Registered Electrical Sources for Effective TMS Treatment of Epilepsy
Phase: NA
Conditions: Epilepsy
Sponsor: Electrical Geodesics, Inc.

Request for Investigational Device Exemption 
for the GES 400 and STM9000 system 
for Suppressing Epileptic Discharges
Version 3, November 2015, Electrical Geodesics, Inc. and EB Neuro, S.p.A.
Summary
We propose a safety and feasibility trial for treating epilepsy (RESET: Registered 
Electrical Sources for Epilepsy Treatment).   In this approach, the cortical source of 
epileptic discharges is ﬁrst localized with dense array electroencephalography (256-
channel dEEG).  This localization is then registered with neuronavigator software to al-
low precise targeting with slow (0. 5 Hz) repetitive Transcranial Magnetic Stimulation 
(rTMS) with the STM9000.  The purpose in the feasibility study is to introduce Long 
Term Depression (LTD) of the seizure onset zone in order to reduce epileptiform dis-
charges.   The goal in the future pivotal trial will be to extend this approach to suppress 
seizures.  The sponsor of this trial is Electrical Geodesics, Inc. (EGI), the manufacturer of 
the dEEG system (GES 400) and the US distributor of the EB Neuro STM9000 rTMS sys-
tem (manufactured in Italy by EB Neuro, S.p.A.).      
The eventual goal will be a pivotal trial for a de novo 510k for dEEG-guided rTMS 
for suppressing epileptic seizures.  The more limited goal of suppressing epileptic dis-
charges (spikes) will allow careful evaluation of safety while demonstrating feasibility 
of the therapeutic action.  In preparing this request, we have studied the guidance on 
the special controls described for rTMS in the FDA Class II Special Controls Guidance 
Document: Repetitive Transcranial Magnetic Stimulation (rTMS) Systems, Document 
issued on: July 26, 2011.  In addition, because patients with epilepsy are at particular 
risk of seizures that may be induced or exacerbated by rTMS, we also address the 
unique risks of this population, the existing evidence on safety and efﬁcacy of rTMS 
treatment of the epileptic focus, and the mitigation we propose to minimize the risks.     
EGI has received an IDE for a safety and feasibility trial for treating epileptic dis-
charges with a different method and device, the Geodesic Transcranial Electrical Neu-
romodulation (GTEN 100) system.  The primary difference in the present proposal is the 
use of rTMS (instead of the GTEN 100) to induce long term depression and thus sup-
pression of the cortical excitability at the epileptic focus.  Dr. Robert Fisher, EGI’s un-
paid consultant on this project, has received an IRB approval at Stanford University 
Hospital for preliminary studies with dEEG-guided rTMS treatment of focal epilepsy 
with the GES 400 and STM9000.  
!1

Device Description: GES 400 and STM9000 
4
Intended Use
4
Indications for Use
4
Previous Submissions
5
Rationale for dEEG Localization and rTMS Treatment
6
rTMS Treatment of Epilepsy 
7
dEEG Localization of the Interictal Discharge Focus
8
STM9000 rTMS System with BrainNet Neuronavigator
10
STM9000 - Device Architecture and Stimulus Waveforms 
12
BrainNet Neuronavigator 
12
Testing the Motor Evoked Potential (MEP) with the Ampliﬁer - STM9000
13
Registering the 256 dEEG Sensors with the Patient’s MRI
13
Localizing the Epileptogenic Zone
15
Individual Cortical Surface Models for Interictal Focus Targeting
15
Validation of the Electric Head Model with bounded Electrical Impedance Tomography (bEIT)
18
Software Life Cycle and Risk Management
19
Risks of GES 400 dEEG Assessment and STM9000 rTMS Treatment and 
Mitigation of Risks
19
Risks of Simultaneous rTMS with the MicroCel 100 Geodesic Sensor Net
19
General Risks of rTMS Treatment
20
Risk of Inducing Seizures by rTMS Treatment
21
Risk of Unwanted Plasticity
22
Mitigating the Risk of Unwanted Plasticity 22
Safety and Feasibility Clinical Trial Design
24
Overview of dEEG Acquisition, Spike Detection, and Spike Localization
25
Overview of the Electric Head Model Construction
25
Overview of rTMS Targeting
27
Clinical Trial Sites
27
Patient Recruitment
27
Inclusion Criteria
28
Exclusionary Criteria 
28
Escape Criteria
28
Baseline, Treatment, and Follow up Protocols
29
Primary Endpoint
30
Secondary Endpoints
30
Safety Endpoint
30
Study Success
30
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Pooling Data Across Sites
31
Study Procedures
31
Informed Consent
31
Localizing Epileptiform Discharges (EDs)     
32
bEIT Validation of the Head Model
32
Determination of rTMS Intensity
32
Review of the EEG for Safety and for Spike Counts  
33
 Additional Monitoring of Risk
33
Overview of Study Protocol
33
Bibliography
35
!3

Device Description: GES 400 and STM9000 
The proposed diagnostic and treatment protocol begins with identiﬁcation and lo-
calization of interictal epileptiform discharges (including spikes and other discharges) 
with the Geodesic EEG System (GES) 400, including the Net Station 5 dEEG software 
and the GeoSource 2.0 source localization software (both FDA cleared).  
The assumptions of this approach are twofold.  First, when there is a single or 
dominant interictal discharge focus, this is typically the site of seizure onset.  Second, 
treatment of this site with slow rTMS will result in seizure suppression (Sun, et al., 
2012).  For the safety and feasibility trial, the ﬁrst goal will be statistically signiﬁcant 
suppression of the patient’s epileptiform discharges from the treated region.  
Once the focus is localized with dEEG with the GES 400, treatment involves induc-
ing long term depression (LTD), and thus decreased cortical excitability, with slow (0.5 
Hz) rTMS pulses using the STM9000 system.  The seizure focus, identiﬁed in the pa-
tient’s MRI with the Net Station and GeoSource software, is then targeted with the pa-
tient’s MRI with the NetBrain Neuronavigator software.  This software guides the posi-
tioning of the STM9000 butterﬂy coil with a 3D localizer (Northern Digital Imaging’s 
Vicrascan) in relation to the patient’s MRI, thereby visualizing the location of the 
STM9000 pulses in relation to the patient’s brain.  
Safety of the procedure is evaluated through continuous dEEG monitoring with 
the GES 400 during and after the treatment session.  
Intended Use
The intended use of the GES 400 STM9000 dEEG-rTMS system is the identiﬁcation, local-
ization, and treatment of epileptic foci in the brain for the temporary suppression of epileptiform 
discharges.
Indications for Use
The GES 400 STM9000 dEEG-rTMS system is indicated to temporarily reduce the fre-
quency of epileptiform discharges in adults with focal, superﬁcial, partial onset seizures that con-
tinue to occur despite at least two trials of anti-epileptic drugs at therapeutic levels.   
!4

Previous Submissions
Table 1 summarizes the EGI and EB Neuro products relevant to both the Geodesic 
EEG System (GES) 400, the STM9000, and their accessory software packages.
 
Table 1.  Summary of products, clearances, and descriptions.
The GES 400 was cleared under K131882 on February 12, 2014. The intended use of 
the GES 400 is:
The Geodesic EEG System 400 Series (GES 400) is intended to measure and record the 
electrical activity of the patient’s brain. It can be used on adults, children, and infants.  
Product Name
Clearance Status
Description;
Any Changes 
for dEEG-rTMS
GES 400
K131882
dEEG System.
No change.
STM9000
Not cleared.  Submitted as 
510k for peripheral nerve 
stimulation (PNS). 
rTMS System.
No change.
NetBrain Neuronavigator
Not cleared.
Software for positioning the 
focus of the rTMS coil in relation 
to the patient’s MRI.
Net Station 5.2
Letter to ﬁle
No change.
Geodesic Sensor Nets
K131882
A low-proﬁle TMS-compatible 
sensor net, the MicroCel 100, has 
been added to the product line.
Geodesic 
Photogrammetry System
K043309
No change.
GeoSource 2.0
K092844
Electrical Source Imaging (ESI) 
with atlas model. GeoSource 3.0 
will include individual head 
models.
Modal Image Pipeline
Not yet cleared.
To be submitted for 510k
Spike Beacon
Not yet cleared.
To be submitted for 510k
!5

The GES 400 consists of a number of hardware components, proprietary electrode 
arrays called Geodesic Sensor Nets, and the proprietary software Net Station.  As is typ-
ical in EEG, the GES 400 uses small amounts of current (less than 10 µA) to test contact 
impedance of the electrodes with the scalp.  The GES 400 uses two other cleared acces-
sories: the Geodesic Photogrammetry System (K043309) for locating the sensors in 3D 
and the GeoSource 2.0 EEG source localization software (K092844).  During this trial, we 
anticipate upgrade to the next generation GeoSource 3.0 software, which will soon be 
submitted for a 510k as an upgrade of GeoSource 2.0.  Spike identiﬁcation and marking 
by the clinician will be supplemented in the present trial with the new Spike Beacon 
software, which will soon be submitted separately under a 510k.    
The STM9000 has been submitted to the FDA by EB Neuro under a 510k for pe-
ripheral nerve stimulation (see Appendix 1: STM9000_Device_Description PNS).  The 
NetBrain Neuronavigator software has not been cleared, but will be submitted for sepa-
rate clearance/approval as well.  
Rationale for dEEG Localization and rTMS Treatment
Epilepsy remains refractory to drug treatment in one-third of patients.  Although 
the drugs developed in recent years have more tolerable side effects than traditional 
anti-epileptic drugs, their efﬁcacy remains limited: one-third of patients continue to 
have seizures (Bergey, 2013).  Furthermore, the side effects of modern drugs remain sig-
niﬁcant, and these side effects degrade the quality of life for many patients who must 
take them.  Some patients discontinue the drugs, even at the risk of continued seizures.  
Neurosurgical resection of the epileptogenic zone is an effective treatment.  How-
ever, particularly in the US in recent years, neurologists are reluctant to advocate for 
neurosurgery with patients and families.  This is presumably for legal and social rea-
sons rather than medical reasons, because the medical evidence strongly supports neu-
rosurgical resection.  Nonetheless, neurosurgical resection is now increasingly avoided 
(Engel, 2013).  
There are several invasive technologies for electrical stimulation of the brain, in-
cluding electrodes placed in the anterior thalamus, or intracranial electrodes stimulated 
in response to apparent seizures, or electrodes that affect the brain indirectly through 
stimulation of the vagus nerve.  Nonetheless, even though these methods require 
surgery and implanted devices, the clinical efﬁcacy of these methods remains poor, 
roughly on a par with that of anti-epileptic drugs (Bergey, 2013).   
In this era of advanced human neuroscience, the failure to treat epilepsy effectively 
is a major failure of modern science and medicine.  Even if their seizures are sup-
pressed, many children suffer from the sedation of anti-epileptic drugs.  If their seizures 
are not suppressed, the seizures may cause permanent brain damage.  Uncontrolled 
seizures can injure the brain and lead to sudden unexpected death in epilepsy (SUDEP).  
!6

Eliminating or reducing seizures could signiﬁcantly improve the quality of life for mil-
lions of people.  
For the present safety and feasibility trial, we propose to deﬁne feasibility as the 
statistically signiﬁcant suppression of epileptiform discharges, including spikes and 
other discharges.  Although seizure suppression will be the goal of the pivotal trial, 
there is evidence that cognitive development is impaired in children with frequent 
spikes, even if seizures are controlled (Ebus et al., 2012; Rudzinski & Meador, 2013).  
Even though we view it primarily as a proof of feasibility of seizure suppression, spike 
suppression itself may be clinically signiﬁcant.
Interictal spikes are imperfect surrogates for seizures.  Interictal spiking tends to 
decrease before a seizure (Lange, Lieb, Engel, & Crandall, 1983) and increases after 
seizures, but not with changes in medication (Gotman & Kofﬂer, 1989).  Low interictal 
spike frequency in patients with unilateral mesial temporal sclerosis predicts a good 
postsurgical outcome (Krendl, Lurger, & Baumgartner, 2008), but it is not known 
whether reducing spike frequency would contribute to reducing seizures with surgical 
or medical therapies.  Several studies have investigated the effects of neurostimulation 
on spike counts, usually ﬁnding that stimulation reduces spiking (Labar et al., 2013).  
Spike reductions have been observed with stimulation of the vagus nerve (Koo, 2001; 
Kuba et al., 2010; Olejniczak et al., 2001), centromedian thalamus (Velasco, Velasco, 
Marquez, & Velasco, 1993; Velasco et al., 1995) and hippocampus (Vonck, Boon, Achten, 
De Reuck, & Caemaert, 2002).  Responsive cortical stimulation produced changes in 
spiking consistent for an individual patient, but with increases for some and decreases 
for others (Labar et al., 2013).  Most relevant are two studies showing spike reductions 
with rTMS (Cantello et al., 2007; Fregni et al., 2006).  The study by Cantello (Cantello, et 
al. 2007) saw interictal spikes decrease in one third of patients receiving rTMS (p=n.s.), 
but not in patients receiving placebo stimulation. Fregni (Fregni,et al. 2006) documented 
a mean 31% reduction of interictal spiking immediately after rTMS (p<0.0012), still 
present at week 4 and 8 following a 5-day stimulation paradigm.
rTMS Treatment of Epilepsy 
In a review of the initial case reports and uncontrolled trials treating epilepsy with 
rTMS, Nitsche and Paulus (Nitsche & Paulus, 2009) observed considerable variability in 
the patients (nature of epilepsy and localization of the seizure focus), methods (frequen-
cy and intensity of rTMS), and the results (therapeutic effect).   In three randomized and 
sham controlled trials (RCT), two of the trials treated patients with focal epilepsy with 
high intensity rTMS delivered at a slow (1 Hz) rate: one of these reported suppression of 
seizures that was statistically signiﬁcant, whereas the second study reported marginally 
signiﬁcant suppression.  In the third RCT, patients with mixed etiology were included, 
!7

the rTMS was lower intensity, and only suppression of epileptiform discharges rather 
than seizures was observed.
The importance of careful targeting of epileptic foci with high intensity slow (in 
this case 0.5 Hz) rTMS was emphasized in the successful suppression of seizures report-
ed by Sun, et al (Sun et al., 2012).  In a RCT design, the high intensity treatment was at 
90% of resting motor threshold (rMT), whereas the sham condition was 20% of rMT.   
The epileptic focus was determined from conventional 10-20 System EEG, semiology, 
and MRI.  In many of these patients a frontal or parietal focus allowed the presumed 
epileptogenic tissue to be targeted within the reach of rTMS, which is roughly a depth 
of 2 to 3 cm (Wagner, Zahn, Grodzinsky, & Pascual-Leone, 2004).  Both groups had an 
average of 9 seizures per week prior to treatment.  The sham (20%) group continued at 
about 9 per week for the 10 weeks of follow up after treatment.  In contrast, the active 
90% rMT treatment group had an average of 2 seizures per week starting at the ﬁrst 
week after treatment and continuing for the ten weeks of follow up.  In addition, the pa-
tients in the active rTMS treatment group group reported a signiﬁcant reduction on 7 of 
9 psychiatric symptom scales on the SCL-90 questionnaire.   Impressed with the Sun, et 
al., results, we have adopted several elements of their methodology in the present de-
sign.          
Other evidence for therapeutic efﬁcacy has come from rTMS treatment for sus-
tained or repetitive seizures.   Rotenberg and associates (Rotenberg, Bae, Takeoka, et al., 
2009) reported applying fast (20 to 100 Hz) bursts or sustained slow (1 Hz) rTMS in 7 
patients with epilepsy partialis continua (EPC).  In three patients there was a brief 
(20-30 minute) suppression of the seizures.  In two more of these patients the suppres-
sion lasted up to one day.  In six additional reports that Rotenberg et al found in the lit-
erature, three patients showed suppression of seizures with rTMS treatments (Roten-
berg, Bae, Muller, et al., 2009).  Importantly, none of the patients showed worsening of 
seizures with rTMS.   This relative safety of rTMS in epileptic patients is consistent with 
the review of TMS safety by Rossi et al (Rossi, Hallett, Rossini, & Pascual-Leone, 2009), 
with the important caveat that patients must not be taken off their anti-epileptic med-
ication. 
dEEG Localization of the Interictal Discharge Focus
In several of case reports on treating refractory status epileptics (RSE) with rTMS at 
Beth Israel Deaconess Medical Center (BIDMC), the investigators have reported not 
only that rTMS is practical in the ICU setting (Liu, Pang, Herman, Pascual-Leone, & 
Rotenberg, 2013), but that it can be guided effectively by dEEG localization of the 
epileptic focus.   Vanhaerents et al report on a young man with progressive epilepsy 
leading to drug-refractory status epilepticus, deﬁned as repetitive seizures without full 
recovery of consciousness (VanHaerents, Herman, Pang, Pascual-Leone, & Shaﬁ, in 
press).  Treatment efforts included trials of multiple anti-epileptic drugs (AEDs), at dos-
!8

es that led to impaired cognitive status, multiple admissions to the ICU for treatment to 
burst-suppression coma with IV anesthetics, and high dose cortiosteroids.  Nonetheless, 
the patient continued to have up to 30 seizures per day.  
Localization of the patient’s focal seizures with EGI’s 256 dEEG and the GeoSource 
2.0 software showed a medial left occipital focus.  Guided by the Sun et al. (2012 results, 
this focus was treated with daily sessions of 1800 high intensity (95-100% of motor 
threshold) rTMS pulses at 1 Hz.  Both seizures and spikes over the occipital focus de-
clined to zero by the fourth day of treatment, and the patient was seizure free at dis-
charge.  At one month after start of treatment, he received three additional rTMS treat-
ments.  At seven months, his EEG showed increased interictal discharges, and he re-
ceived 5 additional rTMS treatments, which reduced the discharges.  A nine months, he 
has remained seizure free and has been able to reduce AEDs to the point that he can re-
turn to his academic work (Van Haerents, et al., in press).    
In a more recent unpublished case by the same group of investigators at BIDMC, a 
similar effective course of rTMS treatment was observed with another young man with 
frequent daily focal seizures.  This case is particularly important because it underscores 
the importance of accurate dEEG localization.  The initial rTMS treatment, guided by 
GeoSource 2.0 localization (with typical sensor positions and the atlas head conductivi-
ty model) and by the patient’s semiology (auditory aura apparently induced by the 
seizure) was ineffective.   Using the GeoSource 3.0 software (with the Modal Image 
Pipeline), an individual head conductivity model was constructed using the patient’s T1 
weighted MRI, including cortical surface extraction for establishing oriented cortex di-
9
Figure 1. Left: Block diagram of the major components of the STM9000.  Right: Photo of the STM9000 
conﬁgured with chair and BrainNet Neuronavigator. 

pole patches (Li, Malony, & Tucker, 2006; Li, Papademetris, & Tucker, in press-b).   Actu-
al sensor positions were obtained with the Geodesic Photogrammetry System (Russell, 
Eriksen, Poolman, Luu, & Tucker, 2005) and registered precisely with the patient’s MRI.  
The source localization of the interictal discharge then showed a slightly different focus 
in the temporal lobe, more inferior than auditory cortex.  Targeting of this focus with 
high intensity slow (1 Hz) rTMS resulted in a cessation of the seizures.  Three weeks af-
ter the treatment, the patient had remained seizure free. 
STM9000 rTMS System with BrainNet Neuronavigator
The STM9000 rTMS system (Figures 1 and 2) is a conventional Transcranial Mag-
netic Stimulator (TMS) composed of a current generator that produces energy dis-
charges on a stimulating probe (Coil) placed to contact with the patient’s skin.  Ap-
pendix 1 provides a detailed technical device description (oriented to peripheral nerve 
stimulation), that follows the guidelines for rTMS in the FDA Class II Special Controls 
Guidance Document: Repetitive Transcranial Magnetic Stimulation (rTMS) Systems, 
Document issued on July 26, 2011. 
The butterﬂy coil of the STM9000 generates conventional rTMS waveforms, as 
shown in the measurements in Figure 3 (and Appendix 1).  In the TMS device, a capaci-
tor C is charged to a high voltage.  The energy stored in the capacitor C is supplied to 
10
Figure 2. Left: Alternate conﬁguration of STM9000 on cart without neuronavigator.  Right: Air 
Cooled 70 mm Butterﬂy coil. 

the coil, which generates a magnetic ﬁeld having a damped sine waveform.  The mag-
netic ﬁeld induces electric current in the body, which creates the physiological effect.
The STM9000 is provided with a hardware module for recording TMS-induced 
MEP (Motor Evoked Potentials) named the Ampliﬁer- STM9000.  The Ampliﬁer-
STM9000, if connected to STM9000, is able to detect the electromyographic (EMG) re-
sponse of the patient to TMS-induced activity of the motor cortex.  The video monitor of 
STM9000 displays the motor evoked potential so detected, allowing the operator to de-
tect and quantify the motor threshold level for the patient (Appendix 1).
11
Figure 3. Left to right: Biphasic waveform; Monophasic waveform; Damped sinusoid waveform; 
double or two-pulse waveform.
Figure 4. BrainNet Neuronavigator showing position of the rTMS coil (upper right of top image) 
with its electric ﬁeld distribution (vizualized with hot metal, red-yellow, color palette), and then 
positioned over the motor cortex (bottom image).   

STM9000 - Device Architecture and Stimulus Waveforms
The magnetic stimulator STM9000 works on the principle of the RLC-series cir-
cuits.  A capacitor C is charged to a relatively high voltage, by means of a high voltage 
power supply (HVPW Module), the process is controlled by a microcontroller circuit 
(HVI Module). The same circuit (HVI Module) activates a power switch that connects 
the capacitor C to the inductance L of the coil. Therefore the energy stored in the capaci-
tor C is sent to the coil, which generates a magnetic ﬁeld having a damped sine wave-
form. The damping is due to a resistive component R in the circuit connecting the ca-
pacitor C and inductance L of the coil. The waveform can be controlled and limited to 
the following morphologies:  biphasic: the ﬁrst period of a damped sinusoid; monophasic:
the ﬁrst period of a rectiﬁed damped sinusoid; sinusoid: a damped sinusoid.  The 
STM9000 is able to generate a double stimulation in temporal succession, using a dou-
ble capacitor C and a double control circuit (HVI Module) with relative switch (Ap-
pendix 1). This architecture supports two-pulse stimulation protocols.  The monophasic 
pulse is used in the present protocol, with the 0.5 Hz stimulation rate.
BrainNet Neuronavigator 
The positioning of the rTMS current delivery in relation to the patient’s brain is 
achieved by importing the structural MRI into the BrainNet Neuronavigator software 
(Figure 4).  The position of the rTMS coil in space is calibrated with the Vicrascan 
(Northern Digital, Inc.) 3D locator hardware shown in Figure 1.  The position of the pa-
tient’s head is calibrated similarly, with a 3-ball locator afﬁxed to the headband.  An es-
timate of the electric ﬁeld distribution is built from the coil model and imaged in color
12
Figure 5. Left: With 11 video cameras, the exact 3D sensor positions are captured with EGI’s Geodesic 
Photogrammetry System (GPS). Middle: the infrared images allow computer vision detection of all sen-
sors in the Geodesic Sensor Net.  Right:  The 3D sensor coordinates are then registered with the individ-
ual’s MRI to allow precise planning of current delivery in relation to the person’s head tissues. 

in Figure 4, allowing the operator to position the coil in a way that optimizes the target-
ing of the desired location.   
Testing the Motor Evoked Potential (MEP) with the Ampliﬁer - STM9000
Our testing of the STM9000 over the last two years has used the Ampliﬁer - 
STM9000 to measure the MEP evoked by the STM9000 to establish the motor threshold.  
In the recently completed study of the efﬁcacy of the pulsed GTEN (Geodesic Transcra-
nial Electrical Neuromodulation) protocol in inducing Long-Term Depression or LTD of 
the cortex (Luu, et al., in preparation), the Ampliﬁer - STM 9000 was used to measure the 
MEP as the primary dependent variable reﬂecting the GTEN-induced LTD.   It per-
formed safely and reliably in all these studies. 
In the GTEN normal validation study, we examined 12 normal subjects over 3 ses-
sions each and observed that slow (0.5 Hz) cortical-surface-cathodal electrical GTEN 
pulses (100 ms each) resulted in signiﬁcant depression of cortical excitability as mea-
sured by the MEP.  The sham GTEN procedure did not change the MEP.  Cortical-sur-
face anodal GTEN decreased cortical excitability but not signiﬁcantly so.   
The procedure for determining TMS motor threshold targeted the cortical area cre-
ating the MEP from the ﬁrst dorsal interosseous muscle (FDI muscle) with relaxed mus-
cle tone.  Based on the Rossini et al protocol, initial TMS intensity was set to 35% of the 
maximum stimulator output. The intensity was increased by intervals of 5% until MEPs 
in the right FDI muscle are consistently above 50uV (peak-to-peak amplitude).  Then 
the stimulator output level was decreased by 1% until 5 out of 10 MEPs were above 
50uV and 5 out of 10 MEPs were below 50uV.  This output level is then determined as 
the resting motor threshold. 
For evaluating GTEN efﬁcacy, the baseline MEP was elicited with 130% of TMS 
power determined for the subject’s motor threshold.  Using this same TMS power, the 
MEP amplitude was assessed at 5 min intervals up to 30 min, then at 60 and 90 min.   
A similar protocol will be used with the Ampliﬁer - STM9000 to determine the pa-
tient’s motor threshold in the present clinical trial for dEEG-guided rTMS treatment of 
neocortical epilepsy.
 
Registering the 256 dEEG Sensors with the Patient’s MRI
To achieve close registration of the rTMS treatment with the localization of the 
epileptic focus as deﬁned by the dEEG, the dEEG sensors are located in space with the 
Geodesic Photogrammetry System (GPS; Figure 5) and then registered with the MR im-
age with the Modal Image Pipeline software (Figure 6).   
!13

The Modal Image Pipeline is a set of software modules that allow processing of 
MRI, CT, images and sensor positions in preparation for Electrical Source Imaging or 
ESI with the individual’s MRI data.   Key features of the Modal Image Pipeline are au-
tomated tissue segmentation (scalp, skull, cerebrospinal ﬂuid, gray and white matter) 
and cortical surface extraction (Figure 6).  The Modal Image Pipeline (for preparing the 
individual head model) and GeoSource 3.0 (for Electrical Source Imaging with the indi-
vidual head model) are being prepared for FDA submission.  That submission will 
present validation results showing that localizing spikes and seizures with the individ-
ual head models are at least as accurate as the results with atlas models with GeoSource 
2.0.  Those atlas model results have been validated by comparison with intracranial 
recordings and by surgical outcome. 
14
Figure 6.  EGI’s Modal Image Pipeline software provides segmentation of each major head tissue 
type, to allow a high resolution electrical (ﬁnite difference method) model that simulates how 
electrical currents, both natural and impressed, propagate through the head.  The extraction of 
the cortical surface (upper right) is important for specifying the location and orientation of corti-
cal sources in Electrical Source Imaging (ESI).    

Localizing the Epileptogenic Zone
In the application of rTMS to suppress epileptiform discharges (and eventually 
seizures), Electrical Source Imaging (ESI) is ﬁrst conducted with the dense array EEG 
(dEEG) to localize epileptiform events with EGI’s GeoSource software.  As illustrated in 
Figure 7, dense array ESI with GeoSource 2.0 has been shown to be accurate in deter-
mining the epileptogenic zone, as veriﬁed by intracranial recordings and by neurosurgi-
cal outcome in suppressing or eliminating seizures (Brodbeck et al., 2010; M. Holmes et 
al., 2010; M. D. Holmes et al., 2008; Yamazaki, Terrill, Fujimoto, Yamamoto, & Tucker, 
2012; Yamazaki, Tucker, et al., 2012; Yamazaki, Tucker, Terrill, Fujimoto, & Yamamoto, 
2013).  
Individual Cortical Surface Models for Interictal Focus Targeting
The next generation of ESI will be enabled by individual electric head models for 
Finite Difference Method calculations of electrical volume conduction and sources con-
strained to the oriented cortical surface (Figures 8 and 9).  These anatomical and cortical 
15
Figure 8. The Modal Image Pipeline begins with tissue segmentation from the individual’s MRI (upper left), with 
white matter extraction (upper middle) and gray matter extraction and hemisphere separation (upper right).  If the 
patient’s CT is not available, the skull and bones are modeled by nonlinear warping of a database CT to the subject’s 
MRI (lower left).  The cortical surface extraction (lower middle right) is followed by tessellation of the cortical surface 
into patches, such as 1 sq cm, with an equivalent dipole computed for the net (vector sum) orientation of that patch 
(lower right).   

surface geometry data, along with the exact sensor positions, are imported into the 
GeoSource 3.0 ESI software.  The visualization interface for GeoSource 3.0 is called the 
Reciprocity Engine (Figure 10) because it integrates the reciprocity of the dEEG mea-
surement of the brain’s electrical ﬁelds with the impress of current for head model veri-
ﬁcation (with bEIT) and with Geodesic Transcranial Electrical Neuromodulation (de-
scribed in EGI’s IDE G150023).  
The ﬁrst step in electrical source imaging is review of the electric head model to 
conﬁrm the accuracy of tissue segmentation, CT skull registration, and cortical surface 
extraction (Figure 10, top).  With the improvements in accuracy of the anatomically cor-
rect electric head model, the localization of the epileptiform activity as has been validat-
16
Figure 9. Construction of an individual electrical head model for the GeoSource 3.0 soft-
ware. FromTop: Tissue segmentation for the Finite Difference Model; Photogrammatic 
location of EEG sensors; Scalp rendering of the MRI; Registration of the sensor positions 
with the scalp surface to exactly match the positions in the photographs. 

ed within reasonable accuracy with GeoSource 2.0 (Figure 7) can be improved further 
through integrating the analysis with the patients individual anatomy.
17
Figure 10. Electrical Source Imaging (ESI) of epileptiform activity with GeoSource 3.0 and the Reci-
procity Engine visualization software.  The individual head model (top) includes the segmentation of 
tissue compartments with appropriate conductivity values for ﬂesh (gold), skull and bone (green), CSF 
(dark blue), gray matter (red), white matter (yellow), eyeballs, and air (light blue).  Cortical surface ex-
traction (top left) is evaluated in relation to gray and white matter segmentation (top right).  The elec-
trical ﬁelds recorded in the EEG (positive = red; negative = blue; bottom left) are modeled by dipolar 
sources (gold arrow).  

Validation of the Electric Head Model with bounded Electrical Impedance Tomography (bEIT)
Once the anatomical (geometric) components of the electric head model are veri-
ﬁed by inspection, the electrical conductivity of the head tissues is tested for each pa-
tient with the bounded Electrical Impedance Tomography (bEIT) protocol (Figure 11) 
that we have optimized and validated over the last ten years (Salman et al., 2006; 
Volkov, Zherdetsky, Turovets, & Malony, 2009).  EIT is a well-known method of visualiz-
ing the internal tissues of the body through injecting current, measuring the potential 
created on the body surface, and computing the impedance or conductivity of the body 
tissues through Ohm’s law (Salman et al., 2006).  Because we know the geometry of the 
tissues from segmenting them from MRI and CT images (Figures 8 and 9), we devel-
oped bounded EIT to bound or constrain the problem with the known geometry of the 
MRI (or atlas), together with the exact sensor positions from geodesic photogrammetry.  
The resulting bEIT protocol is not the ill-posed imaging reconstruction of classical 
EIT, but a well-posed ﬁtting of the conductivity to each tissue compartment (whose im-
age or geometry is now easily obtained from MRI or an MRI atlas).  When applied with-
in the dEEG assessment workﬂow, the bEIT validation (Figure 11) can be completed 
through impressing high frequency (200 Hz) low power signals between multiple pairs 
of source and sink electrodes in a scanning pattern to interrogate multiple regions of the 
head (particularly of the various skull bone plates).  The current is limited to 100 µA in 
hardware, and the electrodes are 1 cm2 in surface area (including electrolyte), so that the 
18
Figure 11. The bEIT validation procedure evaluates the prediction of the electric head model against the 
measured paths of injected currents through head tissues.  Left:  Illustration of the selection of three 
source electrodes (red) and 3 sink electrodes (blue).  Middle:  The forward projection of the electrical 
currents that are estimated to be impressed at the cortical surface.  Right:  The validity of the estimated 
current paths is tested through the bEIT computation, in which the EEG potentials at all non-injecting 
electrodes predicted by the Finite Difference Method (FDM, green) is compared to the measured poten-
tials created by the injected currents between channels 2 and 26 for Subject 12 (red). 

current density is limited to 100 µA/cm2.   If the potentials created at the head surface 
are within 10% of the prediction by the electrical head model for 90% of the channels, 
then we consider the accuracy of the currents impressed on the cortical surface to be 
veriﬁed within the noise limits of the typical recording. 
Software Life Cycle and Risk Management
EB Neuro has developed the BrainNet neuronavigator software under the CE 
Medical Device Directive, with equivalent requirements for a moderate level of concern.  
The Net Station, GeoSource 2.0 and 3.0, , have been developed under EGI’s Quality Sys-
tem for a moderate level of concern.  EGI’s Quality System is audited internally on a 
regular basis, and it is audited externally by a CE notiﬁed body as well as by the FDA 
(March 2015).  Design documents for the GTEN 100 include the Design Concept Report, 
Marketing Requirements Document, and Software Requirements Speciﬁcation.  Key 
functional components of the software have been designed and tested at the unit level, 
with regular regression testing and hazard reviews.    
Risks of GES 400 dEEG Assessment and STM9000 rTMS Treatment and 
Mitigation of Risks
Many of the risks of dEEG-guided rTMS treatment of epilepsy with the GES 400 
and STM9000 system are described by the FDA guidance document, Repetitive Tran-
scranial Magnetic Stimulation (rTMS) Systems, Document issued on: July 26, 2011.  We 
ﬁrst address these general risks and their mitigation.  In addition, the risk of inducing 
seizures is particularly important for patients with epilepsy.  We provide Appendix 1, 
which details the design of the STM9000 in relation to the FDA 510k submission for pe-
ripheral nerve stimulation.
Risks of Simultaneous rTMS with the MicroCel 100 Geodesic Sensor Net
The MicroCel 100 Geodesic Sensor Net (Figure 14) is a low-proﬁle Net designed to 
allow close placement of the TMS coil to the head.  The electrodes are carbon-ﬁber ABS 
plastic coated in AgCl, conﬁgured with the electrode and strain relief to stand off the 
head less than 5 mm.  Use of the slow (0.5 Hz) rTMS pulses of the present protocol with 
the STM9000 directly over the electrode results in no perceptible heating of the elec-
trodes.   
Direct application of the butterﬂy coil’s discharge with fast repetitive stimulation 
over an EEG electrode can cause heating of the electrode.  The Instructions for Use pro-
vide guidelines for avoiding this hazard.  The proposed clinical trial involves a slow (0.5 
Hz) stimulation rate that does not cause noticeable heating even when applied directly 
!19

over an electrode.  This was ﬁrst veriﬁed in the Hazard Review of the STM9000 and 
GES 400 on July 3, 2013.   This was conﬁrmed with testing of heating under various 
stimulation rates in the MicroCel 100 design hazard review, March 20, 2014.  It was veri-
ﬁed after review of one year of experience with combined dEEG and rTMS in our inter-
nal use in the GES 400 hazard review, May 11, 2015.  As noted by the Safety of TMS 
Consensus Group (Rossi et al., 2009), the risk of electrode heating from TMS pulses are 
non-existent to rare, depending on stimulation protocol.  For single and paired TMS 
pulse protocols, there are no risks associated with scalp electrode heating.  Induction of 
currents in electrical circuits, which can impair operating of medical devices (such as 
EEG), is also possible but only when the TMS pulse is delivered near the device’s cir-
cuitry.  TMS use with scalp EEG does not pose this risk, as the TMS stimulating coil is 
not placed near the EEG ampliﬁer.
General Risks of rTMS Treatment
Two important risks, identiﬁed by the FDA rTMS guidance document, are failure 
to identify the correct patient population and ineffective treatment.  These are related 
risks, because effective treatment requires that the targeted cortical region (the focus of 
the epileptic spikes and the presumed seizure onset zone) be within reach of rTMS tar-
geting.  The GES 400 STM9000 dEEG-rTMS system is intended for suppressing epilepti-
form discharges (and eventually seizures) in patients with focal, superﬁcial, partial on-
set seizures.  The restriction to superﬁcial cortical sites is because the magnetic ﬁeld fall 
off from the TMS butterﬂy coil limits effective induced electrical current ﬂow to ~ 2 cm 
from the head surface (Wagner, et al., 2004).  As shown by the Wagner, et al., simula-
tions, the induced current is limited primarily to the crown of the cortical gyrus, al-
though the cortical surface radial induced current (aligned with the pyramidal neurons 
and thus thought to be most effective) is then limited to the most superﬁcial walls of the 
adjacent sulcus.  
We will attempt to mitigate this risk by careful selection of patients whose interic-
tal foci can be localized with conﬁdence with the GES 400 and GeoSource software and 
re found to be within likely reach of the STM9000 coil (Appendix 1).  The most success-
ful rTMS treatment of epilepsy was reported by Sun, et al (2012), who state that most of 
the patients who responded successfully had frontal and parietal foci (within reach of 
the TMS coil), whereas those with medial temporal lobe foci did not respond as well.  
We visited Dr. Sun in March of 2015 and reviewed her targeting protocol, as well as the 
advances that could be made with the individual head modeling and ESI with the 256 
dEEG from the GES 400, analyzed in GeoSource 3.0 and the Reciprocity Engine.  We are 
reasonably conﬁdent at this point that the limitation to patients with superﬁcial foci will 
allow us to achieve precision in the target planning and therefore mitigate the risk of 
ineffective treatment. 
!20

Another general risk of rTMS is scalp discomfort, damage, or other adverse effects.  
The magnetic ﬁeld and electrical induction of the STM9000 is tested by bench tests, as 
shown in Figure 3 and in Appendix 1 (STM9000_Device_Description PNS.pdf).  There 
is risk of minor pain or irritation, to the scalp and head muscles, during rTMS treat-
ment, including the slow (0.5 Hz) rate of pulses used here.  The informed consent form 
describes the potential for this pain and irritation and lets the subjects know they can 
stop the procedure at any time.
The Instructions for Use provide warnings of potential hazards for other medical 
devices, which must be kept distant from the STM9000 and butterﬂy coil.  The STM9000 
must not be used with patients who have implanted medical devices.  We have not seen 
adverse tissue reaction to the use of the STM9000 rTMS coil.
In addition, we have tested the joint operation of the STM9000 rTMS system with 
the GES 400 dEEG system, including the artifacts introduced in the dEEG recording by 
rTMS operation.  With adequate attention to the anti-aliasing ﬁlter (for the A/D con-
verter) the signal quality of the dEEG remains adequate with rapid ( < 10 ms) recovery 
after the rTMS pulse.  This is important to allow safety monitoring with dEEG during 
rTMS treatment.   
The GES 400 dEEG system is tested for electrical safety by CSA.  We have evaluat-
ed electrical safety in the joint operation of the GES 400 with the STM9000, such as re-
quired for dEEG monitoring of the brain’s response to rTMS treatment.   Extensive test-
ing of joint operation has been conducted over the last two years of preclinical studies 
and has been documented in the hazard review of the MicroCel 100, March 20, 2014, 
and of the GES 400, including the MicroCel 100, May 15, 2015 (available on request).   
If the noise of the rTMS coil exceeds OSHA standards for the interval of treatment, 
as measured with a sound pressure level meter, the patient will be ﬁtted with earplugs.
Risk of Inducing Seizures by rTMS Treatment
It is well known that repeated electrical stimulation of the normal brain may lead 
to augmenting or after-discharges, leading to seizures.  Persons with epilepsy may 
show enhanced cortical excitability that places them at increased risk.  However, the re-
search evidence suggests that seizures are highly unlikely with slow rTMS pulses (at 0.5 
Hz), even with patients with epilepsy, as shown in a recent review of the literature (Bae 
et al., 2011).  The important caution is that patients with epilepsy must not be take off 
their anti-seizure medication.  When seizures have been observed during the slow rTMS 
treatment session, the seizures that have been recorded have been the patient’s typical 
seizures in both duration and semiology, suggesting these were not induced by the 
treatment (Rotenberg, Bae, Muller, et al., 2009).     
Nonetheless, the risk of inducing seizures or increasing seizure likelihood is a seri-
ous concern, and we consider it a signiﬁcant risk.  To mitigate the risk, we will monitor 
carefully for seizures during and after the treatment.  During the three pretreatment 
!21

evaluations in the one-month baseline, we will characterize the patient’s interictal 
events, plus any ictal events that are recorded, during the dEEG evaluations sessions.  
We will train the treatment technician to monitor the EEG for these speciﬁc epileptiform 
events (spikes and other discharges) for that patient during each treatment session.  Be-
cause the source site of the interictal events is also the presumed epileptogenic zone and 
the target of the rTMS treatment, this is also the site (and scalp topography) that would 
be expected to generate seizures if the treatment causes or kindles seizures.  The  prepa-
ration for each patient’s treatment will identify not only the source of the epileptiform 
discharges, but the scalp topography, such that the technician can select a speciﬁc mon-
tage (screen arrangement) for the channels that reﬂect the patient’s spikes (and likely 
seizures).       
During the 17 minute rTMS treatment intervals, all dEEG channels will be moni-
tored.  The 24 bit ADs of the NA 400 allow adequate dynamic range (+/- 200 mV) with a 
DC input coupling (avoiding the RC network of AC coupling), such that even channels 
nearby the rTMS pulses seldom clip.  During the rest (resting EEG and break) intervals, 
all 256 channels will be monitored.  To assure seizures are not worsened, the post treat-
ment monitoring for safety is continued for 3 hours after the ﬁrst treatment session. 
If there is any increase in epileptiform activity during the treatment or the monitor-
ing interval, interictal or ictal, the consulting epileptologist will review the EEG, the 
baseline EEGs, and the patient’s history to decide if treatment should be discontinued.  
The patient and if relevant the family will be consulted in this decision.     
Risk of Unwanted Plasticity
  The short term effects of transcranial neuromodulation including rTMS are typi-
cally assumed to be mediated by increasing or decreasing of cortical excitability.  The 
longer term effects appear to reﬂect stable changes in cortical plasticity, including long-
term potentiation (LTP) and long-term depression (LTD) (Monte-Silva et al., 2013).  The 
rationale of the present interventions is that inducing long term depression (with slow 
rTMS pulses at 1 per 2 sec) in the epileptogenic zone will be effective in suppressing 
seizures.  However, the scientiﬁc understanding of this manipulation is limited, such 
that there is risk of changing plasticity in ways that are unwanted or maladaptive.
Mitigating the Risk of Unwanted Plasticity
In addition to manipulating epileptiform activity, the rTMS treatment may change 
other aspects of the patient’s cortical function that may create unwanted changes in 
brain function or plasticity.  The large general literature for slow rTMS suggest there are 
unlikely to be serious unwanted changes.  The primary effect on the target brain region 
is expected to be the induction of long-term depression.  We will evaluate general cogni-
tive function in each patient with scores on the California Verbal Learning Test and the 
Wisconsin Card Sorting Test, paying close attention to any changes from the expected 
!22

improvement in performance with practice from the normative data.  We will review 
the Quality Of Life In Epilepsy ratings and the seizure diary with each patient and fami-
ly, systematically reviewing any complaints or reports that may suggest the treatment is 
creating unwanted changes in brain function.
23
Figure 13.  EEG response to TMS as affected by anti-epileptic medication and placebo.
Figure 12. The protocol for interleaving rTMS treatment and dEEG assessment (recorded 
and evaluated during the breaks as well as the resting EEG intervals). 

Safety and Feasibility Clinical Trial Design
To achieve long lasting suppression of epileptiform activity, including seizures, the 
two most effective studies both applied slow rTMS with repeated treatment over suc-
cessive sessions (Fregni et al., 2006; Sun et al., 2012).  One of these (Sun, et al., 2012) was 
particularly effective, achieving signiﬁcant seizure suppression (an average of 2 seizures 
per week versus 8 or 9 per week for the sham treated group) for up to ten weeks.  These 
investigators applied blocks of slow rTMS separated by rest intervals.  
In the proposed safety and feasibility trial, we will implement the within-session 
timing of the slow rTMS protocol of Sun et al., (2012), administering this protocol for 
ﬁve days for one week (rather than the two weeks of  Sun, et al), given that our more 
limited objective for demonstrating feasibility is a statistically signiﬁcant suppression of 
epileptic discharges.  Each treatment block consists of 500 pulses, each monophasic, at a 
rate of 0.5 Hz (2 per second).  With 500 pulses over 1000 seconds, each of the three 
treatment intervals is 17 min (Figure 12). 
!24
Figure 14.  Overview of dEEG evaluation session, EEG review, spike detection, and spike localization.  

During rTMS, we will continuously record the EEG.  Later, off-line averaging will 
be performed for the ﬁrst 60 stimuli (minutes 1-2) and the last 60 stimuli (minutes 16-17) 
of the 17 minute session.  Figure 13 from Premoli, Castellanos et al. (2014) shows the av-
eraged evoked EEG waveform with rTMS.  Premoli, et al., have shown that the N45 po-
tential reﬂects GABAA receptor mediated interneuronal activity and the N100 potential 
GABAB receptor mediated potentials.  Changes in N45 and N100 will provide a picture 
of functional inhibition in that region of brain during rTMS.
Once safety and feasibility have been determined (meeting endpoints of safety, 
comfort, and preliminary efﬁcacy), the pivotal trial will then evaluate the full two weeks 
of daily (5 days per week) treatment against the sham rTMS control.  
Overview of dEEG Acquisition, Spike Detection, and Spike Localization
Figure 14 shows the assessment workﬂow that is conducted for each evaluation 
session.  These evaluation sessions are typically 40 minutes to one hour and include the 
initial patient evaluation, the weekly dEEG evaluations during the baseline, the dEEG 
evaluation conducted during each of the 5 rTMS treatment sessions, and the monthly 
dEEG evaluation during the three-month follow-up.  The MicroCel Geodesic Sensor Net  
is applied to collect 256 dEEG (about 10 min) and the positions of the sensors are digi-
tized with the Geodesic Photogrammetry System (GPS).  The positions from the ﬁrst 
session are then registered with the patient’s MRI to create the Electric Head Model 
(Figure 15).  Subsequent Net applications are veriﬁed against the GPS photos from the 
ﬁrst session and the positions adjusted so that the same Electric Head Model is accurate 
for all sessions.  
To quantify and localize the patient’s interictal epileptiform activity, the Net Sta-
tion (5.2) software includes modules for dEEG Acquisition, analysis Tools (ﬁltering, bad 
channel replacement, artifact detection and cleaning).  During the project, we will intro-
duce spike detection and counting with the Spike Beacon software (to be submitted).   
The epileptologist reviews the dEEG (and the Spike Beacon results) to assure that the 
spike detection (manual or automated) is accurate and representative for the patient’s 
typical, dominant, spike focus.  Localization of the spike onset is conducted with the 
GeoSource 2.0 software.  However we plan to introduce the GeoSource 3.0 software as 
an amendment to the present protocol once all validation studies are completed and 
FDA clearance is obtained, using the Electric Head Model constructed from the patient’s 
MRI with EGI’s Modal Image Pipeline (Figure 15).   
Overview of the Electric Head Model Construction
Constructing the Electric Head Model begins with the patient’s T1-weighted MRI, 
typically acquired through a DICOM server, with the Osirix MD software (Figure 15).  A 
plugin for Osirix provides export to the format for EGI’s Modal Image Pipeline (MIP) 
!25

26
Figure 16.  Overview of export of interictal focus localization to the Net Brain rTMS neu-
ronavigator software, which then guides the rTMS targeting with the STM9000.

software.  The processing in the Modal Image Pipeline (Li, Papademetris, & Tucker, in 
press-a) is summarized in Figures 8 and 9.  The Reciprocity Engine is the visualization 
software for examining the anatomical correctness of the individual Electric Head Mod-
el, and for visualizing the source localization results with GeoSource 3.0 (Figure 10). 
Overview of rTMS Targeting
Once the interictal focus is identiﬁed with GeoSource 2.0, the Talairach coordinates 
are then transferred to the rTMS targeting software, EB Neuro’s Net Brain (Figure 16).   
There are two methods for placing the coil to achieve accurate targeting of the identiﬁed 
interictal focus (Figure 16).   The cart for the STM9000 includes a mechanical arm that 
holds the butterﬂy coil in place.  In addition the butterﬂy rTMS coil can be held manual-
ly.  For both methods, the Net Brain Navigator software provides continuous feedback 
on the relative position of the coil energy (and thus induced current ﬂow) with the pa-
tient’s MRI model that is registered to the head position (that is tracked continuously by 
the Northern Digital camera system). 
Clinical Trial Sites
At the present time, four clinical sites are planned (Eugene, Seattle, Palo Alto, Bos-
ton), depending on the availability of funding (such as with an application to the the 
NINDS CREATE Devices SBIR mechanism).  An expert epileptologist will provide med-
ical guidance at each site.  Data analysis will be supervised by the Study Monitoring 
Committee, composed of the epileptologists and principal investigators from all sites, 
plus EGI’s statistician Dr. Jasmine Song.  Racial and gender composition will be as it 
appears in each sample.   
Patient Recruitment
 To determine safety and feasibility, 10 adult patients (22 and older, including 
males and females) are recruited who continue to have seizures after having achieved 
adequate dosage on each of two antiepileptic drugs.  Patients are selected who have fo-
cal spikes (and other discharges of focal onset, including seizures) identiﬁed through 
Electrical Source Imaging (ESI) applied to a routine dense array EEG (dEEG) evaluation.  
The patients must have superﬁcial focal spikes, close enough ( ~ 2 or 3 cm) to the head 
surface to be reachable by rTMS.  Where possible, preference is given to patients with 
frequent spikes (estimated as > 30 per hour in the diagnostic EEG session), to allow ad-
equate measurement of the spike frequency reduction endpoint.  All patients agree to 
maintain their current antiepileptic drug dose throughout the study, including the one 
month baseline and the ten week follow-up period.  
!27

Inclusion Criteria
(1) Failure of adequate seizure control with prior use of at least 2 anti-seizure 
drugs. 
(2) at least one clearly identiﬁed and localizable likely seizure onset focus, as de-
ﬁned by the discharges (typically epileptiform spikes) and as identiﬁed by dEEG as-
sessment through one or more routine clinical dEEG evaluations.  This focus must be 
2 to 3 cm from the head surface (to be reachable by TMS).  Where multiple spike foci 
are present and meet these criteria, then the focus with either clinically relevant 
symptoms or the most spikes (or both) will be chosen as the target for treatment. 
(3) two or more partial seizures, with or without secondary generalization, in the 
last month, but less than 10 seizures per day. 
(4) Anti-seizure drug regimen has remained unchanged for the month before study 
entry, and there is reasonable likelihood of stability for the duration of the study, 
with the exception of allowing short-term rescue medications, such as lorazepam.  
(5) a history of epilepsy for at least 2 years.
(6) age of 22 years and older.
Exclusionary Criteria 
(1) If of childbearing potential, the patient must agree to use an effective method of 
birth control during the study and cease participation if pregnant.
(2) Nursing mothers are excluded.
(3) A history or condition of progressive brain disorders, serious systemic diseases, 
symptomatic cerebrovascular disease, cardiac disease, or alcohol abuse.  Special 
conditions, for example, non-malignant brain tumors and vascular malformations, 
can be considered for entry on a case-by-case basis.  Patients are not excluded on the 
basis of previous psychiatric hospitalizations or suicide attempts. 
(4) A history or condition of status epilepticus or psychogenic seizures.
(5) Presence of a cardiac pacemaker, vagus nerve stimulator, or metal implantation 
in the body (other than the teeth) including neurostimulators, cochlear implants, and 
implanted medication pumps.
(6) Previous surgery involving opening the skull.
(7) Unable to express presence of pain or discomfort.
Escape Criteria
For individual patients, the study will be terminated for any of the following rea-
sons:
(1) Unacceptable discomfort or pain in response to the rTMS treatment.
(2) A tonic-clonic seizure occurring during a stimulation session.
(3) Emergence of a ﬁrst-in-life tonic-clonic seizure at any time during the study.
!28

(4) Status epilepticus.
(4) Doubling or more of the baseline seizure frequency.
The study will be halted if 3 subjects meet escape criteria (other than unacceptable 
pain or discomfort) and the FDA consulted to review the adverse events before the 
study is restarted.  The Data and Safety Monitoring Board will be informed if one sub-
ject meets escape criteria (other than unacceptable pain or discomfort).  
Baseline, Treatment, and Follow up Protocols
The length of the baseline evaluation period is adjusted to insure that sufﬁcient 
seizures are captured for that patient to allow determination of the patient’s typical 
seizure rate.  This will allow conﬁdence that any increase in the seizure rate during 
treatment is a safety concern.  As recommended by our consultant, Dr. Robert Fisher of 
Stanford University Hospital, the baseline monitoring period will be 5 times the length 
of time between the patient’s typical seizures.  Thus a patient with one seizure per two 
weeks will have a baseline monitoring of 10 weeks.  The minimum monitoring interval 
will be one month.  At least two two-hour routine dEEG evaluations will be conducted 
in the baseline evaluation period, including the opportunity for sleep for patients who 
may have interictal events in sleep or drowsiness.  The patient (and/or family) will 
maintain a seizure diary during the baseline, treatment, and 10 week follow-up inter-
vals.  The seizure diary will be reviewed by the study coordinator in a phone contact 
once per week. 
After the baseline evaluation period, the two-hour dEEG-rTMS treatment session 
then targets the identiﬁed focal epileptogenic zone 5 days per week for one week.  In 
each treatment session there are three 17 minute blocks of treatment, with 500 pulses 
each.  To assure seizures are not worsened, the post treatment monitoring for safety is 
continued for 3 hours after the ﬁrst treatment session.  
Both evaluation and treatment sessions are conducted by personnel who are 
trained in the dEEG assessment and rTMS operation, including the ability to recognize 
epileptiform discharges in the dEEG signals.  At least one person on the research staff at 
each session will be certiﬁed in ﬁrst aid in the case that a seizure occurs.  The epileptol-
ogist at each trial site will provide medical supervision, including recognition of possi-
ble adverse events and decision to terminate treatment. 
The one week treatment period is followed by a weekly 90 minute follow up ses-
sion on months 1, 3, and 6 of the follow up period.   Each follow up session includes 30 
minutes of dEEG evaluation, a review of the seizure diary, cognitive function testing 
with the California Verbal Learning Test, the Wisconsin Card Sorting Test, and the Qual-
ity of Life in Epilepsy report.  If the patient has interictal events in sleep or drowsiness, 
!29

the 30 minute dEEG evaluation in follow up will be extended to up to two hours to al-
low sleep (both in the baseline and in the post-treatment follow-up sessions.  
Primary Endpoint
 The primary endpoint is the frequency of epileptiform discharges (spike rate ex-
pressed per hour) for the six evaluation sessions over the 10 weeks following treatment, 
in comparison to the mean frequency for the pre-treatment evaluation sessions (at least 
2 baseline sessions over one month).  Spike detection will be conducted with the Spike 
Beacon software, including methods of topographic clustering as well as template 
matching.  The spike count will be expressed as spikes per hour, with a minimum of 20 
minutes of quality EEG recording required for each follow up session.  Once the para-
meters for automated detection are set for the baseline evaluation, these will be applied 
for each treatment and follow-up assessment.  The epileptologist at each site will review 
the spike detection and quantiﬁcation to assure the measures are clinically relevant.
Secondary Endpoints
A secondary endpoint is the weekly frequency of seizures, as recorded in the 
seizure diary, during the one week of treatment and each of the ten weeks of follow up.  
This will be the primary endpoint for the pivotal trial.  This frequency will be contrasted 
with the seizure frequency (expressed as a weekly rate) for the pretreatment baseline 
and statistical tests will examine the statistical contrast with baseline for each post-
treatment evaluation plus the trends over time.   
In case there is a change in a patient’s seizure medication during the treatment or 
follow up, the analysis for this patient will be considered to have no change in seizure 
frequency from baseline. 
Additional secondary endpoints will be any improvement of cognitive function 
testing beyond the practice effect (estimated from norms), and any improvement in 
quality of life ratings.   
Safety Endpoint
The safety endpoint will report all adverse events from baseline through the 10 
week follow-up for each patient in the study.
 
Study Success
The statistical endpoint for demonstrating treatment feasibility is a signiﬁcant 
suppression of spike frequency at the p < .10 level or better for at least 4 of the evalua-
tion sessions in the 10-week followup, in contrast to baseline for this group of 10 sub-
!30

jects.   The missing data during one or more of the follow-up evaluations will be inter-
polated by the adjacent sessions data for the statistics, including trend analysis.
 Statistical analyses of the seizure suppression will be examined to provide sug-
gestions of effect size for the power analyses for the pivotal trial. 
Pooling Data Across Sites
Although a separate statistical analysis will be conducted at each site, pooled 
analysis across the several sites will be assembled unless the individual site analyses 
provide indication that the populations or treatment effects are substantially different 
for a given site.  Each site is supervised by a different principal investigator/epileptolo-
gist and is regulated by a separate Institutional Review Board or ethics board, such that 
decision making is unique to that site.  Local decisions are attentive and optimally re-
sponsive to any safety issues.  Nonetheless, the investigators have agreed to uniformity 
of all factors of patient selection, localization of foci, and treatment protocols, such that 
there are no known contraindications at this point to data pooling across sites. 
  
Power Analysis and Missing Data Analysis
The present Safety and Feasibility Study is focused on spike suppression.  We 
have no preliminary data for estimate of the effect size.  Nonetheless, we expect ade-
quate power for statistical analysis assuming we are able to recruit patients with fre-
quent spikes. 
Study Procedures
Informed Consent
Both the recruitment information and the informed consent document explain sev-
eral aspects of the study:  
• Only patients whose dEEG exam conﬁrms that their spikes (and seizures when 
recorded) have at lease one focal onset are eligible for the slow rTMS experimental 
treatment trial.
• rTMS (repetitive Transcranial Magnetic Stimulation) is a method of applying 
magnetic ﬁelds through the head in order to induce electrical currents in the cortex of 
the brain. The goal of these currents, applied at a slow rate (one pulse every two sec-
onds) is to achieve a lasting decrease in the neuronal activity of the epileptic (seizure-
causing) zone of cortex.   The experimental treatment protocols have been designed 
on the basis of previous scientiﬁc studies, including successful suppression of epilep-
tic seizures with TMS (in the Fregni, et al., 2006 and Sun, et al., 2012 trials).  
!31

• There is a risk that the treatment will cause seizures.  However, the slow pulsed 
rTMS protocol has been applied in several studies of epilepsy, and there is no evi-
dence that it caused seizures, or that it made seizures worse or more frequent.  None-
theless, there is always a small risk of causing seizures, and medical procedures are in 
place both to monitor for seizures (with the dEEG recording in each session) and to 
provide ﬁrst aid if a seizure occurs.
• The primary feeling of the rTMS pulse is a brief tingling sensation.  There is the 
risk of scalp itching and/or scalp pain.  Each patient should understand that they 
should speak up if there is any discomfort, that the technician is trained to carefully 
monitor their comfort level, and that they can quit the treatment at any time by simply 
saying they want to quit.  If there is any emergency, the patient is shown how to sim-
ply pull the Geodesic Sensor Net off the head.
Localizing Epileptiform Discharges (EDs)     
The cortical target for rTMS treatment is the presumed seizure onset zone, which is 
estimated by localizing the source of epileptiform discharges (spikes) with the dEEG 
recording.  The EDs are recorded during the baseline in three routine (typically half 
hour or 40 minute) dEEG evaluations.  A nap or sleep EEG may also be collected if 
seizures typically occur during sleep or sleep transition.  Only patients with a single 
clearly identiﬁable site of epileptiform discharge (ED) onset will be included.  EDs will 
typically involve spikes or sharp waves, although more complex seizure-like EDs and 
clinical seizures recorded during the routine dEEG will be included.  In order to be able 
to target the ED with the rTMS treatment, the ED must be within 2 or 3 cm of the head 
surface.   
bEIT Validation of the Head Model
The effectiveness of treatment depends on the accuracy of the localization of the 
epileptic discharges.  During at least one of the baseline dEEG sessions, the bounded 
Electrical Impedance Tomography (bEIT) procedure (Figure 11) is used to verify the 
electric head model developed for that subject.  If the mean prediction of the recovered 
bEIT signal across recording electrodes is not within 10% for 90% of the electrodes, the 
model is judged to be ﬂawed and the treatment is postponed until an accurate targeting 
model is created.  
Determination of rTMS Intensity
The resting motor threshold (rMT) will be recorded from the left motor cortex, 
with the motor evoked potential (MEP) recorded from the contralateral abductor polli-
cis brevis (APB) muscle with the MEP Ampliﬁer of the STM9000. The rMT is deﬁned as 
the minimum stimulus intensity that evokes a MEP above 50 µV in the contralateral 
!32

APB muscle at least ﬁve out of 10 consecutive stimulations.   The rTMS treatment inten-
sity will be set to 90% of the patient’s rMT for that session.
The rTMS coil will be positioned over the interictal focus, as determined by the 
GeoSource 3.0 software and translated to the Net Brain neuronavigator in relation to the 
patient’s MRI anatomy.  The consistency of coil placement during each treatment ses-
sion is assured by auditory feedback from the Net Brain neuronavigator software if the 
coil “hot spot” is allowed to drift off of the designated focus target.  
Review of the EEG for Safety and for Spike Counts  
The dEEG is reviewed during each treatment session by the dEEG technician, who 
is trained on the typical epileptiform events shown by that patient.  The dEEG is then 
reviewed after each treatment and follow up session by a trained electroencephalogra-
pher.  To supplement the manual spike counting, spikes are counted with an automated 
spike detection and clustering algorithm (EGI’s Spike Beacon software).  If there is an 
apparent change in the spike (and possibly seizure) localization, as indicated by the 
spike topography clustering, Electrical Source Imaging is conducted with GeoSource to 
determine if there is a change in localization.  If there is a change in localization, or a 
doubling of spike frequency over the baseline, or if there is non typical seizure activity, 
the results are conveyed to the epileptologist supervising the clinical trial to evaluate 
the risk for the patient’s continuation of the trial.   These safety criteria are in addition to 
the escape criteria stated above.
The experimental procedures for each patient session are summarized in Table 3.  
 Additional Monitoring of Risk
In the follow up sessions, routine dEEG evaluations, cognitive function assess-
ments, and quality of life ratings are conducted at weeks 1, 2, 4, 6, 8, 10.  At each follow 
up session, cognitive function is assessed with the California Verbal Learning Test, a 
widely used and easily administered test (www.pearsonclinical.com), the Wisconsin 
Card Sorting task, a well-known measure of executive function that is normed for re-
peat assessment, and quality of life is assessed with the Quality of Life In Epilepsy 
Questionnaire (http://www.rand.org/health/surveys_tools/qolie.html).   
Overview of Study Protocol
Table 3 presents an overview of the treatment protocol.  An exception is that the 
dEEG will be monitored for seizures for 3 hours after the ﬁrst treatment session.
!33

Table 3.  Summary of treatments and assessments.
Session
Procedure
Pre-Treatment Evaluation
At least two dEEG evaluations in the pre-treatment baseline 
(which is at least one month long).  
•artifact free dEEG recording of at least 20 minutes during each 
evaluation to capture epileptiform discharges.  
•Review of seizure diary.  
•MRI to build the individual electric head model. 
•California Verbal Learning Test & Wisconsin Card Sorting Test
• Quality of Life Questionnaire
• bEIT scan to verify electrical head model. 
Each (of 5) Treatment 
Sessions
• Application of the Geodesic Sensor Net.
• Geodesic Photogrammetry System (GPS) to localize sensors.
• 10 minutes resting dEEG.
• rTMS treatment, 3 sets of 500 pulses (dEEG during 600s intervals 
between sets).
• 30 minutes resting dEEG.
Follow up sessions, 
months 1, 3, and 6.
• Review of seizure diary.
• Application of the Geodesic Sensor Net.
• Geodesic Photogrammetry System to localize sensors.
• 30 minutes resting dEEG.
• California Verbal Learning Test & Wisconsin Card Sorting Test
• Quality of Life Questionnaire
!34

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