Transcranial Direct Current Stimulation of the Motor Cortex in Essential Tremor : A Randomized Controlled Pilot Study
Phase: NA
Conditions: Essential Tremor, Transcranial Direct Current Stimulation
Sponsor: Lebanese American University

1 
 
Transcranial Direct Current Stimulation of the Motor Cortex 
in Essential Tremor: A Randomized Controlled Pilot Study 
 
Principal investigator  
Rechdi Ahdab, MD, PHD  
Neurology Division, Lebanese American University Medical Center Risk Hospital, Beirut, 
Lebanon  
 
Co-investigators  
Naji Riachi, MD  
Neurology Division, Lebanese American University Medical Center Risk Hospital, Beirut, 
Lebanon 
 
Joumana Freiha, MD 
Neurology Division, Lebanese American University Medical Center Risk Hospital, Beirut, 
Lebanon  
 
Romy Zgheib, MD  
Neurology Division, Lebanese American University Medical Center Risk Hospital, Beirut, 
Lebanon  
 
 
 
 
 
 
 
 
 
 

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Proposal outline  
I. 
Introduction / background   
II. 
Study objectives  
A. 
Primary objective  
B. 
Secondary objectives  
III. 
Study outcomes  
A. 
Primary outcome  
B. 
Secondary outcome  
IV. 
Study methodology/design  
A. 
Study design  
B. 
Study setting  
C. 
Participants  
D. 
Inclusion criteria 
E. 
Exclusion criteria 
F. 
Study Population 
G. 
Recruitment and randomization  
V. 
Study procedure  
A. 
Initial visit 
B. 
tDCS sessions  
C. 
Post tDCS 
VI. 
Statistical analysis 
VII. 
Data management 
VIII. Adverse event reporting 
IX. 
Quality assurance, monitoring & safety  
X. 
Dissemination of results and publication policy  
XI. 
References   
 
 
 
 
 
 
 

3 
 
I. 
Introduction  
Essential tremor (ET) is a common progressive neurological disorder and is the most 
common movement disorder. Worldwide , up to 5% of the population suffer from this 
disorder with an increased incidence with advanced age (Agarwal and Biagioni 2018). 
Although essential tremor is considered as a benign disorder, studies have shown that quality 
of life in patients with ET is affected. Patients reported that the tremor interfered with their 
activities of daily living (Louis and Machado 2015) , as well as, causing them anxiety and 
embarrassment (Chandran and Pal 2013). 
 
The 2017 Movement society concusses statement includes the following criteria for the 
clinical diagnosis of essential tremor (Bhatia et al. 2018): 
1. Isolated tremor syndrome of bilateral upper limb action tremor.  
2. At least 3 years history of tremor.  
3. With or without tremor in other locations (head, voice and lower limbs).  
4. Absence of other neurological signs such as dystonia, ataxia and Parkinsonism.  
 
The treatment possibilities currently available for patients with ET are scarce and were 
mostly discovered incidentally. The limitations of existing therapeutic options is partly 
attributable to the absence of an established clear-cut mechanism of ET seeing as 
neurotransmitter deficits, microscopic pathologies, and the genetic defects that cause ET have 
yet to be identified (Deuschl et al. 2011).  
At present, patients with ET can be prescribed either pharmacological or non-
pharmacological treatments. The options available have been approved for the treatment of 
ET; however it is important to note that many of the studies conducted to determine the 
efficacy of these remedies were based on small sample sizes and performed over a brief 
observation period (Schneider and Deuschl 2015). 
1. 
Pharmacological Treatment: The medications available include Propranolol or 
Primidone as first line therapy as well as Benzodiazepines (Alprazolam), Topiramate 
or Gabapentin as second line treatments. The major downside to the available 
pharmacological remedies is that most of the patients may not tolerate the adverse 
events associated with these medications. Moreover , the available treatments have 
limited effectiveness and possess various contraindications that ultimately limit their 
use (Schneider and Deuschl 2015) (Hedera et al. 2013) (Zesiewicz et al. 2011). 

4 
 
2. 
Non-pharmacological Treatment: Surgical interventions are reserved for severe 
refractory cases of ET as they are rather invasive. Considering the predictable 
postoperative morbidity (Sadeghi and Ondo 2010) and major side effects experienced 
by patients limit their optimal use (Zesiewicz et al. 2013). These include Deep Brain 
Stimulation, Thalamotomy, Gamma Knife Thalamotomy and MRI-guided focused 
ultrasound. The adverse effects of these modalities may be unpredictable due to 
equipment malfunction and may include weakness, seizures, cognitive defects and 
others. (Zesiewicz et al. 2013) 
 
The proposed mechanism that underlies ET, the central oscillating network, is mainly 
composed of the olivocerebellar system, thalamus and motor cortex (Raethjen and Deuschl 
2012). The thalamocortical projections originates in the lower brainstem, passes through the 
thalamus and projects to the motor cortex. An interruption in the projections between the 
thalamus and the motor cortex limits the ability of the cortex to reorganize and restore ET 
(Chalah et al. 2015). In addition, unilateral subdural motor cortex stimulation was able to 
reduce contralateral hand tremor in two of the three studied patients with ET (Moro et al. 
2011). Chalah et al described a case of 76 year old female with essential tremor that 
disappeared following a cortico-subcortical prerolandic stroke despite complete motor 
recovery (Chalah et al. 2015). These finding highlight the role of the motor cortex in ET 
production and possible therapeutic role of transcranial direct current stimulation.  
 
Transcranial direct current stimulation (tDCS) has been used to treat a wide range of 
psychiatric and neurological disorders such as depression (Boggio et al. 2008), migraine 
(Antal et al. 2011), stroke (Schlaug et al. 2008) and Parkinson’s disease (Benninger et al. 
2010). tDCS is a type of non-invasive brain stimulation technique proven efficacious in 
modulating human cortical function by producing prolonged but reversible shifts in cortical 
excitability (Priori et al. 1998). This technique has the potential to be an ideal treatment 
option for essential tremor.  
 
One of the most accepted effects of tDCS is its ability to modify neuronal membrane polarity 
depending on the polarity used (Nitsche and Paulus 2001). In other words, when the anode is 
placed over the motor cortical area, tDCS increases cortical excitability both during and 
following the stimulation. Whereas cathodal stimulation decreases cortical excitability. The 

5 
 
duration of tDCS effect depends on the duration and intensity of the stimulation (A. and W. 
2000; Priori et al. 1998).  
Most tDCS studies have adopted similar stimulation techniques. A pair of sponges (25-
35cm2) soaked in normal saline solution are placed over the stimulation site. The tDCS 
electrodes, made of metal or conductive rubber, are then wrapped in a perforated sponge 
pocket.  Constant current of 1–2 mA is then delivered to the patient's scalp through anodal 
and cathodal electrodes with a ramp up and ramp down period of 30s at the start and end of 
the session (Zhao et al. 2017). Sham-controlled studies are easier with tDCS, because 
subjects rarely experience sensations related to the treatment. Ramping for 10 seconds at the 
beginning and end of tDCS, combined with a stimulation duration of 30 seconds in the sham 
condition, results in similar sensory experiences which make real tDCS and sham tDCS 
difficult to distinguish (Gandiga et al. 2006). 
 
Importantly, tDCS has been shown to be safe in a number of trials (Brunoni et al. 2011). 
Worldwide, no major side effects have been reported in thousands of known human subjects 
(Nitsche et al. 2009). There is also individual data on patients who received over 100 sessions 
of tDCS for treatment of schizophrenia and depression that states that no adverse effects 
arose from cumulative exposure (Bikson et al. 2016). However, minor side effects such as 
sensation of itching under the electrodes, mild skin erythema and headaches have been 
reported but these are rarely disturbing and resolve after stimulation is halted (Brunoni et al. 
2011). 
 
Our primary goal is to evaluate the effects of cathodal tDCS of the motor cortex in essential 
tremor patients, particularly its effect on tremor amplitude, and quality of life. Should tDCS 
prove effective, this would be a breakthrough in the treatment of this condition, given its 
excellent safety profile, simplicity and affordability. 
 
II. 
Study objectives  
Primary objectives 
The primary objective of the study is to assess the effect of cathodal tDCS stimulation of the 
motor cortex on tremor amplitude  
 
Secondary objectives:  

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The secondary objectives are to:  
• Assess change from baseline tremor on clinical rating scale  
• Assess change in quality of life  
 
III. 
Study outcomes  
Primary outcome:  
Change in tremor amplitude using an accelerometer pre and post cathodal tDCS of the motor 
cortex.   
 
Secondary outcome:  
Measure change in baseline tremor and effect on quality of life using the TETRAS scale  
 
IV. 
Study methodology / design 
Study design  
A randomized, sham-controlled, double blind and crossover study.  
It will be carried at LAUMC-RH, Beirut, Lebanon over the course of 2 years. 
 
Study setting  
Lebanese American University Medical Center Risk Hospital (LAUMC-RH), Beirut, 
Lebanon  
 
Participants  
We will recruit 40 Patients diagnosed with essential tremor based on the 2017 movement 
society criteria (Bhatia et al. 2018) 
Inclusion Criteria 
Exclusion Criteria 
 
Patients who fulfil the 2017 
Movement society concusses 
statement criteria for 
essential tremor  
 
Age 18 and above  
 
 
Isolated focal tremor (voice, head)  
 
Orthostatic tremor with a frequency of more 
than 12 Hz  
 
Task and position specific tremor  
 
Sudden onset and stepwise deterioration of 
tremor 
 
History of substance abuse or dependence in 
the past 

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 
Comorbid medical conditions and medications 
capable of producing or enhancing tremors 
 
History of neurological disorders, brain 
tumors, brain surgery or abnormal neurological 
examination 
 
Epileptic disorders  
 
Cardiac pacemakers  
 
Metallic hardware in the head or scalp 
(surgical clips) 
 
Eczema or skin abrasion at the intended site of 
stimulation 
 
Currently pregnant or plan for pregnancy in 
the next 6 months 
 
Patients with prior experience with tDCS 
 
Major psychosocial problems or medical 
problems rendering informed consent 
impossible 
 
Study Population: 
The minimum sample size required for the study was obtained using the Chow et al. method. 
A difference of 30% in the accelerometer score will be considered significant. The minimal 
sample size needed per sequence is 17, so a total of 36 samples. In order to account for any 
possible dropout from the study we plan to enroll a total of 40 participants for the study.  
They will be randomly assigned to either one of the two arms (cathodal tDCS versus sham 
tDCS) as per study methodology discussed below.   
 
Recruitment and randomization  
Patients who had visited or will visit LAUMC-RH with a diagnosis of ET on their records 
would be contacted and those interested in participating in the trial would be randomly 
assigned into either (1) cathodal tDCS or (2) sham tDCS.  
One researcher who will not be blinded to group assignment will perform cathodal tDCS or 
sham tDCS. However, another researcher who will assess the outcome measures will be 
blinded to group assignment. The third blinded researcher will collect the demographic data 

8 
 
and assess adverse events. All participants will be blinded to the order in which the 
cathodal/sham conditions will be given. 
 
V. 
Study procedure 
Initial visit: 
The first visit is an inclusion visit, where the examining physician takes a comprehensive 
history, performs a neurological exam, and verifies the inclusion/exclusion criteria. The 
physician will explain the protocol to the patient and provide him/her with information 
regarding the consent form, and the other questionnaires to be filled. The patient will be 
called within the following days to check if he/she agrees to participate in the research and 
therefore plan for the stimulation session.  
 
tDCS sessions: 
Prior to starting the first tDCS session, the patient will be asked to fill his/her first TRG 
essential tremor assessment (TETRAS) scale which includes an activity of daily living 
subscale and a performance subscale (Elble et al. 2012). 
The physician will then quantitatively analyze the tremor on the most affected side using an 
accelerometer. Two measures are obtained with the accelerometer: the tremor frequency and 
amplitude. Sensors are fixed on the skin at a given landmark (index finger) (Grimaldi and 
Manto 2010). The tremor will be assessed in two different positions: (1) at rest and (2) 
postural. 
Subsequently TMS of the motor cortex contralateral to the hand used above will be 
performed with a figure-of-eight coil (70 mm) on a Magstim machine. To determine the 
optimal site of stimulation (hotspot), the coil will be moved around the primary motor cortex 
(M1) eliciting the largest MEP motor-evoked potentials (MEPs) from the first dorsal 
interosseous (FDI) of the hand tested above.  
 
Finally, cathodal tDCS will be administered through a pair of conductive rubber electrodes 
covered by saline soaked sponges (35 cm2). The current will be delivered continuously at 2 
mA for 30 min through a battery-driven constant-current stimulator. The cathode will be 
positioned on the area representing the primary motor cortex and the anode over the 
contralateral supraorbital area.  

9 
 
tDCS stimulation (cathodal and sham) will be done daily for 5 consecutive days during weeks 
1 and 5. Each stimulation session will last 30 minutes. tDCS will be performed while the 
patient is at rest, without any concurrent cognitive or motor task. The two tDCS sessions will 
be separated by a 23 day washout period. 
 
Post tDCS/Clinical evaluation   
Patient will be asked to fill out their TETRAS at days 1 and 5 of each tDCS session (cathodal 
and sham), and days 12 and 19 after each tDCS session (cathodal and sham). Please refer to 
figure 1. 
Accelerometer assessment of the tremor will be performed at days 1 and 5 of each tDCS 
stimulation session (cathodal and sham). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Figure 1: Study design and procedure 
Patients diagnosed with ET, inclusion/exclusion criteria, and consent form 
Randomization 
Cathodal tDCS 
Sham tDCS 
Week 1   
Week 2   
Week 3   
Week 4  
Day 1: clinic 
• 
TETRAS 
• 
TMS 
• 
Accelerometry 
• 
tDCS session 1  
Day 2 – 3 – 4: clinic 
• 
tDCS sessions 
Day 5: clinic 
• 
tDCS session  
• 
TETRAS 
• 
Accelerometry 
Cathodal tDCS 
Sham tDCS 
Week 7  
Week 6  
Week 5   
Cross-over  
Total washout period 
23 days  
Day 12: TETRAS (at home) 
Day 19: TETRAS (at home) 
Day 29: clinic 
• 
TETRAS 
• 
TMS 
• 
Accelerometry 
• 
tDCS session 1  
Day 30 – 31 – 32: clinic 
• 
tDCS sessions 
Day 33: clinic 
• 
tDCS session  
• 
TETRAS 
• 
Accelerometry 
Day 40: TETRAS (at home) 
Day 47: TETRAS (at home) 

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VI. 
Statistical Analysis 
The analysis will be conducted using the R statistical package. Demographic data will be 
summarized using frequencies, means, standard deviations and confidence intervals. The 
change in the TETRAS and Accelerometer scores will be assessed using Wilcoxon paired test 
at different time points (illustrated in figure 1) and the correlation between thee TETRAS and 
Accelerometer scores will be tested using the Pearson method.  
 
VII. Data Management 
The study records will be kept as confidential as possible.  We will protect carefully the 
information about the patient.  What we learn from samples will be described only in a way 
that does not identify the patient. To protect the patients' privacy, samples will be linked to a 
secret code. Names will only be recorded on the informed consent form. We will keep the 
secret code in a locked and carefully protected file, with access only granted to the principal 
investigator of the study and authorized personnel. The records will be monitored and may be 
audited without violating confidentiality. Published data resulting from the study will not 
mention the names of the people who participated in this study. The data will be published in 
peer-reviewed journals. Following the study, the data will be safely stored and kept for 
quality assurance. 
 
VIII. Adverse Event Reporting 
The minor adverse events reported in association with use of tDCS (sensation of 
itching under the electrodes, mild skin erythema and headaches) will be provided the 
necessary short-term medical care by the investigator. They usually resolve spontaneously 
after stimulation is halted. 
 
IX. 
Patients’ withdrawal:  
No available conditions in the study protocol can trigger the patient’s withdrawal. However, 
the patient can withdraw consent, at any point during the study, without any consequences.  
 
X. 
Quality assurance, monitoring & safety 
No external committees will be overseeing the study. No interim analysis will be done. To 
prevent skin irritation, sponge electrodes will be soaked in saline water.  

12 
 
The investigator is responsible/in charge of recording and reporting all the adverse events and 
serious adverse events (SAEs) that might happen throughout the entire research protocol, 
from the time of taking consent, and throughout the whole period required to monitor the 
participants. SAEs will be recorded on a comprehensive form provided for this purpose. This 
form will be completed, printed, dated, signed, and the principal investigator will be promptly 
notified. Moreover, regardless of the time of onset following the protocol, all SAEs suspected 
to be the result of the research protocol should be reported to the investigator unless other 
reasonable explanation exists. All the other adverse events (AEs) will be reported only on the 
medical file of each patient, including the date of onset, characteristics, intensity, and 
duration, etiologies, taken actions, treatments, and resolutions if any. There are no specific 
safety measures related to this research and no important safety data to be collected. 
 
XI. 
Dissemination of Results and Publication policy 
The data will be published in peer-reviewed journals.  If the results show a significant 
improvement in essential tremor patients, further studies will be designed to study the optimal 
maintenance tDCS dose and the long term effect of tDCS.  
 
 
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