Geodesic Transcranial Electrical Neuromodulation(GTEN100) Device
Phase: NA
Conditions: Epilepsy
Sponsor: Electrical Geodesics, Inc.

G150023/S003/A003
Supplement Request for Amending the IDE for EGI’s 
Clinical Feasibility Trial 
of the Geodesic Transcranial Electrical Neuromodulation 
(GTEN 100) for Suppressing Epileptic Discharges 
March 2016 
Electrical Geodesics, Inc. 
Overview
In this supplement (S003/A003), we corrected the text of the original IDE (an obsolete version 
was used in S003/A002).  We request the following modiﬁcations to the IDE:
• Remove references to the “blocked sustained tDCS” protocol. 
• Add a “probe treatment evaluation” protocol.
• Propose that GTEN treatment may be applied during sleep if the patient’s 
spikes were recorded during sleep.
• Propose to extend the inclusion to patients with temporal lobe as well as 
neocortical foci for their interictal discharges.  
Changes Requested
Reason for Change
Located on Page:
Drop reference to Blocked 
Sustained tDCS Protocol
Only the Pulsed GTEN Protocol 
will be used
Multiple pages, marked in red.
Specify 2 US and 1 China sites
No funding for other US sites
28
Describe Probe Treatment and 
Evaluation
Pilot Treatment for Brief Safety 
and Feasibility Test
30
Propose GTEN treatment during 
sleep if possible
Many patients show most spikes 
during sleep during the 
evaluation sessions
33, 34
Propose including patients with 
primary temporal lobe foci
Most patients show medial 
temporal as well as neocortical 
foci  
31, 35
Reformat the Informed Consent 
Document for the UW IRB 
Format, plus include the probe 
test
The UW IRB requires its own 
Consent Form; plus the probe 
test was added
37, 37
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Overview to Original IDE Request (at the end of Q140561):
[EGI requests an Investigational Device Exemption (IDE) for the GTEN 100, following FDA’s 
guidance that this device presents signiﬁcant risk when used to suppress spikes and seizures in 
adults and adolescents with epilepsy. We have now revised our analysis of risk, and the 
mitigation of that risk, in this proposal for a clinical feasibility trial. The purpose of this trial is to 
determine safety and preliminary evidence of efﬁcacy of the GTEN 100 for temporary 
suppression of epileptic discharges (spikes). If the clinical feasibility trial proves successful, we 
would then propose a pivotal trial, to evaluate suppression of seizures, in a future 
presubmission request. 
In this revision, we retain the key material from the previous presubmission supplement, and 
focus this revision on the restatement of risk and the mitigation of that risk, following the 
feedback in the FDA document “Q140561-S001 Comments to Sponsor” and the FDA-EGI phone 
conference of January 15, 2015, as summarized in EGI’s notes. ] 
"2

Table of Contents
GTEN 100 Device Description 
4
Risks of GTEN Treatment and Mitigation of Risks 
14
Therapeutic Mode of Action
26
Relative Strengths of TMS and TEN 
27
Clinical Feasibility Trial Design 
28
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GTEN 100 Device Description 
The Geodesic Transcranial Electrical Neuromodulation (GTEN 100) device is a hardware and 
software modiﬁcation of the Geodesic EEG System 400 Series (GES 400). The hardware 
modiﬁcation changes the current injection from 100 μA total for the GES 400 (for impedance 
testing and the bounded Electrical Impedance Tomography or bEIT scan) to up to 2 mA total 
(and limited to 200 μA per electrode). Note that these levels are higher than the 1 mA total and 
100 μA per electrode in the ﬁrst Q140561 Pre-Sub request. This increase in current will improve 
the therapeutic dose delivered to the brain, and this does remains within the safety guidelines 
for tDCS (2.5 mA total dose) recommended by a recent international panel of experts (F Fregni 
et al., in press). In addition, we have succeeded in minimizing scalp pain by adding lidocaine to 
the electrolyte, such that the 200 μA dose is comfortable with the 1 cm2 electrodes of the GTEN 
100. 
The guidelines for estimating both the safety and the efﬁcacy of neuromodulation with the 
intracranial current levels achieved by the GTEN 100 comes from the literature on transcranial 
direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS), as 
reviewed below. 
The software upgrade of the GES 400 for the GTEN 100 is a new GTEN Control Interface 
window in the Net Station 5.0 software to allow the physician (or supervised technician) to 
select the electrodes and waveform for current delivery for the neuromodulation protocol. 
There is also a GTEN Planning Module that allows computation of the estimated dose in 
relation to head tissue conductivity and cortical surface reconstructed from the patient’s MRI 
and bounded Electrical Impedance Tomography (bEIT) recordings. 
Double Sentinel Circuit for Fault Protection 
The GTEN 100 design has been modiﬁed to add a second Sentinel Circuit, in series with the ﬁrst 
one, to assure that total current will be limited to 2 mA (and thus 2 A/m2 as in the FDA 
“Q140561-S001 Comments to Sponsor”. A triple fault (circuit fault and two Sentinel Circuit 
faults) is still possible, of course, but the risk is now very small. 
Impedance Conditioning and Lidocaine Iontophoresis 
In preparation for the neuromodulation session, an accessory for the the GTEN 100 is a new 
protocol for decreasing electrode-to-skin impedance (the Dermal Iontophoretic Bond or DIB 
protocol) by applying DC currents in order to draw ions from the electrolyte across the outer 
skin layer (stratum corneum) with iontophoresis. Scalp contact impedances are typically 
decreased from an initial ~ 100K Ohms to 20 to 40K Ohms after a few minutes of treatment. 
This iontophoretic impedance conditioning protocol now allows the use of lidocaine with the 
gel electrolyte, such that the iontophoretic transfer results in topical anesthesia around the 
anode electrode sites, allowing higher current levels (200 μA) to be applied painlessly. The 
iontophoretic current delivery includes cathodal (sink) electrodes adjacent to the anode 
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(lidocaine delivery) electrodes, so that there is minimal or no current delivery to the brain 
during iontophoretic delivery. Once the topical anesthesia is achieved, the anodal current can 
then be discontinued for those electrodes that will be cathodes (sinks) in the treatment protocol, 
while the topical anesthesia remains. 
Computational Modeling of Head Tissues for Treatment Planning 
The GTEN 100 includes an accessory software module, the GTEN Planning Module, that uses 
computational modeling of a ﬁnite difference model of electrical volume conduction through 
head tissues to target speciﬁc brain regions. The GTEN Planning Module includes the capacity 
for veriﬁcation with bounded Electrical Impedance Tomography (bEIT), in which small (10 μA) 
currents are injected at a speciﬁc frequency to test the planned GTEN targeting; if potentials 
measured at that frequency at multiple non-injecting electrodes are consistent with the model 
prediction, then the current ﬂow through the head must also be consistent with the prediction, 
and the GTEN plan is acceptable. 
The GTEN 100 can be used with an atlas model of the head (similar age and sex as the patient). 
The atlas model has been validated for Electrical Source Imaging (ESI) in epilepsy diagnosis 
with EGI’s FDA cleared GeoSource 2.0 software. In addition, the GTEN 100 can also be used 
with an individual electrical head model for the patient, which can be constructed from the 
patient’s MRI (and the patient’s CT or an atlas CT to characterize the skull bone density). The 
patient speciﬁc head model, and the warping of the atlas brain conductivity model to the 
patient’s head shape (deﬁned by photogrammetric localization of the 256 sensors and ﬁducial 
points) is constructed with the Modal Image Engine software and prepared for Electrical Source 
Imaging (ESI) with GeoSource 3.0 software. GeoSource 3.0 will be submitted for 510k clearance 
later in 2015 with GeoSource 2.0 as the predicate device and the Modal Image Engine as 
accessory software. 
Intended Use 
The intended use of the GTEN 100 is the application of electrical current to the brain for the purpose of 
manipulating the function and plasticity of the brain. 
Indications for Use 
The Geodesic Transcranial Electrical Neuromodulation 100 system is indicated to temporarily reduce the 
frequency of epileptic spikes in adults and adolescents over 12 years of age with partial onset seizures that 
continue to occur despite at least two trials of antiepileptic drugs at therapeutic levels. 
Previous Submissions 
Table 1 summarizes the EGI products relevant to both the Geodesic EEG System (GES) 400 and 
the GTEN 100. 
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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. 
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 typical in EEG, the GES 
400 uses small amounts of current (less than 10 μA) to test contact impedance of the electrodes 
with the scalp. 
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The GTEN 100 uses the same hardware as the GES 400, the Geodesic Sensor Nets, and Net 
Station, with the exception that the current injection capability of the GES 400 hardware has 
been upgraded. It now allows 2 mA total. In addition, an independent hardware limit to that 
current has been added through an integral safety circuit monitoring the injected current (the 
Sentinel Circuit®). To assure patient comfort, the impedances of all current delivery electrodes 
(anode or cathode) are monitored such that the target current level per electrode is maintained 
at about 200 μA (and the total is never more than 2 mA total). In addition, the GTEN 100 uses 
two other cleared accessories: the Geodesic Photogrammetry System (K043309) and GeoSource 
2.0 (K092844), which will soon be upgraded to GeoSource 3.0. 
Rationale for the GTEN 100 for Suppressing Seizures 
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 signiﬁcant, 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. However, 
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 reasons rather than medical 
reasons, because the medical evidence strongly supports neurosurgical resection. Nonetheless, 
neurosurgical resection is now increasingly avoided (Engel, 2013). 
There are several invasive technologies for electrical stimulation of the brain, including 
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 limited, roughly on a par with that of antiepileptic 
drugs (Bergey, 2013). 
The failure to treat epilepsy effectively is a major failure of modern science and medicine. Even 
if their seizures are suppressed, 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 medial temporal lobe structures, potentially worsening 
epilepsy. If we can successfully control seizures in adults and adolescents with GTEN therapy, 
then in the future we will extend this noninvasive therapy to control seizures in children, and 
greatly improve the quality of life for millions of people. Even if seizures are only partially 
suppressed, the reduction may be clinically signiﬁcant. For the present trial, we deﬁned the 
clinically signiﬁcant suppression as a 50% reduction. For those whose seizures continue 
chronically after two trials with antiepileptic drugs, it seems clear that a 50% reduction, even if 
temporary (over a few months) would be a meaningful improvement in quality of life. 
In addition, there is considerable evidence now that cognitive development is impaired in 
children with frequent spikes, even if seizures are controlled (Ebus et al., 2012; Rudzinski & 
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Meador, 2013). It seems likely that brain function will be similarly impaired by spikes in 
adolescents and adults. 
In the proposed safety and feasibility study, we now set the primary endpoint for 
demonstrating feasibility as a statistically signiﬁcant suppression of epileptic spikes. 
"
Figure 1. EGI’s Modal Image Engine software provides segmentation of each major head tissue type, to 
allow a high resolution electrical (ﬁnite difference) 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 cortical sources in Electrical Source Imaging (ESI). 
The cortical surface geometry is also needed for modeling the modulation current that is normal to the 
cortex and presumably therefore effective in altering the activity of neurons in the laminar cortex. 
GTEN 100 Treatment Planning 
A software accessory for the GTEN 100 is the GTEN Planning Module, a component of EGI’s 
Modal Image Engine software. The Modal Image Engine is a set of software modules that allow 
processing of MRI, CT, images and sensor positions in preparation for Electrical Source Imaging 
ESI with the individual’s MRI data, as well as for GTEN 100 treatment. Key features of the 
Modal Image Engine are automated tissue segmentation (scalp, skull, cerebrospinal ﬂuid, gray 
and white matter) and cortical surface extraction (Figure 1). The Modal Image Engine (for 
preparing the individual head model) and GeoSource 3.0 (for Electrical Source Imaging with the 
individual head model) are being prepared for FDA submission later in 2015. That submission 
will present validation results showing that localizing spikes and seizures with the individual 
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head models are at least as accurate as the results with atlas models with GeoSource 2.0. The 
atlas models have been validated by comparison with intracranial recordings and by surgical 
outcome, as described below. 
Geodesic Transcranial Electrical Neuromodulation in Epilepsy 
The GTEN 100 and the GTEN Planning Module software have been developed under EGI’s 
Quality System, with design controls and hazard review documented at each stage. Testing of 
the GTEN 100 with normal subjects has been conducted under human subjects review by EGI’s 
Institutional Review Board, which has Multiple Project Assurance authority recognized by the 
US National Institute of Health. 
The GTEN 100 is similar to conventional transcranial direct or alternating current stimulation 
(tDCS, tACS) systems that are now widely used in research, with three major differences. The 
ﬁrst difference is using 256 electrodes to deliver current rather than 
Figure 2. 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 
sensors in the Geodesic Sensor Net. Right: The 3D sensor coordinates are then registered with the 
individual’s MRI or an atlas to allow precise planning of current delivery in relation to the person’s head 
tissues. 
2 large sponge electrodes. The second difference is that the same 256 electrodes that deliver 
current are also used in the localization of the epileptiform EEG (primarily spikes) generated by 
the epileptogenic zone. The third difference is that GTEN current delivery is computed with an 
accurate physics simulation of the tissue conductivity of the person’s head. 
Whereas tDCS and tACS typically use large sponge electrodes, GTEN achieves improved 
targeting of cerebral currents through ﬂexible selection of patterns of source and sink electrodes 
with the 256-electrode Geodesic Sensor Net (Figure 2). The geodesic partitioning of the head 
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surface with the Geodesic Sensor Net provides optimal electrode coverage of the head, 
including the face and neck. Whole head coverage is required for both effective measurement 
and effective targeting, particularly for basal brain surfaces. Exact sensor positions are 
registered with the computational electrical head model (either the patient’s MRI or an MRI 
atlas) with the Geodesic Photogrammetry System (Figure 2). The neuromodulation (source-sink 
electrode) pattern is designed to target the epileptogenic zone through computational modeling 
with a high resolution electrical volume conduction simulation of the person’s head tissues 
(with the GTEN Planning Module). The Modal Image Engine software (Figure 1) segments the 
tissues of the head, allowing estimation of each tissue’s conductivity with bounded Electrical 
Impedance Tomography (bEIT; described below). In addition, cortical surface extraction (Figure 
1 upper right) followed by dipole tessellation (for example, 1 cm sq patches) allows estimation 
of both the electrically active cortex in Electrical Source Imaging (ESI) and the cortical target for 
GTEN manipulation of cortical activity. 
Coping with Tissue Abnormalities 
We have had considerable experience in modeling the cortex and head tissues of patients with 
epilepsy, including those with malformations of cortical development (MCD), which are rather 
subtle anomalies, as well as those with cortical resections, which are typically large anomalies. 
The image segmentation and electrical conductivity modeling works well, with careful review 
of the results, in both cases. There are indeed abnormal anatomical conditions, such as the 
extensive demyelination of advanced cases of progressive multifocal leukoencephalopathy 
(PML), where we have found that our tissue segmentation (gray-white separation) and cortical 
surface reconstruction break down. Nonetheless, we are conﬁdent that the head modeling (and 
thus GTEN targeting) workﬂow will be robust for the great majority of patients with epilepsy in 
the proposed trial. Patients with previous resections and thus skull defects will be excluded. We 
will carefully evaluate any abnormal cerebral anatomy that may be inconsistent with our 
assumptions about head tissue impedance. The bEIT scan, described below, provides an 
independent in vivo test of the head conductivity model developed for each patient. 
Figure 3. Intracranial recordings in epilepsy have provided independent validation of the localization 
accuracy of ESI with 256 dEEG. After the wound of the intracranial placement heals (left), the Geodesic 
Sensor Net is applied, and simultaneous intracranial recordings and 256 dEEG recordings conﬁrm that 
the intracranial localization of epileptic spikes (yellow dots) are in the right anterior temporal pole. This 
localization was predicted by the preoperative (noninvasive) dEEG source localization with EGI’s 
GeoSource 2 software (yellow voxels at right). 
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Localizing the Epileptogenic Zone 
In the application of GTEN to suppress seizures, Electrical Source Imaging (ESI) is ﬁrst 
conducted with the dense array EEG (dEEG) to localize epileptiform events (primarily spikes) 
with EGI’s GeoSource software. As illustrated in Figure 3, dense array ESI has been shown to be 
accurate in determining the epileptogenic zone, as veriﬁed by intracranial recordings and by 
neurosurgical outcome in suppressing or eliminating seizures (Brodbeck et al., 2010; M. D. 
Holmes et al., 2008; M. Holmes et al., 2010; Yamazaki, Terrill, Fujimoto, Yamamoto, & Tucker, 
2012; Yamazaki, Tucker, et al., 2012; Yamazaki, Tucker, Terrill, Fujimoto, & Yamamoto, 2013). 
Furthermore, we rely on the reciprocity between potentials generated by the epileptic discharge 
source and the current applied by optimal GTEN targeting. EGI’s Geodesic Reciprocity Inverse 
Process (GRIP) technology (US Pats. No. 6,330,470 and 6,594,521) identiﬁes the head surface 
potentials (lead ﬁeld) of the epileptic discharge (spike or seizure), then uses that lead ﬁeld to 
select the pattern of the source and sink electrodes from the 256 array for optimal targeting of 
the epileptogenic zone (identiﬁed by 256 dEEG ESI). This GRIP technology is the primary 
targeting method in the GTEN Planning Module of EGI’s Modal Image Engine software. 
Targeting the Epileptogenic Zone with the Geodesic Reciprocity Inverse Process 
The second difference of GTEN from conventional tDCS (and tACS) is that the identiﬁcation of 
the epileptogenic zone is achieved through Electrical Source Imaging (ESI) with dense array 
electroencephalography (dEEG) collected with the same 256channel Geodesic Sensor Net that is 
used for the GTEN targeting. This allows precise targeting of the epileptogenic zone with EGI’s 
patented Geodesic Reciprocity Inverse Process (GRIP) in the GTEN Planning Module. 
The basic idea of GRIP is that, by the principle of Lorentz reciprocity, the pattern of dipolar 
positive and negative potentials (EEG) created by an active area of cortex (effective current 
dipole) is also the optimal pattern of source and sink electrodes for current delivery to the 
neurons that generated that EEG. Intuitively, electricity goes in the same way that it comes out. 
The physics of Lorentz reciprocity are clear. What is more speculative is the rationale that the 
way that the aligned neurons of the cortex generate far ﬁelds (EEG) provides a guide for how 
induced current alters the activity and polarization of cortical columns and their pyramidal 
neurons to affect ongoing function and thus long term plasticity. By careful analysis of 
therapeutic efﬁcacy in relation to the estimation of dosage delivered normal to the cortical 
surface of the epileptogenic zone, we can test this rationale. 
This oriented targeting is not possible for the majority of the cortex with TMS. To estimate this 
effective surface normal targeting with GTEN, we compute the dot product of the cortical 
surface normal (perpendicular) vector and the estimated current ﬂow vector at the 
epileptogenic cortical site induced by the selected source-sink electrode conﬁguration (Figure 
4). This factor becomes a covariate in the statistical analysis of treatment efﬁcacy, testing 
whether oriented targeting is indeed important or not. 
Minimizing Effects on Nontarget Cortex: Discriminative Cortical Surface Vector Targeting 
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The third difference of GTEN from conventional tDCS is that we achieve precise targeting with 
a high resolution head model, with knowledge of the position and surface of the cortex. This 
allows knowledge of electrical stimulation of non target brain tissue. Even though we can 
model it accurately, and conﬁgure its delivery with the dense (256 channel) electrode array, the 
electrical current cannot be focused, and instead follows the path of least resistance between 
source and sink electrodes, inﬂuencing all tissues in its path. The GTEN Planning Module 
provides an estimation of the current delivery to non-target as well as target regions of cortex. 
In response to the FDA’s concerns over current delivered to subcortical structures, such as the 
basal ganglia, we have now included a subcortical atlas, registered to the subject’s MRI (and to 
the atlas brain models), so that computation of current delivered to each major subcortical 
structure is now estimated by the GTEN Planning Module. 
For the subcortical nuclei, which are non-laminar, the orientation of the current ﬂow is not 
expected to be relevant, so the total current is computed. For the non target cortex, we also 
consider the effect of the unintended current in relation to its orientation to the cortex surface. 
As described above, the source-sink conﬁguration of the GRIP targeting is optimal for 
delivering cortical surface normal currents to the target region (which, by reciprocity, is collinear 
to the equivalent dipole vector in the electrical source estimation). However, other source-sink 
conﬁgurations can also be evaluated for their effective (dot product with the cortical surface 
vector) current ﬂow. 
The GTEN Planning Module incorporates a (patent pending) Discriminative Cortical Surface 
Vector (DCSV) targeting algorithm. This method maintains effective (surface normal) current in 
the target region for each pulse, but it alters the source-sink conﬁguration to minimize the 
electrical current delivered at each pulse or interval to non target brain regions. Imagine that the 
normal surface vector of target patch of cortex is rotated for each interval (or pulse) of 
stimulation, with the center at the target: the target patch is still the centroid of current ﬂow, but 
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somewhat different non target regions receive current during each interval or pulse. Through 
computational optimization (in which the cost function is minimal non target current as well as 
maximal target current), the DCSV algorithm generates a set of source-sink electrode 
conﬁgurations that consistently deliver effective pulsed current ﬂow to the target region but 
that create different (and thus minimized) current ﬂow patterns in non-target regions over time 
(Figure 5). 
Because digital switching of the GTEN 100 is fast, the treatment planning can establish multiple 
electrode conﬁgurations for multiple current paths, and each pulse of current can then be 
delivered through a different electrode conﬁguration. With this ﬂexible manipulation of the 
current ﬂow, for either pulsed or sustained protocols, it is possible to minimize current delivery 
to non-target cortex, and thereby optimize effective therapy (hypothesized to be mediated by 
long-term depression) only in the target (epileptogenic) region. For the Pulsed GTEN protocol, 
the therapy involves 100 ms pulses of surface cathodal current at 0.5 Hz, emulating the effect of 
slow repetitive TMS (rTMS). In both cases, the goal is long-term depression of cortical 
excitability and thus suppression of seizures. 
Validation of Targeting with bounded Electrical Impedance Tomography (bEIT) 
Effective computational targeting with the GTEN Planning Module requires an accurate 
electrical head model. We have tested the GRIP estimation with the FDM electrical head model 
with independent estimation of current density impressed in the volume with the L2 
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computation. In addition, prior to beginning treatment, we test the validity of the electrical head 
model used for each patient (the with patient’s own MRI or an atlas MRI) with the bounded 
Electrical Impedance Tomography (bEIT) protocol (Figure 6) that we have optimized and 
validated over the last decade (Salman et al., 2006; Volkov, Zherdetsky, Turovets, & Malony, 
2009). EIT is a well-known method of visualizing 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 (Figure 
1), we developed 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 image or geometry is 
now easily obtained from MRI or an MRI atlas). When applied within the GTEN Planning 
Module, the bEIT validation (Figure 6) can be completed through impressing high frequency 
(200 Hz) low power (10 μA) signals between the source and sink electrodes that were selected to 
optimize cortical targeting in the GTEN Planning Module. If the measured potentials (from the 
non-targeting electrodes, demodulated at the current delivery frequency) ﬁt the prediction, then 
the delivered currents, the electrical head model, and the distribution of currents throughout the 
volume used in the GTEN Planning Module are veriﬁed as accurate. 
Software Life Cycle and Risk Management 
The GTEN 100 software, including the Net Station GTEN Control Interface and the GTEN 
Planning Module, have been developed under EGI’s Quality System for a moderate level of 
concern. EGI’s Quality System is audited internally on a regular basis, and it is audited 
externally by VDE. 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 GTEN Treatment and Mitigation of Risks 
The goal of GTEN treatment is to safely decrease the excitability of the cortex in order to 
suppress seizures. Whereas conventional tDCS (with large sponge electrodes) involves weak 
currents (and is well within limits for safety), it may not be as effective as rTMS, which induces 
larger currents in the brain. Furthermore, the higher current levels induced by rTMS are well 
within safety limits for tissue damage, and there is now fairly extensive evidence that slow 
rTMS (which we emulate with our protocol) has a very low risk of causing seizures. We 
therefore increased the GTEN current to 2 mA total, added lidocaine to increase comfort at this 
level. 
We recognize the FDA’s determination that, in epileptic patients, the GTEN 100 may present 
signiﬁcant risk of worsening seizures or inducing cerebral discharges (possibly leading to 
kindling). We therefore request an Investigational Device Exemption. In addition, we detail the 
"14

strategy of mitigating the risk of inducing seizures, or inducing kindling, as well as other 
possible risks. 
Risk of Tissue Damage with Electrical Fault 
In the present proposed design of the GTEN 100, in order to achieve therapeutic efﬁcacy more 
similar to TMS than tDCS, we have increased the power supply of the current delivery circuit to 
10V (it was 5V in the previous presubmission). 
In the worst case scenario where electrode-skin contact impedances are all intentionally reduced 
by the user (through severe scalp abrasion against EGI’s explicit instructions and training), total 
circuit impedance could conceivably be as low as 1 kOhm. This would assume 1 kOhm source 
electrode impedance, and 0 kOhm sink impedance assuming that many sinks in parallel are all 
low and thus contribute an overall negligible impedance in parallel, and disregarding other 
head tissue contributions. This failure mode is highly unlikely in practice, but is relevant for 
worst case analysis. 
Historical evidence may help to calibrate the risk of this failure mode. In the history of EGI’s 
products, a circuit failure allowing current to be delivered to the subject (at a painless but 
perceptible level) has been detected and documented in one ampliﬁer channel in the Net Amps 
product series (200, 300, and 400) with over 1000 systems in the ﬁeld. About 70% of EGI systems 
sold have been 128 and 256 channels. Assuming equal numbers of 128 and 256 channels, we can 
estimate one failure in over 134,000 channels in use. The likelihood of more than one channel 
failing, in the same ampliﬁer at the same time, is thus astronomically low. Nonetheless, even 
though the probability of even one failed channel is low, there is always a risk of electrical fault. 
Tissue damage has been detected at a minimum total charge of 216 C/cm2 (2,160,000 C/m2) 
(Yuen, Agnew et al. 1981). In a study for epicranial tDCS stimulation in rats, (Liebetanz, Koch et 
al. 2009), Liebetanz and colleagues report that brain lesions were observed at a minimum 
cathodal electrode current density of 142.9 A/m2 for durations greater than 10 min. 
Mitigating the Risk of Tissue Damage with Electrical Fault 
Even with current applied in a TEN protocol, without scalp abrasion (which is prohibited in EGI 
laboratories) the electrode-scalp impedances almost never drop below 10k Ohms. Nonetheless, 
assuming the worst case of a user scraping the scalp to achieve a very low impedance of 1 
kOhm for the source electrode (and using multiple sinks in parallel to create a near zero sink 
impedance), a single fault failure of the constant current circuit could apply a full, unregulated 
10 V to the circuit. This would result in a current ﬂow at a single source electrode that is 10 V/1 
kOhm = 10 mA, resulting in a current density of ~10 mA/cm2 at that electrode/scalp interface 
in the electrical fault mode. 
A ﬁrst mitigation is created by the fact that this current level would be painful, even with the 
topical lidocaine electrolyte, leading to cessation of the treatment. In general, a practical 
mitigation is that the levels of current that would damage the brain would cause pain at the 
"15

scalp and skin. We instruct patients how to take the chin strap and pull the Geodesic Sensor Net 
off the head whenever they need to, such as in a ﬁre or other emergency. 
A second mitigation is the high reliability of the Net Amps electronics. Note that with a base 
rate of one failure in 134,000 channels, in hundreds if not thousands of hours of operation per 
channel, the odds of two channels failing at the same time are astronomically low. 
"
Figure 7. Finite Difference Model simulation with the EGI high resolution electromagnetic head model 
(Salman et al., 2005) showing (clockwise) one axial slice with the scalp, skull, cerebral spinal ﬂuid and 
cortex geometry, the electrical potentials induced by simulated tDCS ( 6 anterior sources x 6 posterior 
sinks conﬁguration; 1 mA total current injection), the power ( Joule heat) density and the current density 
(strongly inﬂuenced by CSF). However, for purposes of examining the safety of the electrical current 
delivery in case of the worst case fault (for example assuming the pulsed TEN protocol were delivered to 
an unconscious patient for whom the scalp had been scraped), there are 3 pulse trains of 500 pulses of 0.1 
second duration each. The total charge density would be 0.010 A/cm2 * 1 C/(A * s) * (1500 * 0.1) seconds 
= 1.5 C/cm2 (or 15000 C/m2) at the source electrode. 
Furthermore, we assume that the the current source may have failed in a rail mode, with 
continuous 10 V output (instead of a 0.1 sec on duty cycle), the energy deposition might be 
considerably higher, 0.010 A/cm2 * 1 C/(A * s) * (1500 * 2) seconds = 30 C/cm2 (or 300,000 C/
m2) at the source electrode. 
"16

Tissue damage has been detected at a minimum total charge of 216 C/cm2 (2,160,000 C/m2) 
(Yuen, Agnew et al. 1981). Thus, even assuming the worst case circuit failure with the 10V 
power supply and an unconscious patient with an abraded scalp, the single fault charge density 
at the source electrode is never more than 0.14 (30/216) of the charge density that causes tissue 
damage. 
A separate question is the likelihood of damage to brain tissue with the worst case circuit 
failure. In a study for epicranial tDCS stimulation in rats, (Liebetanz, Koch et al. 2009), 
Liebetanz and colleagues report that brain lesions were observed at a minimum cathodal 
electrode current density of 142.9 A/m2 for durations greater than 10 min. For current densities 
between 142.9 and 285.7 A/m2, lesion size increased linearly with charge density (current 
density × time); with an extrapolated zero lesion size intercept of 52400 C/m2. If an EGI 
electrode were placed directly on the brain and a worst case electrical fault were to occur, the 
single fault charge density could exceed by a factor of 5.7 (300,000/52400) the zero lesion tissue 
safety limit at the source electrode, if it is allowed to exist for a full stimulation protocol. 
However, the GTEN 100 electrodes are placed on the scalp (and face and neck). By careful 
modeling of head tissue conductivities (Gabriel, Peyman, & Grant, 2009; Turovets, Poolman, 
Salman, Malony, & Tucker, 2008) (Figures 7 and 8), we can determine that the current delivered 
at the scalp surface is attenuated by a factor of 100 or so at the brain. With an attenuation 
conﬁdently estimated to range from 80 to 120, the total charge density of the proposed GTEN 
protocol to the brain would range from 0.07 (3750/52400) to .05 (2500/52400) of the lower 
bound of tissue damage of 52400 C/m2. 
Figure 7 shows the fall off in current level when 1 mA of current is applied to 6 source 
electrodes and 6 sink electrodes (Salman, Turovets, Malony, Eriksen, & Tucker, 2005). Note that 
in this simulation, although the average current density is 167 μA per each of the six electrodes, 
this simulation models the current injection as a point source (with the FDM and palette 
showing the diffused current in the nearby scalp), whereas the simulation in Figure 8 provides 
ﬁnite element modeling of the current density at the electrode-skin boundary (illustrating the 
effect of the speciﬁc electrode surface area and conductivity pattern).
"17

"
Figure 8. Finite element computations by Moritz Dannhauer and Rob McLeod at the University of Utah 
with EGI’s electromagnetic head model and realistic conductivity values for the skull. Here the scalp 
current density (at the perimeter of the 1 sq cm electrodes, right) is about 4 A/m2 at the edges, and the 
maximum current density at the cortex is estimated as about 0.2 A/m2, an attenuation factor of about 20. 
Risk of Pain in Normal Operation 
In normal operation, the circuit for current delivery is a constant current circuit. It is important 
to emphasize that the worst case calculations with the power supply voltage are therefore not 
relevant to the controlled current delivered in normal operation (we apologize if our previous 
presubmission material was unclear on this point). 
In normal operation, the delivery of electric current through small (1 cm2) scalp electrodes 
causes itching and then pain as the current density is increased. This was a major motivation for 
the development of TMS, which uses the magnetic ﬁeld of the electromagnetic coil to induce the 
"18

mirror image electrical current in the cranial space without electrical current ﬂow through the 
scalp (which has extensive nerve endings). With the GTEN 100, we observe there are 
considerable individual differences in the pain that is experienced. As a result, we train the 
experimenter to encourage reports of itching or pain, and then to cease treatment with any 
reports of discomfort. Because there is no observed tissue damage at any of the levels used in 
our preclinical studies, and only minor reddening of the skin, the pain reﬂects the electrical 
stimulation of the scalp nerves rather than tissue damage. 
Mitigating the Risk of Pain in Normal Operation 
As mentioned above, estimations of safe and painless operation with conventional (large square 
sponges) tDCS (Bikson, Datta, & Elwassif, 2009) have suggested charge densities range from 
343-960 C/m2 (.0343-.0960 C/cm2). However, this calculation makes the common assumption 
in the tDCS literature that current is distributed evenly over the surface of the sponge. Instead, 
as would be consistent with classical physics model of the ﬂow of current in a conductor, the 
current is distributed at the edge of the sponge, such that much higher current (and charge) 
densities have actually been delivered to the scalp at these perimeter locations in the 
conventional tDCS studies. 
The same tendency for current to ﬂow at the perimeter of the conductor is observed in 
simulations with the small (1 sq cm) electrodes of the GTEN 100 (Figure 8). However, the larger 
number of electrodes leads to greater perimeter distribution of the total current (Figure 8, right). 
The ﬁrst step to minimize the risk of pain is informing subjects that they can stop the procedure 
at any time just by letting us know they want to stop. This sensitivity to the patient’s 
communications is an integral part of GTEN technician training. In addition, we tell each 
patient how, in case of emergency, they can take the chin strap and pull the Net off their head. 
However, patients with epilepsy need an effective treatment, which may require brain current 
levels that are as close as possible to those induced by TMS. The present GTEN 100 protocol 
targets a current density at each electrode of 200 μA/cm2. We therefore minimize the risk of 
pain through iontophoretic (current induced) delivery of lidocaine that is mixed with the 
electrolyte. After a few minutes of iontophoretic application of lidocaine, our preliminary 
studies suggest 200 μA/cm2 is painless. If the subject detects any pain or discomfort, the 
current will be reduced so that the GTEN protocol (pulsed or sustained) is in fact painless. 
In normal operation, the total current of the GTEN 100 is limited to 2 mA, and the current at 
each electrode is limited to 200 μA. Recognizing that increased current density (“hot spots”) 
may be observed, we will mitigate this risk through careful inspection of the patient’s skin and 
scalp after each session. A recent report of skin lesions after high current levels with tDCS 
electrodes (on the arm) showed that the ﬁrst effect was reddening (erythemia) and that lasting 
redness (lasting several days) only occurred with repeated stimulation over multiple sessions 
(Khadka et al., 2015). Interestingly, the senior author of that study (Marom Bikson) reports that 
the erythemia does not suggest hot spots as suggested by FEM simulations, but rather that the 
current is fairly evenly distributed over the surface of the electrodes. Nonetheless, by careful 
monitoring after each session, we will assure that any reddening is not allowed to progress to a 
"19

lasting lesion. In many sessions with the GTEN 100 prototype with a range of skin types and 
current levels varying from 100 to 200 μA, we have not seen any evidence of lasting lesions. 
Risk of Lidocaine Toxicity 
In order to achieve effective therapeutic current level of 200 μA/electrode (closer to those of 
TMS) while minimizing patient discomfort due to painful electrical stimulation of skin/scalp 
nerves, we have developed the procedure of adding lidocaine to the electrolyte, and then 
applying current to achieve iontophoretic delivery of the lidocaine to the scalp and skin. Our 
preliminary experiments suggest this will allow painless delivery current densities of 200 μA 
per electrode (200 μA/cm2), even with rapid switching of current levels in the pulsed TEN 
(rTMS emulation) protocol. 
There is a risk that, with multiple electrodes conditioned for source and sinks, the total 
iontophoretic lidocaine delivery will result in toxic systemic levels. 
Mitigating the Risk of Lidocaine Toxicity 
As pointed out by the FDA reviewer, there are multiple mechanisms for the infusion of topical 
lidocaine in the presence of electrical current, including iontophoretic, electroosmosis, and 
passive diffusion. To minimize the risk of toxicity, we will assure that the total dose of lidocaine 
applied to the skin, even if all of it were absorbed, will be below the toxic level. 
Over the counter lidocaine cream (5% concentration, for example: RectoCare®) is mixed in 
equal parts with Eleﬁx electrolyte paste. This is done before each treatment session. 
To calculate the amount of electrolyte/ lidocaine cream under one electrode, the space available 
under EGI’s electrode cup is about 150 cubic mm. The total amount of paste under one cap is 
150 mg. Half of this is an over-the-counter 5% lidocaine cream (and half is Eleﬁx gel). The total 
amount of lidocaine is therefore 3.75 mg. If we assume 10 high current electrodes are treated, 
then if all were absorbed, the dose would be 10 times smaller than the systemic toxic threshold 
for a average patient weight of 70 kg ( 5mg/kg x 70 = 370 mg). Of course , the amount absorbed 
is a fraction of what is present at the skin. For example, lidocaine patches, even after 12 hours on 
the skin, still contain about 95 % of initial amount of drug and are recommended to be disposed 
with appropriate care. 
Risk of Tissue Damage in Normal Operation 
Tissue damage must be considered separately from pain. Pain is noticeable with changes in 
current density, including the offset of the current, apparently through stimulating scalp nerves. 
Furthermore, pain decreases to become unnoticeable with constant direct current (DC) in the 
typical tDCS paradigm. Tissue damage, however, is a function of current density over time, or 
charge density. Estimations of both safe and painless operation with conventional (large square 
sponges) tDCS (Bikson et al., 2009) have suggested that safe charge densities in the typical tDCS 
experiments with large wet sponge electrodes range from 343-960 C/m2 (.0343-.0960 C/cm2). 
Nonetheless, there are reports of skin lesions when hard tap water (containing calcium 
carbonate) was used instead of saline (Palm et al., 2014). Furthermore, there have been reports 
"20

of skin lesions at the corners of large sponge electrodes, even though the estimation of charge 
density over the surface area of the electrode is lower than the safety limit (Rodriguez, Opisso, 
Pascual-Leone, & Soler, 2014). As shown in by the FEM simulation in Figure 8, the charge 
density is unlikely to be distributed evenly over the surface of the electrode, but rather is 
concentrated at the perimeter (and particularly the corners of square electrodes). 
In a study for epicranial tDCS stimulation in rats, Liebetanz and colleagues report that brain 
lesions were observed at a minimum cathodal electrode current density of 142.9 A/m2 for 
durations greater than 10 min (Liebetanz, Koch et al. 2009). For current densities between 142.9 
and 285.7 A/m2, lesion size increased linearly with charge density (current density × time); 
with an extrapolated zero lesion size intercept of 52400 C/ m2. 
Mitigating the Risk of Tissue Damage in Normal Operation 
In normal operation, the total current of the GTEN 100 is limited to 2 mA, and the electrode-
scalp impedances are measured continually to assure that each electrode (for example 10 
cathodes and many anodes) is maintained at or less than a current level of 200 μA (current 
density of 200 μA/cm2). 
In the pulsed GTEN protocol, over 0.1 seconds (for example, a single pulse injected over 10 
channels) in normal operation, the total charge density per electrode would be 0.0002 A/cm2 * 1 
C/(A * s) * 0.1 seconds = 0.00002 C/cm2 (i.e. 0.2 C/m2) at the source electrode. Over the full 
pulsed GTEN session protocol of 3 pulse trains of 500 pulses of 0.1 second duration each, the 
total charge density would be 0.0002 A/cm2 * 1 C/(A * s) * (1500 * 0.1) seconds = 0.03 C/cm2 
(i.e. 300 C/m2) at the source electrode. 
Tissue damage has been detected at a minimum total charge of 216 C/cm2 (2,160,000 C/m2) 
(Yuen, Agnew et al. 1981). The normal GTEN 100 current ﬂow at the source electrode is .001 (.
204/216) of that limit. We have never seen skin damage, or any effects other than temporary 
reddening of the skin (erythemia) with the GTEN protocols and the Geodesic Sensor Net 
electrodes, even when current density varies from 200 to 400 μA over many minutes. 
We also consider the risk of tissue damage in the brain. In a study for epicranial tDCS 
stimulation in rats, (Liebetanz, Koch et al. 2009), Liebetanz and colleagues report that brain 
lesions were observed at a minimum cathodal electrode current density of 142.9 A/m2 for 
durations greater than 10 min. For current densities between 142.9 and 285.7 A/m2, lesion size 
increased linearly with charge density (current density × time); with an extrapolated zero lesion 
size intercept of 52400 C/m2. 
Figure 8 shows an attenuation factor of about 20 X from the current level for multiple scalp 
electrodes (each at about 4 A/m2) to the cortical surface (peaking at about 0.2 A/m2). A similar 
calculation from one electrode (the worst case failure situation under less than astronomical 
odds for creating charge density of 2040 C/m2) shows an attenuation of about 100 X, from 
about 20 A/m2 at the scalp to achieve 0.2A/m2 on the cortex. With the attenuation of scalp 
charge density (2040 C/m2) by head tissues ranging from a factor of 80 to 120, the GTEN 100 
"21

normal mode charge density at the brain ranges from 26 C/m2 to 17 C/m2 or a factor of .0005 
(26/52400) to .0003 (17/52400) of the safe limit for current to the brain. 
The FDA reviewer cited earlier studies suggesting that the attenuation may be a factor of 30 
rather than 100. Our modeling, with accurate skull conductivity from CT and with validation 
through bEIT studies, provides more accurate justiﬁcation for the values than these early 
literature values. Nonetheless, we agree with the FDA that caution is warranted in assuming 
attenuation. As a result, we propose to mitigate the worst case failure through an additional 
layer of fault protection circuitry. 
Note that (although it was not clearly explained in the previous submission), the GTEN 100 
includes circuitry to limit the current per channel to 200 μA. The fault protection is designed to 
limit total current assuming this circuit fails. 
The GTEN 100 design has now been revised to include a second Sentinel Circuit®, in series with 
the ﬁrst one, to insure that failure requires a triple fault (the circuit fault, and failure of both 
Sentinel Circuits). The Sentinel Circuit is a separate electronic monitor circuit that detects if the 
current level exceeds the planned 2 mA value (such as if there is a fault in the electronics 
circuit). In that event, the Sentinel Circuit disconnects the current generator. 
Risk of Seizures in Normal Operation 
An important risk of the GTEN treatment is the risk of causing seizures. This risk may not be 
simply related to the level of current, but rather involves the more complex and poorly 
understood neurophysiology of epilepsy. The evidence on treating epilepsy with both tDCS and 
rTMS is relevant to assessing the risk of seizures. 
Mitigating the Risk of Seizures in Normal Operation 
It should be emphasized that patients must agree to maintain their regular anti epileptic 
medication during the course of the study. 
There are two studies we found that have examined the effects of a single session of tDCS 
treatment of the apparent epileptogenic zone (F. Fregni, Thome-Souza, et al., 2006; Rotenberg et 
al., 2008). Both showed beneﬁcial short term effects of the treatment in suppressing epileptiform 
discharges, with no increase in seizure frequency. 
For the pulsed GTEN protocol emulating the effects of slow rTMS, the literature on seizure risk 
with slow rTMS in epilepsy is relevant. An important caution is that there have been only a few 
studies of slow rTMS therapy in epilepsy. Nonetheless, a recent review of the literature for rTMS 
therapy suggests that there appears to be minimal risk of inducing seizures by the slow rTMS 
treatment (Bae et al., 2007). The seizures that have been recorded during the slow rTMS 
treatment session have been the patient’s typical seizures in both duration and semiology, 
suggesting these were not induced by the treatment (Rotenberg et al., 2009). 
Thus, for the present feasibility study, the literature suggests the risk of seizures is low. To 
mitigate the risk, we will monitor carefully for seizures during and after the treatment. During 
"22

the three-month pretreatment baseline evaluations, we will characterize the patient’s interictal 
events, plus any ictal events that are recorded, during three two-hour dEEG evaluations. We 
will train the treatment technician to monitor the EEG for these events during the treatment 
session. Because the source site of the interictal events is also the presumed epileptogenic zone 
and the target of the GTEN treatment, this is also the site (and scalp topography) that would be 
expected to generate seizures if the treatment causes or kindles seizures. The preparation for 
each patient’s treatment will identify not only the source of the epileptiform discharges, but the 
scalp topography, such that the technician has a select montage (screen arrangement) for the 
channels that reﬂect the patient’s spikes (and likely seizures). 
During the 17 minute GTEN treatment intervals, the EEG channels that are not used for (source 
or sink) current delivery will be monitored. The 24 bit ADs of the NA 400 allow adequate 
dynamic range (+/200 mV) that even channels nearby the current delivery seldom clip. During 
the rest (resting EEG and break) intervals, all 256 channels will be monitored. For the ﬁrst ten 
patients, we will monitor the EEG for three hours following the completion of the treatment; for 
the rest of the patients we will monitor the EEG for 30 minutes following the completion of 
treatment. 
If there is any increase in epileptiform activity during the treatment or the monitoring 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 Inducing Kindling of Seizures 
It is well known that repeated electrical stimulation of the normal mammalian brain may lead to 
augmenting or progressive kindling of discharges, leading to seizures. Persons with epilepsy 
may show enhanced cortical excitability that places them at increased risk. In the animal 
literature, kindling occurs when repeated electrical stimulation of the cortex elicits cortical after-
discharges (continuing when the stimulation stops); in some reports the discharges not only 
lead to seizures, but may lead to epilepsy, with spontaneous discharges and/or seizures in the 
absence of stimulation (Bertram, 2007). 
Mitigating the Risk of Inducing Kindling of Seizures 
The same procedures of careful EEG monioring used to mitigate the risk of seizures will 
mitigate the risk of kindling. Speciﬁcally, the EEG of each patient will be monitored during and 
after the treatment session, including a speciﬁc inspection of the channels near the target site. If 
the GTEN treatment is observed to lead to any epileptiform discharges that are unlike the 
patient’s typical discharges (spikes) in frequency or localization, the treatment will be 
discontinued. A speciﬁc warning for possible kindling is the observation of repeated discharges 
that are associated with the repeated application of stimulation, speciﬁcally the pulses of the 
pulsed GTEN protocol. If these are observed, treatment will be stopped. 
Risk of Unwanted Plasticity 
"23

The short term effects of transcranial neuromodulation are typically 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) as evidenced by learning effects that are mediated by NMDA (Monte-Silva et al., 2013). 
The rationale of the present interventions is that inducing long term depression 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 GTEN treatment may change other 
aspects of the patient’s cortical function that may create unwanted changes in brain function or 
plasticity. The large general literatures for tDCS and slow rTMS suggest there are unlikely to be 
serious unwanted changes. Nonetheless, we will achieve more focal and potentially more 
effective current delivery than in previous research with tDCS, and we will achieve deeper 
current delivery than previous research with slow rTMS. 
The primary effect on the target brain region is expected to be the induction of long term 
depression. We will evaluate general cognitive function in each patient with scores on the 
California Verbal Learning Test, paying close attention to any changes from the expected 
improvement in performance with practice from the normative data. The patient’s baseline 
performance with the CVLT is assessed during the pre-treatment baseline assessment. We will 
also review the Quality Of Life In Epilepsy ratings and the seizure diary with each patient and 
family, systematically reviewing any complaints or reports that may suggest the treatment is 
creating unwanted changes in brain function. Finally, for each patient we will examine the 
effective dose delivered to non target brain regions as a function of the DCSV targeting recorded 
by the GTEN Planning Module to insure that the electrical dosage (and the presumed induction 
of long term depression) is appropriately limited to the target cortex. 
Pre-Clinical Testing with Normal Volunteers 
We have studied the comfort and safety of the GTEN protocols, and evaluated their efﬁcacy in 
manipulating cortical excitability, with normal volunteers. A preliminary report was presented 
at the June 2014 Organization for Human Brain Mapping (Tucker, Turovets, Anderson, & Luu, 
2014). In the ﬁrst series of experiments, we limited the GTEN current delivery to 1 mA total, and 
applied this through 7 to 10 of the electrodes of the Geodesic Sensor Net for the anodal current 
and 7 to 10 electrodes for the cathodal current. Both saline and gel (Eleﬁx) electrolytes were 
used. Typical tDCS protocols were evaluated, with head surface anodal current predicted to 
increase cortical excitability, and head surface cathodal current predicted to decrease cortical 
excitability (T. Wagner et al., 2007). Using typical tDCS procedures including ramping up the 
DC stimulation over several seconds, the 1 mA current levels were generally comfortable for the 
subjects, when distributed over 7 to 10 electrodes. The motor cortex was identiﬁed anatomically 
by the hand knob, and a typical tDCS targeting of the motor cortex was achieved with the 
GTEN Planning Module. The effect on cortical excitability was tested through TMS stimulation 
of the hand area to create a thumb Motor Evoked Potential (MEP), with the TMS strength (% of 
"24

initial motor threshold) deﬁning cortical excitability. Figure 9 shows the TMS and GTEN 
targeting. 
"
Figure 9. Left: targeting of Motor Evoked Potential (MEP) with TMS (the red bulls eye is the TMS target). 
The cortex is rendered with a convex hull slice. Middle: GTEN source (red = anodal) and sink (blue = 
cathodal) pattern for a radial current ﬂow pattern targeting the hand knob of motor cortex. Right: inﬂated 
brain to show sulcal current delivery. 
Consistent with the tDCS literature, head surface anodal current generally increased cortical 
excitability as indexed by the TMS MEP, and head surface cathodal current generally decreased 
cortical excitability. Also consistent with the literature, individual responses varied considerably. 
In the next series of experiments (now in preparation for publication), we tested the comfort 
level with higher current levels (200 μA for each 1 cm2 electrode), using the typical tDCS 
protocol. Iontophoretic impedance conditioning was used to lower typical electrode-scalp 
impedances to 20 to 40K Ohms. There were large individual differences with comfort as well, 
but with the Geodesic Sensor Net 1 cm2 electrodes and 7 to 10 with the primary cathodal or 
anodal current, most subjects reported minimal or no sensation at 50 μA, feelings of itching or 
minor pain at 100 μA, and noticeable itching and painful irritation at 200 μA. We then mixed 
lidocaine with the gel electrolyte, applied anodal current for iontophoretic delivery (see above 
for dose analysis) during the iontophoretic impedance conditioning, and then repeated the 
experiments at 200 μA. Subjects consistently reported this was a painless procedure. Only when 
we asked them to feel the scalp with their ﬁngers did they notice the slight numbing of the scalp 
under the active (7 to 10 focal anodal or cathodal) electrodes. 
We have now completed testing with normal volunteers with the Pulsed GTEN protocol. Initial 
tests (with the investigators) without lidocaine conﬁrm that the pulsed stimulation is more 
painful than ramped and sustained tDCS, even at 100 μA. However, with the lidocaine 
iontophresis, the 200 μA per electrode results in no noticeable sensation with the pulsed 
protocol. These pulsed experiments will be completed and submitted for publication, with the 
requirement that safety and comfort are both veriﬁed with normal volunteers prior to initiating 
clinical feasibility trials with the Pulsed GTEN protocol. 
"25

Therapeutic Mode of Action
In addition to insuring safety, we want to suppress seizures effectively. The literature on 
electrical neuromodulation in epilepsy suggests that tDCS typically has only a short term 
therapeutic effect in suppressing epileptiform discharges or EDs (Auvichayapat et al., 2013; 
Faria, Fregni, Sebastiao, Dias, & Leal, 2012). However, other evidence (Monte-Silva et al., 2013; 
Monte-Silva, Kuo, Liebetanz, Paulus, & Nitsche, 2010) suggests that repeated blocks of tDCS can 
induce lasting changes in cortical excitability (even though these studies were not with 
epilepsy). 
In addition, the literature on epilepsy treatment suggests that slow (1 Hz or 0.5 Hz) repetitive 
transcranial magnetic stimulation (slow rTMS) has a lasting effect, including seizure 
suppression, assuming that the epileptogenic zone is accurately targeted (F. Fregni, Otachi, et 
al., 2006; Sun et al., 2012). Considering these several lines of evidence, we propose to implement 
a Pulsed TEN protocol to emulate the brain currents induced by slow rTMS to induce LTD and 
decrease cortical excitability. 
Both tDCS and TMS achieve neurophysiological effects through creating electrical currents in 
the brain. Whereas the induction of current by the magnetic ﬁeld of the TMS coil has the 
advantage of delivering higher brain currents while minimizing painful current ﬂow through 
the scalp, the current ﬂow is almost exclusively tangential to the head surface (because of the 
mechanical constraints of the coil), and the current is limited to roughly two centimeters of 
depth from the head surface, depending on the coil design (Pascual-Leone, Davey, Rothwell, 
Wassermann, & Puri, 2002)). As a result, even if the epileptogenic zone is localized correctly, 
effective targeting (current ﬂow normal to the cortical surface) is difﬁcult (and often impossible) 
with TMS. This conclusion is supported by the ﬁnding that TMS is often successful with 
neocortical foci, but may not be successful with deep medial temporal foci (F. Fregni, Otachi, et 
al., 2006; Sun et al., 2012). 
The initial, single treatment session application of cathodal tDCS in epilepsy has suggested 
there is a suppression of epileptiform activity, but only over days or weeks (Auvichayapat et al., 
2013; Faria et al., 2012). Our goal is suppression over several months. Several recent lines of 
evidence have suggest that the effects of tDCS stimulation can be made more lasting in two 
ways: (1) separating the repeated blocks of stimulation by short intervals of no stimulation, and 
(2) by repeating treatment over successive days. 
In a cathodal tDCS study, Monte-Silva et al. (2010) showed that two, 9-minute tDCS sessions 
separated by brief (3 or 20 minute interval) breaks (i.e., no stimulation) 
"
"26

Figure 10. The protocol for interleaving GTEN treatment (either Blocked Sustained tDCS or Pulsed 
GTEN) and dEEG assessment (recorded and evaluated during the breaks as well as the resting EEG 
intervals). 
enhanced the inhibitory after effect as well as prolonged it (up to two hours). They also showed 
that 9-minute sessions separated by 3 or 24 hours reduced the immediate aftereffects, but within 
25 minutes after tDCS was completed the aftereffects were then enhanced and sustained for up 
to 2 hours. In a more recent study, Monte-Silva et al. (2013) showed that 13-minute anodal 
stimulation sessions separated by 3 or 20 minute intervals extended the aftereffects beyond 24 
hours post-stimulation. From both studies, when tDCS is applied within the aftereffect window 
of the ﬁrst tDCS session, it has the ability to enhance the lasting aftereffects (i.e., inhibit or 
facilitate neuronal function depending on cathodal vs anodal polarity) as well as to prolong 
these effects in time. 
Two studies have found that tDCS applied over multiple days produces learning effects that last 
for weeks to several months. Reis et al. applied 20-minute anodal tDCS over ﬁve consecutive 
sessions (each separated by 24 hours) as subjects performed a visuomotor task (Reis et al., 2009). 
The effect of anodal tDCS on task performance was measured at ﬁve intervals, the longest 
interval being 85 days after tDCS. Reis et al. found that tDCS enhanced motor learning and that 
this enhancement persisted for up to 85 days post tDCS treatment. More recently, Olma et al. 
applied anodal tDCS to the visual cortex over ﬁve consecutive days (each separated by 24 
hours) as subjects performed a visual motion perception task (Olma et al., 2013). Anodal tDCS 
in this paradigm resulted in an improvement in motion perception that lasted up to 28 days. 
Of course these are not just direct neurophysiological effects of tDCS, but rather learning 
changes in the brain where the process of learning has been augmented by tDCS. Treating 
epilepsy may be more challenging because there is no systematic or deliberate learning regimen, 
but rather a more simple attempt to suppress cortical excitability. 
With these effects in mind, n each treatment session there are three 17 minute blocks of 
sustained TEN, separated by 10 minute breaks or rest periods, with pre-session and post-session 
resting EEG as shown in Figure 10. This treatment session is administered each day for ﬁve 
days in one week. The successful Sun, et al., protocol included slow rTMS treatment 5 days per 
week for two weeks and suppressed seizures for up to 6 months. However, for the present 
feasibility study, we propose to treat for 5 days in one week, with feasibility and targeting 
accuracy demonstrated through observing spike suppression at weeks 2, 8, 16, and 24. Seizure 
suppression will also be evaluated each month in the seizure diary. 
Relative Strengths of TMS and TEN 
It is generally assumed that TMS induces large electrical currents in the brain, and indeed these 
are sufﬁcient to stimulate neuronal discharges, such as evidenced by the motor evoked 
potential. In contrast, TEN (tDCS and tACS) generally induces much smaller currents in the 
brain, and there may be concern that the proposed TEN protocols cannot be as effective as the 
slow rTMS treatment protocols in the literature (F. Fregni, Otachi, et al., 2006; Sun et al., 2012). 
"27

The earlier textbook models of the current density induced by TMS suggest that current 
densities induced in the cortex are on the order of 3000 μA/cm2 (30 A/m2) (T. A. Wagner, Zahn, 
Grodzinsky, & Pascual-Leone, 2004). However, Wagner, et al. (2004) point out that these 
textbook models of TMS used unrealistically high head tissue permittivity for the magnetic 
ﬁelds. With more realistic permittivity values, the estimate obtained in the Wagner et al. 
simulation was 300 μA/cm2 (3 A/m2) current density at the cortex. 
In contrast, in the simulation of Figure 8, the total current of 2 mA was impressed at the 7 source 
scalp electrodes to create a current density of 286 μA/cm2 (0.2 A/m2) on the cortex. If we limit 
the scalp current density to 200 μA/cm2, as with the proposed protocol for the GTEN 100, then 
the cortical surface current density will be 0.13 A/m2, a factor of 23 less than TMS. 
However, the effective modulation of brain activity may depend not on the absolute current 
density, but on the current ﬂow that is normal to the cortical surface. This is because the neurons 
of the cortex are aligned perpendicular to the cortical surface, and the induced current serves to 
alter neuronal polarization along the apical dendrite to somatic axis of the cortical pyramidal 
neurons (Datta, Zhou, Su, Parra, & Bikson, 2013). Wagner et al (2004) point out that as little as 
30% of the current induced by TMS may be oriented normal to the cortical surface. This implies 
that TEN, which can be directed from the 256 channel array to be oriented mostly normal to the 
cortical surface, may achieve effective dosage that is within a factor of 10 less than the 
magnitude of the effective TMS induced current. 
Importantly, a major advantage of TEN over TMS is the ability to reach deep sources. In the 
simulations of TMS by Wagner, et al. (2004), the depth penetration of TMS was 2 cm into brain 
tissue, where it reached only the crown of the gyrus, and there the current was largely 
tangential to the gyral crown (rather than surface normal). We must assume, therefore, that the 
targeting in the existing studies of slow rTMS for epilepsy (Fregni, et al., 2006; Sun, et al., 2012) 
was highly approximate. Although Fregni et al. used focal cortical dysplasias to guide targeting, 
it is highly unlikely that these were all within 2 cm of the cortex, or that effective targeting of 
current direction was achieved. 
Therefore, considering these several factors, we can reasonably expect that the electrical dosage 
of the GTEN 100, with the safety and comfort level set at 200 μA per electrode for the study 
protocol pulses (Figure 10), when targeted appropriately to the epileptogenic focus with the 256 
array and the high resolution head model, will be an effective treatment for seizure suppression. 
Clinical Feasibility Trial Design 
The goal of this unblinded and uncontrolled (“open-label”) feasibility study is to evaluate the 
safety, comfort, and preliminary efﬁcacy of GTEN 100 treatment in achieving temporary 
suppression of epileptic activity, as assessed primarily by spikes and secondarily by seizures. 
The GTEN 100 applies small, electrical currents (up to 200 μA per electrode and up to 2 mA 
total) in a pattern that targets the cortical site of epileptiform discharges in order to decrease the 
excitability of the epileptogenic cortical tissue. 
"28

For this safety and feasibility study, two clinical sites are being planned in the US (Eugene, 
Seattle) and one in China (Shanghai). An expert epileptologist will provide medical guidance at 
each site. The Chair of the Study Monitoring Committee will not be associated with these sites 
or with EGI: Dr. Douglas Rose, Cincinnati Children’s Hospital Medical Center. Racial and 
gender composition will be as it appears in each sample. Study protocols and safety procedures 
have been approved by IRBs in Eugene and Seattle, and are under review at Huashan Hospital 
in Shanghai. 
Patient Recruitment 
Adult and adolescent patients (12 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 focal spikes (and other discharges of focal onset, 
including seizures) identiﬁed through Electrical Source Imaging (ESI) applied to a routine dense 
array EEG (dEEG) evaluation. All patients agree to maintain their current antiepileptic drug 
dose throughout the study, including the two month baseline and the two month follow-up 
period. 
Inclusion Criteria 
(1) Partial onset seizures (simple or complex) with failure of adequate seizure control after prior 
use of at least 2 anti-seizure drugs at effective doses. 
(2) A clearly identiﬁed and localizable focus of epileptiform discharges, as deﬁned by the 
discharges (typically epileptiform spikes) and as identiﬁed by dEEG assessment through one or 
more routine clinical dEEG evaluations. 
(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. 33 
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) 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. 
(3) A history or condition of status epilepticus or psychogenic seizures. 
"29

(4) 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. 
(5) Previous surgery involving opening the skull.
 
(6) Allergy to or condition contraindicating lidocaine. 
(7) Unable to express presence of pain or discomfort. 
Escape Criteria 
For individual patients, the study will be terminated for any of the following reasons: 
(1) Unacceptable discomfort or pain at stimulation currents of 200 uA. 
(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. 
(4) Status epilepticus. 
(5) A two-fold increase of seizure frequency over the baseline seizure frequency. If the frequency 
of seizures is very low, then an apparent increase during treatment (not reliably quantiﬁed as a 
two-fold increase) will be discussed with the patient, family, physician and Study committee. 
The entire study will terminate if 5 subjects meet escape criteria. 
Baseline Evaluation
During a one-month pre-treatment baseline evaluation period, the patient (and/or family) will 
maintain the seizure diary, which will be reviewed by the study coordinator in a phone contact 
once per week. In addition, 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. Each baseline evaluation also includes the California 
Verbal Learning Test, and the Quality of Life in Epilepsy report. 
Probe Treatment and Evaluation 
The GTEN Plan is developed to apply current pulses to the epileptic focus, as it is identiﬁed 
from the dEEG source localization of the spike onset. The GTEN Plan will often include more 
than one treatment option, primarily depending on the orientation of the cortical region 
identiﬁed as the epileptic focus. To evaluate a treatment targeting option, a probe treatment may 
be conducted, consisting of one 17-min pulsed treatment block (Figure 10) followed by one hour 
of dEEG evaluation and spike counting. If multiple targeting options are evaluated, the one 
with the best evidence of spike suppression will be selected for the 5 session treatment 
intervention. 
The probe treatment and evaluation protocol is thus a subset (one block instead of 3 blocks of 
17-minute pulses) of the approved treatment protocol. 
"30

The same GTEN Planning Module is used to develop each probe treatment targeting plan, with 
the primary difference being the cortical region that is targeted. This is a judgment made by the 
scientists (Drs. Tucker and Luu at EGI) on the basis of the ability to target the cortical region, 
which is very difﬁcult in medial temporal regions, and the epileptologist (Dr. Holmes at 
Harborview) on the basis of the likely relation of the spike development to seizure onset. Often 
there are multiple possible targets, and the probe treatments and evaluations may allow us to 
contrast their efﬁcacies. 
Treatment Protocol
A two hour GTEN treatment sessionthen targets the identiﬁed focal epileptogenic zone for 5 
days during one week. For the ﬁrst ten patients the post treatment monitoring is continued for 3 
hours after the treatment session.  For those patients whose spikes were more frequent during 
sleep during the baseline evaluation sessions, an effort will be made to have them fall asleep as 
the lidocaine takes effect and before the GTEN treatment begins, so that the treatment matches 
the excitable state during which spikes occur.  
All sessions are conducted by personnel who are trained in the dEEG and GTEN 100 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 epileptologist at each trial site will provide medical supervision, including 
recognition of possible adverse events and decision to terminate treatment. 
Follow up Protocol
The one week treatment period is followed by a weekly seizure diary review by phone with the 
study coordinator for six months, plus a dEEG follow up evaluation session in weeks 2, 4, 8, 16, 
and 24. Each follow up session includes dEEG evaluation during the entire session, including 
during the review of seizure diary, cognitive function testing with the California Verbal 
Learning Test, and the Quality of Life in Epilepsy report, as well as a resting dEEG interval. If 
the patient has interictal events in sleep or drowsiness, the resting dEEG evaluation will include 
a quiet period for a nap. 
Primary Endpoint and Study Success 
The primary endpoint is a temporary suppression of epileptic spikes. With assessments of spike 
rates at weeks 2, 4, 8, 16, and 24, the study will allow estimation of how temporary a 
suppression is achieved by the one-week treatment. The routine dEEG sessions typically collect 
dEEG for over an hour, and spike rates per hour will be the standard metric. To be successful, 
and to warrant progression to a randomized clinical trial, this clinical feasibility study must 
demonstrate successful targeting and suppression of the epileptogenic zone, as evidenced by 
temporary but statistically signiﬁcant spike suppression in contrast to the pre-treatment 
baseline.  All spike rates (baseline, treatment, and follow-up) will be counted as spikes per hour 
and classiﬁed in relation to waking or sleep stage (N1, N2, N3).  
Secondary Endpoints and Study Success 
"31

The secondary endpoint is monthly suppression of seizures, assessed by the seizure diary each 
month for six months following treatment, in comparison to the mean seizure frequency for the 
one-month pre-treatment evaluation baseline. It is clearly advantageous if there is seizure as 
well as spike suppression as we plan the design of the pivotal trial. 
Additional secondary endpoints will be (1) any improvement of cognitive function testing 
beyond the practice effect (estimated from norms and the improvement in the sham control 
group); (2) any improvement in quality of life ratings. 
Study Monitoring Committee 
The safety and comfort decisions for each patient are made by the epileptologist at each site. 
The safety, comfort, and efﬁcacy of each treatment protocol across sites are reviewed by the 
Study Monitoring Committee. Vigilance will be maintained throughout the pivotal study to 
insure safety (no provoked seizures and no adverse effect to non target brain regions). 
Treatment will be discontinued for any patient that shows treatment-induced seizures, deﬁned 
as seizures that are not the patient’s typical seizures or that occur twice as frequently as the 
patient’s typical seizures, as assessed during baseline. If there are more than ﬁve patients with 
worsening seizures (meeting escape criteria as stated above), the treatment will be suspended at 
that site. The Study Monitoring Committee (and the FDA when possible) will decide if the trial 
with that treatment should be terminated at all sites. 
At each site, careful attention will be given to the dosage that patients tolerate well, primarily in 
relation to maintaining adequate comfort with the treatment current and the lidocaine 
anesthetic. We are conﬁdent from the pre-clinical studies that these protocols are tolerated by 
normal volunteers, and should be comfortable patients with epilepsy. If the electrical dosage 
needs to be adjusted for individual patients, then the quantitation of cortical target dosage and 
the dose-response analysis will provide an indication of dosage efﬁcacy (at varying dosage 
levels) across the entire trial. 
Quantitating the Estimated Effective Dose 
Because the effective (surface normal) targeting varies across patients according to the location 
of the epileptogenic zone, the data analysis will attempt to predict the criterion of seizure 
suppression from the quantitation of effective dosage for each patient. Eventually, this 
quantitative prediction may allow indications for use that are gauged in relation to the 
estimated targeting effectiveness in the pre-treatment GTEN planning process. If successful, the 
adaptive estimation of effective cortical dosage would allow the physician to (1) localize the 
epileptogenic zone with dEEG, (2) conduct an initial analysis GTEN Planning Module of the 
effective dose that can be delivered with the 256 array with the 2 mA dose level, (3) conduct a 
pilot session to determine if the patient is comfortable with the dose required for efﬁcacy, and 
then (4) discuss with the patient whether GTEN treatment is a worthwhile option. Post hoc 
analysis of the effective targeting in the clinical feasibility trial will provide initial evidence of 
the importance of cortical surface normal targeting dosage in predicting seizure suppression. 
Power Analysis and Missing Data Analysis 
"32

This clinical feasibility trial will test for a statistically signiﬁcant suppression of epileptic spikes 
at several time points (weeks, 2, 4, 8, 16, and 24) following treatment in contrast to the average 
of two dEEG evaluations during the one-month baseline. Without previous results on the 
Pulsed GTEN treatment, it is difﬁcult to estimate effect sizes for power analysis for this one-
week treatment intervention. 
As pointed out by the FDA reviewer, an extensive statistical plan may not be warranted for a 
feasibility study. Furthermore, although we have considered the results of the rTMS study of 
Sun et al (Sun et al., 2012) to provide some indication of effect size, we agree that we have little 
basis for estimating the power required for determining the signiﬁcance of spike suppression 
with GTEN therapy. We do plan to follow the reviewer’s suggestion to compare spike rates 
following treatment to those from the baseline assessment with a one-sided t-test with a 
signiﬁcance level of 0.025. 
At the same time, we recognize that we are proposing to evaluate two protocols (Sustained 
Blocked tDCS and Pulsed GTEN), and must have sufﬁcient numbers of patients to demonstrate 
feasibility, and to examine the signiﬁcance of spike suppression, for either treatment protocol. If 
one protocol is effective and the other is not, we propose to stop enrolling patients for the 
ineffective protocol and focus recruitment on the effective one to demonstrate efﬁcacy for a 
pivotal study. 
Study Procedures 
Informed Consent 
Both the recruitment information and the informed consent document explain several aspects of 
the study: 
• GTEN (Geodesic Transcranial Electrical Neuromodulation) is a method of applying small 
electrical currents through the head in order to achieve a lasting decrease in the neuronal 
activity of the epileptogenic (seizure-causing) zone of cortex. The experimental treatment 
protocols have been designed on the basis of previous scientiﬁc studies. For the Pulsed TEN, the 
studies have suggested suppression of epileptic seizures with Transcranial Magnetic 
Stimulation (in the Fregni, et al., 2006 and Sun, et al., 2012 trials). GTEN is used instead of TMS 
because of the ability to control the targeting of cortical sites more precisely, as guided by the 
dEEG ﬁelds of the epileptiform discharges. In addition, GTEN is able to target epileptogenic 
zones in deep as well as superﬁcial cortical sites. 
• There is minimal risk of the treatment. The slow pulsed electrical neuromodulation has been 
applied in several studies of epilepsy with the TMS procedure, and there is no evidence that it 
causes seizures. Transcranial electrical stimulation (tDCS) has been applied in several 
experimental studies of patients with epilepsy, with no evidence that it causes seizures. 
Nonethless, there is always a small risk of causing seizures, and medical procedures are in place 
both to monitor for seizures (with the EEG recording in each session) and to provide ﬁrst aid if a 
seizure occurs. 
"33

• The primary feeling of the electrical current is a tingling sensation, and there is risk of minor 
itching and/or scalp pain. A small amount of lidocaine is mixed in the electrolyte to minimize 
the pain at the electrode site, and the procedures will be adjusted to assure that any discomfort 
is acceptable to the patient. 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 simply pull the Geodesic Sensor Net off the head. 
Changes to the Harborview Informed Consent Form
The Informed Consent Document (ICD) approved with the GTEN IDE was the EGI Consent 
Form (GTEN) 12/29/2014.  This was rewritten to conform to the format of the University of 
Washington IRB and approved by the UW IRB.  It was then modiﬁed to include the probe test 
(as described in the present protocol) and approved in November 2015.  A minor error (stating 
the probe test was 10 min rather than 17 min) was corrected and the correction was approved 
March 9, 2016.  
The EGI Parental Consent Form approved with the IDE is unchanged, but is not in use because 
the only active trial site (UW Harborview) is not enrolling adolescents.
Both the EGI IRB Consent form of December 29, 2014 (approved with the IDE) and the UW IRB 
Consent Form (proposed for this trial with the present Supplement) are attached.
With the exception of the probe test, there are only minor differences in these consent forms, 
involving the change of format to the UW IRB Consent Form format.  Following is a section-by-
section summary of the revision, emphasizing where the same information from the (IDE 
approved) EGI IRB Consent Form is included in the UW IRB Consent Form. 
Purpose of the Study: This was rewritten to be easier to read. It contains a similar description of 
treating epileptic discharges with small currents applied to the brain. 
Study Summary: added to ﬁt the UW format.  This section gives an overview of the study. It 
describes the evaluation and treatment phases, including the probe test, as well as the follow 
ups sessions. This information is contained in Study Procedures in the EGI form.   
Study Procedures: This describes the speciﬁcs of each baseline, treatment, and evaluation 
session, including the CVT and QOLIE.      
Risk, Stress, or Discomfort: This was rewritten in the required UW format: it describes the 
same concerns covered in the EGI form: discomfort, skin irritation, adds risk of loss of privacy 
and psychological risk of ineffective treatment.  This mentions the (very minimal) risk of silver 
allergy (from the AgCl electrodes) that was discussed in an EGI GTEN Hazard Review (since 
the IDE).  It emphasizes risk of seizures and the procedures for seizure monitoring, in a very 
similar way as the EGI form. 
"34

Beneﬁts of the Study: The important statement is that there may be no beneﬁts, similar to the 
EGI form.  
Source of Funding: This was added following the UW format, and explains EGI’s ﬁnancial 
support for the trial (equipment, 25% salary for Dr. Holmes, and full salary for Ms. Wise).   
Conﬁdentiality of Research Information: Emphasizes procedures to maintain, and possible 
limits, similar to the EGI form. 
Alternative to Taking Part in This Study and Other Information cover the information that is 
described in the Participation section of the EGI form. 
Localizing Epileptiform Discharges (EDs) 
The cortical target for GTEN treatment will be determined from ESI applied to epileptiform 
discharges (spikes) observed during one or more 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. 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. A variant of the protocol is identiﬁcation of the GTEN targeting through localization 
of seizure onset, such as with long term video dEEG monitoring. 
The GTEN Planning Process 
Given the selection of the epileptogenic treatment target from the pre-treatment 256 dEEG 
evaluation exam with electrical source imaging (ESI), and prior to the ﬁrst treatment session, the 
source-sink electrode pattern for targeting is derived through reciprocity with the interictal 
epileptic focus site with the Geodesic Reciprocity Inverse Process (GRIP). First, the cortical site 
of spike onset is used to generate the forward projection, from an equivalent dipole at that 
cortex site to the 256 electrodes (Figure 4). By reciprocity, the inverse of this forward projection 
then deﬁnes the optimal sink pattern (from the negative potentials) and the source pattern (from 
the positive potentials) to be used for the current injection electrodes to achieve current ﬂow 
normal to the cortical surface (in other words, in the same orientation as the ESI source dipole 
vector) at the target region. 
Next, minimization of non-target current delivery is evaluated for variations of the GRIP 
pattern, with the Discriminative Cortical Surface Vector (DSCV) method. Typically ﬁve to ten 
different DCSV patterns are used, each with effective delivery to the target and maximal 
variation of current delivered to non-target areas compared to the other patterns. As described 
above, given the laminar arrangement of cortical neurons, the efﬁcacy of electrical current in 
modulating membrane and synaptic activity appears to depend on the delivery of electrical 
current normal (perpendicular) to the cortical surface (along the dendritic-soma axis) at the site 
of the epileptogenic zone (as estimated by the site of spike onset). The effective dose computed 
by the dot product of the current delivery with the cortical surface vector, summed over the 
"35

treatment session, will serve as a measure of targeting efﬁcacy and will be retained as a 
covariate for statistical analysis of treatment efﬁcacy. 
bEIT Validation of the Head Model 
Once the GTEN Targeting is complete, the ﬁrst treatment session is scheduled. At the beginning 
of that ﬁrst session, the bounded Electrical Impedance Tomography (bEIT) procedure (Figure 6) 
is used with the selected sink-source electrode targeting conﬁguration to test the prediction of 
the electric head model developed for that subject (with the individual’s MRI or the atlas MRI 
and ﬁnite difference modeling). If the mean prediction of the recovered bEIT signal across 
recording electrodes is not within 10%, the model is judged to be ﬂawed and the treatment is 
postponed until an accurate targeting model is created. 
Once an accurate targeting model is achieved for the sink and source electrodes of the patient’s 
GTEN Targeting of the presumed epileptogenic zone, it can be used for the subsequent 
treatment sessions, with the restriction that the placement of the Geodesic Sensor Net is 
replicated (within 2mm desired accuracy) in each session. Accurate placement is veriﬁed in each 
session with the Geodesic Photogrammetry System (Figure 2). 
Iontophoretic Electrode-Skin Impedance Conditioning and Lidocaine Topical Anesthetic 
Because scalp abrasion is prohibited, the electrode-to-skin impedance of the Geodesic Sensor 
Net typically begins at 50K to 100K Ohms. For consistent and effective delivery of electrical 
currents for neuromodulation, impedances of 20K Ohms are preferred. Furthermore, given the 
single current source of the GTEN 100, it is preferable to have all source (anodal) and sink 
(cathodal) electrodes at about the same impedance level (so that they divide the current evenly 
at about the 200 μA per electrode target). 
Electrode-scalp impedances will be conditioned with the Dermal Iontophoretic Bond (DIB) 
protocol, a (patent pending) method of using iontophoresis to carry ions from the electrolyte 
across the stratum corneum (dead layer) of the skin with DC current, thereby decreasing 
impedance to the desired level. By including lidocaine in the electrolyte solution, we will 
anesthetize the scalp and skin under the electrode to minimize superﬁcial nerve pain from the 
electrical stimulation. Similar to the iontophoresis that is widely used for drug delivery (for 
example for delivering pain relievers in sports medicine), the iontophoretic impedance 
conditioning is safe, can be adjusted to be painless for each subject, and can be carried out in 
parallel with impedance testing at the beginning of the dEEG or GTEN session. The lidocaine is 
delivered during the conditioning procedure through anode electrodes, with cathodes adjusted 
to minimize any current ﬂow through the brain. Over several minutes of the 200 μA/electrode 
current level of GTEN 100 treatment, we typically observe the (non-abraded) electrode-scalp 
impedance to drop to 20K Ohms, and occasionally to 10K Ohms. These impedance levels will 
then be monitored at multiple points during the treatment session. 
Setting Current Levels and Administering Treatment 
The goal is to optimize the current delivered at the target epileptogenic site, while limiting 
overall current delivery to 2 mA, and limiting the current applied to each electrode to about 200 
"36

μA. Once the targeting is planned for each subject, the ﬁrst session will evaluate the comfort 
level, and current levels adjusted to insure they are acceptable to the patient. 
Treatment is applied in a two-hour session (including post session dEEG monitoring), 5 days 
per week for 1week. For the ﬁrst ten patients with each treatment, the ﬁrst treatment session is 
followed by 3 hours of dEEG monitoring to insure there are no seizures. After that the post-
treatment dEEG monitoring is continued for 30 min. 
Review of the EEG for Safety and for Spike Counts 
The dEEG is reviewed after each treatment and follow up session, by visual inspection by a 
trained electroencephalographer and with an automated spike detection and clustering 
algorithm (EGI’s Spike Beacon software), with the quantitation reported as a trial endpoint. 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 if there is an 
increase in spike frequency of over one standard deviation compared to the baseline sessions, 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. 
The experimental procedures for each patient session are summarized in Table 2. 
Monitoring of Risk 
A daily diary with a count and description of seizures is reviewed at each session (treatment 
and follow up). If there is an increase in seizures of two-fold over the patient’s baseline levels, 
the patient’s treatment is suspended and the safety of the treatment is evaluated by the 
epileptologist, patient, and family. In the follow up sessions, routine dEEG evaluations, 
cognitive function assessments, and quality of life ratings are conducted once each week for 
three weeks following the treatment, and then week 8. 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), 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 2 presents an overview of the treatment protocol. An exception is that for the ﬁrst ten 
patients the dEEG will be monitored for seizures for 3 hours after the ﬁrst treatment session. 
Session
Procedure
Pre-Treatment Evaluation
Review of seizure diary each week for one month. Two routine 
dEEG evaluations to capture epileptiform discharges (ED), 
including spikes and seizures.  MRI when available to determine 
possible malformations of cortical development and build 
individual head model.
"37

Table 2. Summary of treatments and assessments. 
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First Treatment Session
• Review of seizure diary.
• Application of the Geodesic Sensor Net.
• Geodesic Photogrammetry System (GPS) to localize sensors.
• bEIT scan to verify electrical head model.  Lidocaine 
iontophoresis conditioning during this scan.
• 10 minutes resting dEEG.
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"38

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