutic effect of a 1-Hz rTMS session on the primary motor 
cortex of patients with tremor by comparing the differences in cortical activity of healthy 
controls and patients with tremor pre-rTMS session to the differences in cortical activity 
of healthy controls and patients with tremor post-rTMS session. We hypothesize that 
after the rTMS session, the cortical activity of patients with tremor will shift towards the 
cortical activity of healthy controls. 
 
Study Design: Subjects diagnosed with Dystonia and/or tremor will be enrolled. 
Diagnosis of Dystonia and tremor will be established in accordance with the Consensus 
Statement of the Movement Disorders Society [1]. In this study, we plan to recruit up to 
60 subjects with Dystonia and/or tremor in the age range of 21-80 years. 
Specifically, our inclusion criterion is: Diagnosis of Dystonia and/or tremor according to 
the Consensus Statement of the Movement Disorders Society. We will exclude patients 
with 1) pregnancy; 2) active seizure disorder; 3) presence of a metallic object such as a 
pacemaker, implants, metal rods, and hearing aid, 4) history of stroke. We will also 
identify subjects who meet inclusion/exclusion criteria from the IRB approved INFORM 
database (IRB#201501166). These subjects have consented to being contacted for 
future research. We will enroll up to 30 healthy controls of similar age distribution and 
sex ratio as the Dystonia and/or tremor group for normative electrophysiological data. 
Controls will be recruited through fliers placed across campus. Additionally, we will use 
databases to identify healthy controls that are willing to be contacted through Health 
Street and Consent2Share. Controls must be free from a diagnosed neurological 
disorder.  We will exclude controls with 1) pregnancy; 2) active seizure disorder; 3) 
presence of a metallic object in their brain, 4) any history of stroke. 
 
Electroencephalography (EEG) will be used as the primary outcome measure. 
Repetitive Transcranial Magnetic Stimulation (rTMS) will be used over the motor 
cortices as an intervention that is expected to have short-term (less than an hour) 

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electrophysiological effects. EEG will be collected before and after administration of 
rTMS. A waiting period will follow to allow the short-term effects of the intervention to 
subside, after which a third EEG procedure will be repeated. 
 
In a subgroup of participants with a mild to moderate severity tremor (n = 20), we will 
use rTMS over the cerebellar cortex and motor cortex on two separate days to collect 
EEG before and after for assessment of electrophysiological effects. The subgroup will 
also receive testing and treatment in addition to what is proposed for the primary group. 
However, the subgroup will complete stimulation delivered to the motor cortex and to 
the cerebellum on two separate days.  The rTMS parameters will be same for motor 
cortex and cerebellum.  The participants who meet the severity tremor criteria and 
agree to participant in the subgroup will be scheduled on two testing days at least one 
week apart to allow adequate wash-out time. For the second visit, we may not repeat 
clinical assessments if the results from the first assessment are deemed sufficient.   
  
Eligible subjects will be invited to the Laboratory for Rehabilitation Neuroscience. We 
will obtain IRB approved informed consent. Subjects will be explained in detail about the 
procedures outlined for the study. In order to characterize the current clinical 
progression of disease we will administer a subset of the following assessments: 
Montreal Cognitive Assessment (MoCA), Beck Depression Inventory (DBI), Ambulatory 
Parkinson’s Disease Monitoring (APDM), The Essential Tremor Rating Assessment 
Scale (TETRAS), and Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). 
Once completed, subjects will be fitted with an EEG cap and have the electrode holes of 
the cap filled with conductive gel. The electrodes will be placed and then resting-state 
EEG and/or task-based EEG will be collected. Resting-state EEG will have subjects sit 
down and rest, without falling asleep, for no longer than 20 minutes. Task-based EEG 
will have subjects perform a pinch grip task lasting no longer than 30 minutes. For the 
pinch grip task, subjects will be signaled to produce a pre-determined amount of force 
on loadcells using one hand. They will be provided with visual feedback on a screen so 
that they may see how much force they are producing relative to the target force. Once 
the EEG procedure is conducted, the rTMS intervention will be administered to the 
targeted region for only the patient groups. Afterwards, the same EEG procedure 
conducted before the rTMS will be performed to capture the effects of the intervention. 
Once completed, the waiting period will occur. Once the period ends, the EEG 
procedure will occur again. Controls will perform all tasks except for the rTMS 
intervention. 
 
Outcome measures: The primary outcome measure will be EEG cortical recordings. 
EEG is an electrophysiological imaging method used to record electrical activity of the 
brain. It is non-invasive and provides information about the behavior of neuronal 
populations below the scalp. This is useful to our study because we expect rTMS to 
alter the excitability of neurons in the motor cortex. We will also collect 
electromyography (EMG) data from hand and neck muscles as a secondary measure. 
 
Clinical assessments: We will use certain clinical assessments to characterize the 
mental state, mental ability and motor symptoms of subjects enrolled in this study. 

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(1) The Montreal Cognitive Assessment (MoCA) is a widely used screening tool 
for detecting cognitive impairment and mild cognitive impairment. 
(2) The Beck Depression Inventory (DBI) is a widely used psychometric test for 
measuring the severity of depression. It consists of 21 multiple-choice self-reporting 
items. 
(3) The Ambulatory Parkinson’s Disease Monitoring (APDM) is used to assess 
sway, balance and gait. This device uses six wearable sensors to assess kinematics of 
the body during everyday movement tasks. 
(4) The Essential Tremor Rating Assessment Scale (TETRAS) is used to quantify 
essential tremor severity and its impact on activities of daily living. This rating scale will 
be video recorded with the participant’s permission to ensure reliability of ratings.   
(5) The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) is used 
to quantify the severity, disability and pain associated with cervical dystonia. This rating 
scale will be video recorded with the participant’s permission to ensure reliability of 
ratings. 
 
Not all of these assessments will be performed as they may not be relevant to 
certain groups. For example, assessment (4) and (5) are only relevant to patients with 
essential tremor and cervical dystonia. 
 
rTMS therapy 
 
Stimulation: rTMS will be delivered over a single M1 hemisphere, using a Magstim 
Rapid2 TMS therapy system (Magstim Inc., Eden Prairie, MN, USA) [7]. The coil that 
delivers the magnetic pulses will be placed over the hand region of M1, which can be 
found near the C3/C4 locations of a 10/20 electrode system [8]. The coil position will be 
marked on the EEG cap with a small circular sticker. 1800 pulses will be delivered in 3 
separate trains of 600 pulses at a 1 Hz frequency and at an intensity of 90% of the 
resting motor threshold (RMT). A 1-minute break will occur between trains for a total 
duration of 32 minutes. This stimulation protocol is adapted from a previous study [9]. 
The RMT will be defined as the lowest stimulation intensity required to evoke a 50 μV 
potential in a target muscle recorded using electromyography (i.e. first dorsal 
interosseus muscle in our case). During rTMS, all patients will wear ear plugs in order to 
protect the ears from the acoustic artefact associated with the discharge of the 
stimulation coil. 
 
 
Safety of rTMS: Repetitive TMS can have undesired side effects [10]. The proposed 
study will use TMS parameters well within the published safety guidelines adopted by 
the International Federation for Clinical Neurophysiology and subsequently updated 
[11][12]. We will conduct careful monitoring of the participants and follow all 
recommended precautions for the application of TMS.   
For the subgroup (n=20), we will use a low frequency (1 Hz) stimulation dose. 
Stimulation at this frequency has not been associated with adverse effects. Table 1 (S. 
Rossi et al., 2009, p. 2016) of the safety guidelines article covers the safety aspects. 
Our study also involves 1800 pulses at 1 Hz frequency (32 minutes long) delivered over 

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two sessions about one week apart, which is a much lower dose compared to FDA 
approval of daily session of 3000 pulses at 10 Hz frequency (45 min daily) for 30 
consecutive sessions for medication refractory depression. 
 
Table 1 
Potential side effects of TMS. Consensus has been reached for this table. 
Side effect 
Single-pulse 
Paired-pulse TMS 
TMS 
Low frequency rTMS 
High frequency rTMS 
Theta burst 
Seizure induction 
Rare 
Not reported 
Rare (usually Possible (1.4% crude risk estimate protective effect) 
in 
epileptic patients; less than 
1% in normals) 
Possible (one seizure in a 
normal subject during cTBS) 
(see para 3.3.3) 
Transient acute hypomania 
induction 
No 
No 
Rare 
Possible following left prefrontal stimulation 
Not reported 
Syncope 
Possible as epiphenomenon (i.e., not related to direct brain effect) 
Possible 
Transient headache, local pain, neck 
pain, toothache, paresthesia 
Possible 
Likely possible, but 
Frequent (see para. 
not reported/ 
3.3) 
addressed 
Frequent (see para. 3.3) 
Possible 
Transient hearing changes 
Possible 
Likely possible, but 
Possible not 
reported 
Possible 
Not reported 
Transient cognitive/ neuropsychologial 
changes 
Not reported 
No reported 
Overall negligible 
(see Section 4.6) 
Overall negligible (see Section 4.6) 
Transient impairment of 
working memory 
Burns from scalp electrodes 
No 
No 
Not reported 
Occasionally reported 
Not reported, but likely 
possible 
Induced currents in 
electrical circuits 
Theoretically possible, but described malfunction only if TMS is delivered in close proximity with the elec brain stimulators, 
pumps, intracardiac lines, cochlear implants) 
tric device (pace-makers, 
Structural brain changes 
Not reported 
Nor reported 
Inconsistent 
Inconsistent 
Not reported 
Histotoxicity 
No 
No 
Inconsistent 
Inconsistent 
Not reported 
Other biological transient 
effects 
Not reported 
Not reported 
Not reported 
Transient hormone (TSH), and 
blood lactate levels changes 
Not reported 
 
Reimbursement: 
 
Participants will receive $80.00 for taking part in a one-day visit to the laboratory. 
Participants who are eligible and choose to participate in the two-day visit subgroup 
study will receive $80.00 for each visit. In addition, they will be reimbursed for travel 
costs (such as flights, hotels, and/or reimbursement for gas) if they live a minimum of 50 
miles away from Gainesville. Finally, during long testing sessions, food and beverages 
for the participant and any family members and/or caregivers that accompany them to 
the visit will be provided at no expense to them. 
 
Data Safety Monitoring Plan 
 
The research team monitors the patient safety and data collection of each study visit.  The 
Data Safety and Monitoring Committee will meet once each year to review the 
recruitment, adverse events, data collection, and other aspects of the study.  The Data 
Safety and Monitoring Committee will be notified of any adverse events that occur during 
the course of the study, within 2 business days of the specific adverse event.  This will 
allow the DSMC to review any issues that arise in a timely manner.  Breaches of 

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confidentiality will also be monitored by the DSMC.  If there is possible harm to subject 
safety or the possibility of, any harm due to something new that was learned during the 
study, the DSMC will be convened.  Christopher Hess, M.D., Aparna Wagle Shukla, M.D., 
and David Vaillancourt, Ph.D. will monitor the safety of the project yearly. Dr. Hess will 
serve as an independent health professional on the Data Safety Monitoring Committee.  
 
Regulatory Approval and Statistics 
 
The study will be approved by the University of Florida Institutional Review Board, and 
all subjects will provide informed consent. The study is highly feasible given the 
relatively large number of patients with dystonia and patients with tremor seen at UF 
and the considerable expertise. 
 
Statistical analysis will be done with R, a free software environment for statistical 
computing and graphics, and Matlab toolboxes (EEGLAB, among others). For the 
resting state data, we will use a mixed model ANOVA on the average power of different 
frequency bands. There will be 2 factors: group (Controls, and tremor groups) and time 
(3 levels: T0, T1, and T2), where T0 is data collected before rTMS, T1 is data collected 
after rTMS, and T2 is data collected after the waiting period. For task-based data, we 
will use EEGLAB to preprocess the data and compute Event Related Spectral 
Perturbations (ERSPs), a time-spectral graph. From the ERSPs we will run 
comparisons at each time-frequency point. Because of the large quantity of time-
frequency points, we will correct for multiple comparisons. 
 
From previous work [3] we have data about the mean and standard deviation of the 
average power of the beta band (12-30 Hz) of activity in the brain of ET patients during 
a force control task similar to the one proposed for this study. We expect to have 3 
groups (controls, dystonia and tremor) each built of approximately 30 people. We 
conducted a power analysis comparing ET vs. control using an independent samples t-
test (alpha = 0.05; two-tailed). With this data we predict a 95% power estimate. 
 
 
ET 
Controls 
Power 
Estimate 
Mean 
SD 
Mean 
SD 
  
Average beta 
band (12-30 Hz) 
power 
-2.24 
1.57 
-3.57 
1.24 
94.7% 
 
 
Possible Discomforts and Risks: 
 
There are some possible discomforts and risks for participants taking part in this study. 
TMS: 
• 
Headaches – Headaches and neck aches can occur. They can be related to 
stabilizing the neck when measuring TMS. They are usually short lasting and respond 
easily to over the counter analgesics. 

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• 
Transient hearing threshold shift – There is a possibility of temporary mild hearing loss 
due to the noise of the TMS machine. The rate of this risk is unknown yet. Earplugs 
will be provided to the participant to reduce the potential for this risk.   
• 
Seizure – A theoretical risk associated with brain stimulation. In clinical trials using the 
NeuroStar TMS Therapy® System, which included over 10,000 TMS treatments, no 
seizures were reported.  Since FDA clearance of the NeuroStar Therapy System, the 
seizure risk is ≤0.1% per patient (less than 1 in 1000 patients).  In the event that the 
participant has a seizure, the study staff will immediately stop the treatment session 
and make sure that the participant is safe during the seizure.  The participant will be 
watched for a period of time after the seizure to make sure he or she is feeling well. 
Individuals with an active seizure disorder are excluded. 
• 
Fainting – Not directly related to magnetic stimulation. It is thought to be related to 
anxiety and psycho-physical discomfort during the procedure. The laboratory is 
equipped, and staff is trained to respond to this risk if fainting occurs. However, the 
participant will be at very low risk (less than 1%) for fainting. Transfer to the 
emergency room might be needed if the participant fails to improve as expected. 
• 
Effect of Magnetic Stimulation – Effect described on implanted devices (such as 
pacemakers, deep brain stimulation leads or cochlear implants). To avoid this 
potential complication, the participant will be excluded from the study if the participant 
has any metallic implants such as pacemakers, implants, metal rods or hearing aids.  
• 
Childbearing Potential- There may be unknown risks to the fetus. Therefore, women of 
childbearing age will complete a pregnancy test for the TMS portion of the study at 
each visit. In order for the women of childbearing age to participate in this study, the 
participant should avoid becoming pregnant from their first day of most recent 
menses.  A negative pregnancy test does not absolutely prove that a woman is not 
pregnant.  If the female participant thinks that there is a possibility that she might be 
pregnant, the study team should be notified immediately. Nursing mothers are not 
eligible for participation in this project.  The possibility exists that complications and 
undesirable side effects, which are unknown at this time, could occur.   
EEG: 
• 
A gel paste is used to attach the sensors during EEG which may mildly and briefly 
irritate the skin on the scalp or face. Hair products cannot be used on the day of 
testing (or should be washed out prior to testing), which may be inconvenient to the 
participant. 
EMG: 
• 
A gel paste is used to attach the sensors during EMG which may mildly and briefly 
irritate the skin. 
 
 

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APDM: 
• 
For the measurement of body movement with the APDM, the participant may lose 
balance or fall while standing with hands on hip and walking a short distance.  The 
study staff will keep a close distance to avoid any falls.  
 
Possible Benefits:  
 
The participant may or may not benefit from taking part in this study. The rTMS may 
have a short-term benefit on tremor or dystonia, and our goal is to understand the 
mechanism under which this occurs. The information learned in this study will benefit 
the neurology and therapy development community. In addition, the information from 
this study might help researchers develop better treatments using rTMS and EEG to 
help others with Dystonia and tremor in the future.  
 
Confidentiality 
 
Information collected about the patient will be stored in locked filing cabinets or in 
computers with security passwords.  Only certain people have the legal right to review 
these research records, and they will protect the secrecy (confidentiality) of these records 
as much as the law allows. These people include the researchers for this study, certain 
University of Florida officials, the hospital or clinic (if any) involved in this research, and 
the Institutional Review Board (IRB; an IRB is a group of people who are responsible for 
looking after the rights and welfare of people taking part in research). Otherwise the 
research records will not be released without participant permission unless required by 
law or a court order. 
 
Researchers will take appropriate steps to protect any information they collect about 
participants. However, there is a slight risk that information about participants could be 
revealed inappropriately or accidentally.  Depending on the nature of the information 
such a release could upset or embarrass them, or possibly even affect their insurability 
or employability.   
 
If the results of this research are published or presented at scientific meetings, patient 
identity will not be disclosed. 
 
Depression measure and suicide risk 
If the Beck Depression Inventory reveals that the patient has feelings of harming 
themselves, we will refer them to mental health services available at Shands at the 
University of Florida.   
 
 
 
 
 
 
 

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References 
 
[1] 
A. Albanese et al., “Phenomenology and classification of dystonia: A consensus 
update,” Mov. Disord., vol. 28, no. 7, pp. 863–873, Jun. 2013. 
[2] 
R. Erro, M. Tinazzi, F. Morgante, and K. P. Bhatia, “Non-invasive brain stimulation 
for dystonia: therapeutic implications,” Eur. J. Neurol., vol. 24, no. 10, pp. 1228-
e64, Oct. 2017. 
[3] 
A. Roy et al., “Cortical dynamics within and between parietal and motor cortex in 
essential tremor,” Mov. Disord., vol. 34, no. 1, pp. 95–104, Jan. 2019. 
[4] 
C. W. Hess, B. Gatto, J. W. Chung, W. Wang, A. W. Shukla, and D. E. 
Vaillancourt, “Cortical Oscillations in Cervical Dystonia and Dystonic Tremor,” 
2020. 
[5] 
J. C. DeSimone, D. B. Archer, D. E. Vaillancourt, and A. Wagle Shukla, “Network-
level connectivity is a critical feature distinguishing dystonic tremor and essential 
tremor,” Brain, vol. 142, no. 6, pp. 1644–1659, Jun. 2019. 
[6] 
S. P. Richardson, S. Tinaz, and R. Chen, “Repetitive transcranial magnetic 
stimulation in cervical dystonia: Effect of site and repetition in a randomized pilot 
trial,” PLoS One, vol. 10, no. 4, Apr. 2015. 
[7] 
“The Magstim® Rapid2 Family - Magstim TMS.” [Online]. Available: 
https://www.magstim.com/product/rapid-family/. [Accessed: 14-Nov-2019]. 
[8] 
T. L. Rich and B. T. Gillick, “Electrode placement in transcranial direct current 
stimulation—how reliable is the determination of C3/C4?,” Brain Sci., vol. 9, no. 3, 
Mar. 2019. 
[9] 
S. R. Filipović, J. C. Rothwell, and K. Bhatia, “Slow (1 Hz) repetitive transcranial 
magnetic stimulation (rTMS) induces a sustained change in cortical excitability in 
patients with Parkinson’s disease,” Clin. Neurophysiol., vol. 121, no. 7, pp. 1129–
1137, Jul. 2010. 
[10] K. Machii, D. Cohen, C. Ramos-Estebanez, and A. Pascual-Leone, “Safety of 
rTMS to non-motor cortical areas in healthy participants and patients,” Clin. 
Neurophysiol., vol. 117, no. 2, pp. 455–471, 2006. 
[11] S. Rossi et al., “Safety, ethical considerations, and application guidelines for the 
use of transcranial magnetic stimulation in clinical practice and research,” Clinical 
Neurophysiology, vol. 120, no. 12. pp. 2008–2039, Dec-2009. 
[12] E. M. Wassermann, “Risk and safety of repetitive transcranial magnetic 
stimulation: Report and suggested guidelines from the International Workshop on 
the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996,” 
Electroencephalogr. Clin. Neurophysiol. - Evoked Potentials, vol. 108, no. 1, pp. 
1–16, Jan. 1998.