Repeated TMS at Low Frequencies to Reduce Seizure Occurrence
Phase: NA
Conditions: Epilepsy, Status Epilepticus, Epilepsia Partialis Continua, Epilepsia Partialis Continua, Refractory (Medically)
Sponsor: Baptist Health South Florida

 
 
 
 
 
 
 
 
 
Title:  Repeated TMS at Low Frequencies to Reduce Seizure  
NCT Number:  NCT03154307 
Protocol Number: 15-135 
Document Date: September 21, 2021 
 

Repeated TMS at Low Frequencies to Reduce Seizure Occurrence 
 
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I. SUMMARY OF THE RESEARCH 
Perform non-invasive neuro-navigated repeated Transcranial Magnetic Stimulation (rTMS) at low 
frequencies (LF) with the intent to reduce the occurrence of seizures over time. Seizure reduction 
and improvements in the quality of life in patients with epilepsy will be associated with increased 
cortical inhibition resulting from the LF-rTMS sessions over time. This procedure using rTMS at 
low frequencies (LF-rTMS) between 0.5 and 1 Hz is a safe and painless method for noninvasive 
focal cortical brain stimulation, which will be evaluated in its efficacy at reducing/suppressing 
seizures. Accordingly, we propose a clinical trial in patients with epilepsy to test whether LF-
rTMS can improve seizure suppression. The location of the presumed 3D source in the brain will 
be stimulated for few minutes (10 to 15mns). With the same rTMS modality, we will also perform 
motor threshold mapping in conjunction with its fully integrated and compatible 
electroencephalography (EEG) module.  
Despite the progress made in the development of multimodal imaging algorithms, there are still 
limitations and drawbacks to be overcome in the area of time and space alignments. The 
simultaneous use (time alignment) of different recording modalities on a same patient (space 
alignment) would validate a given outcome as long as it is imaged or recorded in more than one 
imaging/recording modality.  As such, brain mapping and 3D source localization are consolidated 
in a same 3D space and in context to the 3D source where seizures are anticipated to emanate from. 
The multimodality structure relies in the simultaneous use of TMS, MRI, EEG and 
Electromyography (EMG), all non-invasive, safe, and FDA approved. The complete procedure 
will include tasks of motor threshold mapping using non-invasive brain navigated magnetic 
stimulation, while simultaneously monitoring EEG and EMG. The study is of minimal risk with 
common risks/discomforts of the test limited to mild and brief discomfort of the skin on the scalp 
from the Velcro strap or the EEG electrodes. Also, occasional side effects of the test are minor and 
brief headache from prolonged TMS stimulation.  
The significance of this work is related to addressing the effectiveness of long-term use of rTMS 
for medically refractory patients (failed two or more medications) as a non-invasive alternative to 
other established techniques (i.e. VNS, RNS, among others). For this purpose, we will unify data 
from different sources whose analysis and results are strengthened and validated in more than one 
modality (TMS, MRI, EEG in consortium), which will secondarily provide higher resolution for 
assessing the dysfunction in both temporal and spatial domains. All of these steps are to ensure the 
delivery of the most effective rTMS brain stimulation with the intent to reduce/suppress the 
occurrence of seizures in patients with epilepsy to include both children and adult populations.  
 
II. SCIENTIFIC BACKGROUND & LITERATURE REVIEW 
Transcranial Magnetic Stimulation with both single (sTMS) and repetitive simulation (rTMS) 
capabilities is a non-invasive technology, which serves not only as a powerful tool for mapping 
the eloquent cortex of the brain, but provides great potential for treatment and eliciting new insights 
into a variety of brain disorders, especially for patients who do not benefit from drug treatments. 
The TMS technology was introduced in the 1980s, and since then, it has been used in clinical care 
for several neurological disorders [1–4]. The initial intent of this technology was to improve the 
health of patients with depression as exemplified in studies [5–8]. Its application has now been 

Repeated TMS at Low Frequencies to Reduce Seizure Occurrence 
 
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extended to gauge the merits of magnetic stimulation to other neurological disorders such as 
epilepsy [9–11], Huntington’s disease [12], Parkinson’s disease [13], different effects of 
schizophrenia [14–16], Alzheimer’s disease, and effects of aging [17, 18], in patients who have 
had a stroke [19–21], autism [22, 23], and attention deficit and hyperactivity disorders [23, 24]. 
These are by no means an exhaustive listing of such noteworthy references, but these are examples 
of studies that highlight the extensive use of TMS technology. It should be noted that the use of 
TMS can be performed under two modes of operation, namely, single pulse [25] or repetitive mode 
of stimulation [26, 27].  
The hypothesis is that low frequency brain stimulation focused on and around the seizure onset 
zone will reduce the occurrence of seizures over time. We base this hypothesis on clinical trials 
and reports on the treatment of seizures reported in the literature. It has been shown that high 
frequency rTMS, although beneficial in the treatment of patients with depression, can actually 
cause seizures [28], while low-frequency rTMS has the opposite effect in that it can actually inhibit 
the occurrence of such seizures. Modulating brain activity is shown to depend on the selection of 
the frequency used during stimulation [29, 30]. Therefore, and on the basis of this knowledge, we 
will restrict the brain stimulation process to a low frequency range between 0.5 and 1 Hz rTMS in 
people with focal and generalized epilepsy, while taking into consideration all the safety 
guidelines, ethical issues, and required precautions from prior research in the use of TMS 
technology [31, 32, 33]. 
 
The significance of this work is to address the efficacy of the long-term use of rTMS in the 
treatment of refractory epilepsy patients. Additionally, the integration of multimodal imaging 
where TMS, MRI, and EEG could provide data not available through DCS or fMRI alone, which 
in turn can only augment our understanding of brain mapping and brain dynamics. This study will 
employ a carefully planned low frequency rTMS protocol, with therapeutic sessions over a one-
year time frame, with a possible extension phase protocol if initial study is successful.   
 
III. RESEARCH OBJECTIVES  
 
1. To reduce/suppress the number of seizures in patients with medically intractable epilepsy 
(partial and generalized) with the use of long-term LF-rTMS. Stimulation will be applied 
with determined seizure onset zone by inverse solutions and 3D software algorithms of 
analysis of electroencephalographic data. This objective is based on promising rTMS 
studies that reported reductions in seizure frequency. The primary continuous outcome 
measures for this aim will be seizure frequency, EEG epileptiform discharge frequency, 
seizure severity scale, and psychometric testing.  
2. Statistical analysis will be conducted using ANOVA and secondary outcome measures will 
analyze the number of patients whose seizure frequency decreases by at least 50% (e.g., 
the “responder” threshold used in studies of anticonvulsant efficacy). 
3. Localize through TMS stimulation motor threshold cortex mapping of the abductor pollicus 
brevis-evoked response. This is an important step for determining the appropriate patient-
specific stimulation threshold. 
4. Measure EEG alpha asymmetry before and after rTMS and compare the change in this 
continuous variable among treatment and sham groups in intractable epilepsy. We 

Repeated TMS at Low Frequencies to Reduce Seizure Occurrence 
 
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hypothesize, that rTMS will alter the ratio of right to left EEG alpha power (8-13 Hz). 
Alpha asymmetry is known to be common in patients with epilepsy in contrast to healthy 
controls where alpha symmetry is seen as more prevalent. 
IV. INCLUSION AND EXCLUSION CRITERIA 
All individuals between ages 18 to 80 that are medically refractory who have completed informed 
consent/assent, and able to cooperate with non-sedated navigated TMS testing will be included. 
Exclusion criteria include the presence of implanted electronic devices (e.g., pacemaker, 
medication pump, brain or vagus nerve stimulator, cochlear implant), intracranial metal (e.g., 
aneurysm clip), or inability to cooperate with the rTMS session. 
Goal recruitment will be 90 epilepsy patients, based on the following: 
- 
At least 3 seizures in one month 
- 
No status epilepticus for 1 year 
- 
No change in medication for 1 month 
 
V. METHODS AND ACTIVITIES 
5.1 Interventions and Interactions of the Research Study 
An Informed Consent will be obtained by Baptist Health personnel and the subject will be 
explained the aims and procedures of the research task that will be performed by FIU personnel. 
- 
Positioning of the subject in the TMS chair along with the registration apparatus (spectacles 
or head band) and performing a high-resolution (< 2mm) registration of the subject head 
to the pre-acquired magnetic resonance imaging (MRI) since the TMS machine is MRI-
guided. 
- 
Connecting 1-6 EMG surface electrodes on target muscles to evaluate muscle response to 
TMS stimulation, and  
- 
EEG electrodes will be placed according to the 10-20 system montage.  
The systems (EMG and EEG) will continuously record the activity from the subject throughout 
the procedure. It should be noted that since these acquisition techniques, which are completely 
non-invasive and used regularly in clinical settings, render little or no discomfort to the test 
subjects. There will be a neurologist (Dr. Alberto Pinzon) on the premises during all procedures. 
Sections 5.1-5.3 and 5.4.3-5.4.4 of the “Methods and Activities”, as explained below will be 
performed completely by FIU personnel (Mercedes Cabrerizo, Ph.D. and Ms. Niovi Rojas).  Malek 
Adjouadi, Ph.D. from FIU will supervise all the protocol outcomes.  Dr. Pinzon will refer all 
epileptic patients that will be included in this study research. Also copies of standard care MRI 
images (not taken as part of this study) will be provided by Baptist Hospital Radiology Department 
after enrolled subjects sign a HIPAA agreement to allow it. 
5.2 TMS mapping and recording 
The technology used in this research study is based on the so-called Neuro-navigated Brain 
Stimulation (NBS), a technology developed for mapping the eloquent cortex of the brain as well 
for therapy as currently used on different neurological disorders in different centers and healthcare 

Repeated TMS at Low Frequencies to Reduce Seizure Occurrence 
 
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providers. This newly acquired technology by the CATE center is to improve accuracy in the 
diagnosis and in improving mapping the brain non-invasively. TMS mapping and recording will 
allow for (1) MRI-guided neuro-navigation with electric-field controlled stimulation to precise 3D 
targets in the cortex; (2) powerful and highly focal magnetic stimulator and coils with the ability 
to monitor the point of focality as well depth attenuation; (3) a compatible fully integrated EMG 
for motor functions; and (4) a compatible 60-channel EEG module for integrating brain electrical 
activities at rest and under the TMS stimulation process. TMS thus offers a non-invasive 
alternative to DCS (gold standard). This can be further augmented with the fMRI images in order 
to validate the location of these eloquent cortical areas. 
Since the TMS is FDA approved for motor threshold mapping, the following protocol is used to 
map the eloquent cortex. 
5.2.1 Motor Threshold Mapping Protocol 
All the patients will lie down in a comfortable chair in a supine position. The Nexstim system’s 6-
channel EMG module (SR=1450 Hz, cut-off frequency of 350 Hz for the low pass filter) will 
automatically calculate the motor evoked potential (MEP) amplitudes and latencies as the motor 
cortex (cortex area of the thumb) is stimulated. Disposables Ag-AgCL surface electrodes will be 
used to record the MEP responses displayed in a computer screen in order to assess the validity of 
the response based on the strength of MEPs, reflecting the ability of that area to develop a muscle 
contraction. 
 
This protocol will consist of the following two steps: 
- 
Perform TMS in order to determine the motor threshold for each individual patient.  
- 
In order to obtain the motor threshold, the intensity of the TMS is gradually increased in 
order to elicit responses from the Abductor Pollicis Brevis (APB) muscle near the thumb. 
- 
Once the motor threshold is determined the complete tracking of the motor cortex is carried 
out at an intensity of 10% greater than the motor threshold.  
- 
The entire process of motor cortex mapping is estimated to take 15-20 minutes. 
 
Prior studies have demonstrated that partial motor threshold can vary in a person from session to 
session and for this reason, it will be performed every time patients are treated.  
5.3 Epilepsy Protocol for rTMS at low frequencies in Epilepsy (long-term protocol) 
Repetitive transcranial magnetic stimulation (rTMS) at low frequency range (0.5-1 Hz), LF-rTMS 
is a safe and painless method for noninvasive focal cortical brain stimulation which is efficacious 
in suppressing seizures. Accordingly, we propose a clinical trial in patients with epilepsy to test 
whether LF-rTMS can improve seizure reduction/suppression. The location of the presumed 3D 
source in the brain and its immediate surroundings will be stimulated for 14 minutes at these low 
frequencies.   

Repeated TMS at Low Frequencies to Reduce Seizure Occurrence 
 
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Existing protocols that are related to this work [34-41] are listed in Table 1. These were reviewed 
in order to bring in synergy the strengths of each for carrying out safe and effective rTMS sessions. 
Accordingly, we propose a long term trial in patients with focal and generalized epilepsy, to test 
whether LF-rTMS can reduce/suppress the occurrence of seizures, and determine for how long 
such outcomes can last for each patient. The proposed protocol that will be followed in this study 
is described in Table II on the basis of the knowledge gained from these previous studies. 
Table 1: Existing Protocols. 
Cited 
Literature 
Frequency 
Threshold 
Stimuli 
Schedule 
Coil 
Outcome-
seizures 
Position 
Daily 
Stimulation 
time 
Cantello, 
et al. 
2007 [34] 
0.3 Hz 
100%MT 
65%MSO 
500/trai
n 
2 
trains/day 
For 5 
days 
0 
No change 
vertex 
28 min. 
Fregni, et 
al. 2006 
[35] 
1Hz 
70%MSO 
1200/tra
in 
1 
train/day 
For 5 
days 
8 
Decreasing 
3D 
source 
vertex 
20 min.  
Theodore
, et al. 
2002 [36] 
1 Hz 
120% MT 
900/trai
n 
2 
trains/day 
For 1 
week 
8 
Decreasing 
3D 
source 
 
15 min.  
Tergau, 
et al. 
2003 [37] 
0.33, 1 Hz 
Below MT 
1000/Tr
ain 
1 
train/day 
For 5 
days 
0 
Decreased 
0.33 Hz 
vertex 
55 min. 
17 min. 
Brasil-
Neto, et 
al. 2004 
[38] 
0.5 Hz 
90% MT 
100/trai
n 
Biweekly
/ 4 weeks 
8 
Decreased 
 
3D 
source 
vertex 
3 min. 
Misawa, 
et al. 
2005 [39] 
0.5 Hz 
90%MT 
100 
Single 
session 
repeated 
at 3 
months 
8 
Decreased 
for 2 
months 
3D 
source 
 
3 min. 
Menkes, 
et al. 
2000 [40] 
0.5 Hz 
95%MT 
20/train 
5 
trains/day 
Biweekly 
for 3 
months 
0 
decreased 
3D 
source 
 
0.6 min. 
Rossi, et 
al. 2004 
[41] 
1 Hz 
90% rMT 
900 
Single 
session 
8 
decreased 
3D 
source 
 
15 min. 
MT: Motor threshold, MSO: Maximum stimulator output   
Table 2: Suggested Long-Term Protocol for this Study: Treatment vs. Placebo Groups 
(Stimulation time: 14 minutes) 
Frequency 
Threshold 
Stimuli 
Schedule 
Coil 
Position 
Study 

Repeated TMS at Low Frequencies to Reduce Seizure Occurrence 
 
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Design 
1Hz 
120%MT 
800 
5 days/week for 2 
weeks 
1/week for 1 month 
1/month for 11 
months 
8 
3D Source 
Localization, 
vertex, and bipolar 
frontal 
double-
blinded, sham-
controlled 
1Hz 
120%MT 
800 
5 days/week for 2 
weeks 
1/week for 1 month 
1/month for 11 
months 
8 
coil will be placed 
with an angle of 45 
degrees with 
respect to the 
scalp without 
direct contact 
double-
blinded, sham-
controlled 
 
 
Using a single-blinded, sham-controlled design, we will screen patient’s age 2 to 80 years with 
focal and generalized retractable epilepsy. Baseline data will include a detailed seizure diary over 
4 weeks, psychometric testing/neuropsychology evaluation, and 20-minute EEG recordings. Each 
patient will then begin treatment with 14 minute sessions of 1 Hz rTMS or sham rTMS, 120%MT, 
and 800 stimuli on the position of the calculated 3D source using EEG, MRI, and digitized 
electrode locations. The protocol will be divided in 3 groups (Groups 1, 2 and 3) as follows: 
 Groups 1, 2, and 3: LF-rTMS for 2 weeks (5 days per week for total of 10 days). 
 Group 1: protocol total duration: 1 year: LF-rTMS 1 session/week for 1 month (4 days), 
and LF-rTMS 1 session/month for 11 months 
 Group 2: protocol total duration: 1 year: LF-rTMS 1session/month for 12 months 
 Group 3 (placebo protocol, total duration: 1 year): LF-rTMS 1session/week for 1 month 
(4 days); and LF-rTMS 1session/month. 
 
During each session EEG will be recorded. Also, we would update number of events and frequency 
data from ongoing seizure diary. Psychometric testing will be performed at the beginning of study, 
3 months, and at the end of the study. Thus, each patient will have rTMS testing, psychometrics, 
and EEG recordings. 
Goal recruitment will be 90 medically refractory participants, with 30 participants for each of the 
three groups, based on the following: 
- 
At least 3 seizures in one month 
- 
No status epilepticus for 1 year 
- 
No change in medication for 1 month 
In retrospect, promising rTMS studies have reported reductions in seizure occurrence [35, 42-54]. 
Several studies [45-48] included children, and reported improvement in seizure occurrence in the 
majority of these children, due to a modulation in cortical excitability, induced by low frequency 
rTMS. Other studies measured EEG alpha asymmetry [49] before and after rTMS to assess the 
change in this continuous variable among treatment and sham groups in intractable epilepsy. In 
these studies, it is hypothesized that rTMS could alter the ratio of right to left EEG alpha power 

Repeated TMS at Low Frequencies to Reduce Seizure Occurrence 
 
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(8-13 Hz). Alpha asymmetry is known to be present in patients with epilepsy in contrast to healthy 
controls. The major objective in all of these studies is to seek seizure reduction associated with 
increased cortical inhibition resulting from the LF-rTMS sessions [34, 50-53]. TMS (single or 
repetitive pulse) thus offers a noninvasive option that could serve as a therapeutic tool that will 
reduce the occurrence of seizures. 
5.3.1 Epilepsy Protocol for rTMS at low frequencies in Epilepsy (short-term protocol) 
Epilepsia partialis continua (EPC) can be considered the status epilepticus (SE) equivalent of focal 
onset seizure with retention of awareness. EPC may occur as a single episode, repetitive episodes, 
and it may be chronic progressive or non-progressive. The significance of this work is to address 
the efficacy of the short-term use of rTMS in the treatment of EPC patients. This study will employ 
a carefully planned low frequency rTMS protocol, with therapeutic sessions over a short period of 
time (3 to 5 days), with a possible extension phase protocol if initial study is successful.   
Existing protocols that are related to this work [1-7] are listed in Table 3. These were reviewed in 
order to bring in synergy the strengths of each for carrying out safe and effective rTMS sessions. 
Accordingly, we propose a short term trial in patients with EPC, to test whether LF-rTMS can 
reduce/suppress the status epilepticus, and determine for how long such outcomes can last for each 
patient. The proposed protocol that will be followed in this study is described in Table 4 on the 
basis of the knowledge gained from these previous studies. 
During each session EEG will be recorded. Goal recruitment will be 10 acute phase medically 
refractory participants, based on the following: 
 At least 2 medications failed 
 At least 24 hours of acute phase 
 Family consent or available proxy (legal representative) 
 
Equipment:  
The MagVita TMS is CE approved for “treatment of Major Depressive Disorder. MagVenture’s 
rTMS system is effective and it is an alternative to medications. 
Table 3: Existing Protocols. 
Cited 
Literature 
Frequen
cy 
Threshold 
Stimuli 
Schedule 
Coil 
Outcome-
seizures 
Position 
Stimulation 
time 
Gersner, et 
al. 2016 (1) 
20Hz 
80%MO 
500/train 
10 trains 
of 3s with 
30s 
intertrain 
One time 
 
8 
Reduced 
epileptic 
spike 
frequency 
decreased 
seizures 
during 
stimulation 
vertex 
Single  
5 min. 

Repeated TMS at Low Frequencies to Reduce Seizure Occurrence 
 
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Liu A, et al. 
2015 (3) 
1Hz 
70%MO 
 
1 train 
8 
Reduced 
epileptic 
spike 
frequency 
and seizures  
3D 
source 
20 min. 
Rotenberg, 
2009 (4) 
1Hz:1800 
sec. 
100%MT 
3 trains 
3 trains 
 
Seizures 
stopped 
3D 
source 
1800 sec 
Graff 
Guerrero. 
2004(5) 
20Hz 
50%MO 
15 trains 
15 trains 
of 2 sec 
 
Seizures 
stopped 
3D 
source 
 
Graff 
Guerrero. 
2004(5) 
20Hz 
128%MT 
15 trains 
15 trains 
of 2 sec 
 
Improved 
EEG 
3D 
source 
 
Schrader 
LMKL, 
2005 (6) 
0.5 Hz 
100%MT 
16 trains 
of 900 
sec 
2 trains 
per 
session, 
biweekly, 
for 4 
weeks) 
 
decreased 
seizures 
3D 
source 
 
Misawa S, 
2005 , (7) 
0.5 Hz 
90%MT 
1 train 
of 200 
sec 
1 train 
 
Seizures 
stopped 
3D 
source 
 
 
 
 
 
 
 
 
 
 
MT: Motor threshold, MSO: Maximum stimulator output   
Table 4: Suggested short-Term Protocol for this Study: (Stimulation time: minutes) 
Frequency 
Threshold 
Stimuli 
Schedule 
Coil 
Position 
Study 
Design 
1Hz 
100%MO 
 
Up to 5 days/  
 
8 
3D Source 
Localization or 
vertex 
Open-label 
 
5.3.2 Limitations and Alternative Approaches 
While TMS is a safe, painless, technically easy procedure, because the orientation of the magnetic 
field of stimulation needs to be perpendicular to the electrical field of stimulation, TMS may not 
always generate a response. In such a case, the benefit of the stimulation technique may be limited. 
The abductor pollicis brevis (APB) is a low voluntary recruitment threshold motor unit, easily 
activated in most individuals using TMS. However, should this fail to activate with maximal 
stimulation, another muscle of similar threshold can be substituted: either the first dorsal 
interosseous or the abductor digiti minimi.  These muscles are all in the palm of the hand. 
5.3.3 Emergency Response and Treatment Protocol in case of Seizure 
A neurologist (Dr. Alberto Pinzon) will be on the premises at all times during the rTMS treatment. 
In the immediate vicinity of the TMS machine where the patient is laying down on a comfortable 
chair similar to the ergonomic dental chair, no harmful objects will be present.  In case a patient 
suffers the occurrence of a seizure during an rTMS session, the following steps are undertaken: 

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 Code rescue will be initiated for the management of acute seizure for patient safety 
according to hospital’s protocols and as below.   
 Diastat AcuDial (diazepam rectal gel) will be kept at the chair side in case any seizures are 
provoked. DIASTAT is a gel formulation of diazepam intended for rectal administration 
in the management of selected, refractory patients with epilepsy, on stable regimens of 
AEDs, who require intermittent use of diazepam to control bouts of increased seizure 
activity for patients 2 years and older.  
 If a seizure occurs, testing (TMS) will be postponed at least 1 hour, or until baseline 
function returns.  
 Patient will be placed on their left side in the recovery position to promote airway and 
prevent aspiration. 
 Harmful objects will be moved out of the way, head will be protected. 
 Patient will not be restrained. Objects will not be placed in the mouth. Adequate ventilation 
will be ensured. 
 Respiratory changes such as skin color increase/decrease in respiratory rate and noisy or 
congested breathing will be monitored. If the patient is not breathing, rescue breathing will 
be started immediate medical attention will be followed. Suction apparatus, clean gloves 
and pillows will be available for immediate use.  
 
http://www.epilepsy.com/get-help/staying-safe and http://www.epilepsy.com/get-help/managing-your-epilepsy 
http://www.emergencycareforyou.org/EmergencyManual/WhatToDoInMedicalEmergency/Default.aspx?id=268 
http://www.webmd.com/epilepsy/epilepsy-seizure-what-to-do-in-an-emergency 
5.4 Multimodal Imaging 
This TMS based protocol for epilepsy relies on multimodal imaging to benefit from (1) structural 
MRI for MRI-guided TMS motor threshold mapping and for situating in context the 3D source of 
seizure onsets; and (2) EEG for determining the 3D source exploiting the presence, positioning 
and singular nature of the interictal spike waveforms. 
5.4.1 Magnetic Resonance Imaging -MRI 
All patients that will undergo TMS brain stimulation would have had both magnetic resonance 
imaging (MRI) recording done at any of our collaborating hospitals (Miami Children’s Hospital, 
Baptist Hospital or other) as it concerns this study. Since TMS is an MRI-guided machine, its use 
in conjunction with an MRI of a patient, it becomes possible to perform pinpointed navigated 
mapping of the language and motor areas of the brain. And when a 3D source is determined using 
interictal spikes of the EEG, such a source is also rendered in the context of the 3D brain of the 
patient.  
5.4.3 Electroencephalography recordings - EEG  

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EEG recordings will be performed using the XLTEK EEG (Electroencephalograph) system. EEG 
signals will also be collected before and after some selected rTMS sessions, so that more 
comprehensive subject-specific connectivity maps could be obtained [54-57]. This is performed 
in order to assess the connectivity maps as a function of the determined position of the 3D source. 
This system will be used to record the brain’s spontaneous electrical activity and evoked responses 
non-invasively from the scalp. XLTEK EEG is a robust whole-head EEG system that can be used 
to record EEG activity so as to determine the 3D source of seizures on the basis of interictal spikes, 
or subsequent to this first step. Some of the research themes that will be investigated include (1) 
EEG activity analysis on the basis of the cortical and sub-cortical stimulation using repetitive pulse 
TMS (rTMS); (2) Study the functional connectivity between areas and the changes that occur in 
the brain before and after stimulating motor and language areas, respectively; (3) assess TMS-
induced modulation of brain rhythms with respect to rest state.  
 
Also EEG recordings in some cases may be performed using the Nexstim eXimia EEG 
system, designed specifically to be fully compatibility with the TMS machine, and is another 
major component that can be purchased alongside the TMS machine, which we did.  It is 
important to note that with the new TMS technology, an EEG module is fully integrated, and 
unlike the inherent noise in the integration of EEG and fMRI, both EEG and TMS signals are 
fully compatible as the TMS does not affect the EEG signal. Consequently, EEG signals will 
also be collected during brain mapping, so that more comprehensive subject-specific 
connectivity maps could be obtained [54-57]. This is performed in order to assess the 
connectivity maps as a function of the determined position of the 3D source. 
5.5. Risks Associated with the Recording Modalities 
5.5.1 Risks of TMS 
TMS often causes minor short-term side effects. These side effects are generally mild and typically 
improve after the first week or two of treatment. They can include: 
- 
Headache. 
- 
Scalp discomfort at the site of stimulation. 
- 
Tingling, spasms or twitching of facial muscles. 
- 
Lightheadedness. 
- 
Discomfort from noise during treatment 
- 
Mild and brief discomfort of the skin on the scalp from the Velcro strap or the EEG 
electrodes. 
Uncommon side effects include: 
- 
Mild and brief headaches or neck aches from the TMS stimulation. Serious side effects are 
rare. They can include: 
- 
Seizure occurring during TMS stimulation at high frequencies. This has only been known 
to happen in 1% of children and adults with epilepsy, and in less than 1% of children and 
adults without epilepsy. 

Repeated TMS at Low Frequencies to Reduce Seizure Occurrence 
 
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- 
Mania, particularly in people with bipolar disorder. 
- 
Hearing loss due to inadequate ear protection during treatment. 
5.5.3 Risks of EEG recording 
There are no known risks for this standard noninvasive scalp EEG recordings, except for slight 
discomfort due to the placement of some of the electrodes that may be too tight on the scalp. 
5.5. 3 Minimizing Risks, Harms, and/or Discomforts 
In order to reduce discomfort due to use of EEG electrodes, 'comfort rings' are used. As for rTMS 
stimulation, a mechanical arm with several degrees of freedom is designed to hold the TMS coil 
to eliminate any potential for pressure on the head of the subject, something that could happen if 
the coil were handheld by the clinician. 
Previous studies have demonstrated that motor threshold mapping in normal subjects is not 
associated with provoking seizures [58]. 
VI. 
DATA TO BE COLLECTED AND DATA ANALYSIS PROCEDURES 
Patients will be given a questionnaire to fill out their demographic and health information. 
Original medical records may be requested and stored by primary neurologist. 
For each patient, the following types of data will be collected: 
- 
A 3D MRI volume: This high resolution volumetric imaging data will be collected so that 
the final results could be displayed in concordance with the regions that were found to be 
active according to the task applied (motor or speech). 
- 
Scalp EEG s in order to extract time and frequency domain parameters to assess the 
reaction of the brain to magnetic stimulation using different intensities and frequencies. 
The lateralization index will be calculated to define the dominant cerebral hemisphere for 
the language task. 
- 
DICOM stimulation maps for motor threshold mapping. 
- 
EMG data obtained from 1-6 EMG electrodes used for monitoring different muscle groups. 
 
The data will be collected and stored for each patient undergoing the study. All the data will be 
de-identified by converting into alphanumeric values. The encoded values will be stored in 
password-protected servers accessible only to research personnel (FIU/Baptist) with authorization 
throughout data collection and analysis.  
 
All identifiers will be removed from the data once they are transferred off the TMS computer and 
gathered into a pooling database, where each case will have a unique consecutive identification 
number. This information will be annotated in a separated document kept in the office of the PI 
(Dr. Pinzon).   

Repeated TMS at Low Frequencies to Reduce Seizure Occurrence 
 
13 
 
 
Statistical analysis will be conducted using SPSS 14.0 software. The baseline seizure frequency 
and seizure frequency change after treatment will be computed from average weekly seizure 
frequencies before and after rTMS treatment for each patient. A patient data will be categorized 
into two treatment groups: rTMS treated and placebo groups. 
 
VII. 
DESCRIPTION OF WRITTEN CHILD/ADULT CONSENT PROCESS  
At a potential subject’s visit to the physician’s office or hospital, the investigator(s) will provide a 
comprehensive explanation of the purpose, procedures, possible risks/benefits of the study, and 
participant responsibilities, and discuss the fact that his/her participation is voluntary, that he/she 
may withdraw from the study at any time, and that the decision not to participate or to withdraw 
will not affect his/her regular medical care. Potential participants or their surrogates will be given 
ample opportunity to ask questions and to consider their decision. If the subject or the surrogate 
agree to participate, then a signed and dated written informed consent will be obtained.   
A copy of the consent form will be given to the participant or the surrogate, and another copy will 
be placed in the subject’s medical record. The informed consent form will be obtained by the 
investigators listed to perform informed consent procedures. 
VIII. EXTENSION PHASE 
If the results from this study demonstrate significant medical improvement, patients will be offered 
an extension phase where they could continue receiving the same parameters of stimulation for 
one to two additional years at no expense 
 
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