Electrophysiological Biomarkers During Invasive Monitoring of Mesial Temporal Lobe Epilepsy Patients.
Phase: NA
Conditions: Mesial Temporal Lobe Epilepsy
Sponsor: Emory University

Title: Electrophysiological biomarkers during invasive  
monitoring of mesial temporal lobe epilepsy patients
Date: Sept/09/2021
NCT# NCT04710004 

Emory IRB Biomedical Protocol Outline
For Investigator-Initiated Studies
Title Page
Electrophysiological biomarkers during invasive
 monitoring of mesial temporal lobe epilepsy patients
Short study title: Electrophysiologic biomarkers in MTLE patients 
Name, Title, and Department of Principal Investigator
Robert Gross, MD, PhD
Professor, Department of Neurosurgery
Ph: 
Emory University 
Sponsor
Robert Gross, MD, PhD
Professor, Department of Neurosurgery
Ph: 
Emory University 
External (non-Emory) Collaborators (if applicable)

No external collaborators.
Protocol version number and version date
Version 2.0 , September 9, 2021

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Revision #
Version Date
Summary of Changes
2.0
September 9, 2021
Changes to the Intracranial Stimulation Protocol 
section (Study Design and Methods): 
(i) addition of 2 new stimulation frequency pulse-
width combinations for safety threshold testing; 
(ii) Addition of stimulation-trains of up to 15 minutes 
for use in revised memory testing protocol.
Change to ADMES effects on memory (Study Design 
and Methods):
(iii) Revisions to the  memory testing procedure to 
include object recognition tasks after initial encoding 
and 15-minute distraction period along with 
continuous 15-minute neurostimulation-trains and 
(“Electric WADA”).

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Table of Contents
Study Summary.........................................................................................................................4
Objectives- The Primary Aim and Outcome Measures................................................4
Background................................................................................................................................5
Study Endpoints........................................................................................................................6
Study Design and Methods....................................................................................................6
Procedures Involved ............................................................................................................13
Data and Specimen Banking ..............................................................................................14
Sharing Results with Participants ...................................................................................14
Study Timelines .....................................................................................................................15
Inclusion and Exclusion Criteria ......................................................................................15
Vulnerable Populations.......................................................................................................15
Local Number of Participants............................................................................................15
Recruitment Methods ..........................................................................................................15
Withdrawal of Participants................................................................................................16
Risks to Participants.............................................................................................................16
Potential Benefits to Participants....................................................................................18
Data Management and Confidentiality...........................................................................19
Provisions to Monitor the Data to Ensure the Safety of Participants ..................19
Site Monitoring Plan.............................................................................................................22
Provisions to Protect the Privacy Interests of Participants....................................22
Economic Burden to Patients ............................................................................................22
Consent Process .....................................................................................................................22
Setting........................................................................................................................................23
Resources Available .............................................................................................................23
References ...............................................................................................................................24

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Study Summary
Study Title
Electrophysiological biomarkers during invasive
 monitoring of mesial temporal lobe epilepsy patients
Study Design
Nonrandomized interventional
Primary Objective
Identify biomarkers related to the precictal state; 
determine stimulation patterns that modify biomarkers
Secondary Objective
Assess free recall during stimulation
Research Intervention
Brain stimulation via clinically implanted electrodes
Study Population
Subjects with medial temporal lobe epilepsy undergoing 
phase II surgical work up with clinically implanted 
intracranial electrodes
Sample Size
18 Subjects
Study Duration
2 years
Study Duration for 
Individual Patients
3 recording sessions over 1 week
Study Specific 
Abbreviations
ADMES- asynchronous distributed multi-electrode 
stimulation
CT- computerized tomography
EEG- electroencephalography
EMU- epilepsy monitoring unit
IV – intravenous
LFP- local field potential
MRI- magnetic resonance imaging
MTLE- mesial temporal lobe epilepsy
NHP- nonhuman primate
RNS- responsive neurostimulation
SEEG- stereo electroencephalography
Funding Sources
None
Objectives- The Primary Aim and Outcome Measures
The objective of this study is to identify biomarkers related to the brain state prior to 
medial temporal lobe seizures and to use brain stimulation effectively change these 
biomarkers.  
Specific Aim 1. Identify biomarkers related to the pre-ictal state 
Specific Aim 2: Perform an acute parameter search to determine the stimulation pattern 
that most effectively modifies these biomarkers. 
Specific Aim 3: Identify changes in memory (free recall) during asynchronous distributed 
multi-electrode stimulation (ADMES)

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Background
While resective surgery for medically intractable epilepsy can be curative, only a small 
proportion of the 1 million people in the US with this condition can under go surgery due 
to risk of neurological deficits[1].  For example, some patients with mesial temporal lobe 
epilepsy (MTLE), the target population for this study, can be at risk for significant 
memory decline and associated disability[2].  The only option for these patients at present 
is electrical neuromodulation which, although effective at reducing the number of 
seizures, only achieves seizure freedom in ~10% of patients ([3, 4]).  As seizure freedom 
is the clear goal of therapy, there is a large unmet need for novel approaches.  
Currently responsive neurostimulation (RNS, Neuropace, Inc) is the only FDA approved 
implantable neurostimulation device approved for neuromodulation directed at the 
hippocampus[3].  Recommended stimulation protocols include the use of high frequency 
(130-200 Hz) stimulation synchronized across implanted electrodes in response to 
detected seizures[5, 6].  In contrast, we have found that delivering asynchronous pulses 
distributed across a multi-electrode array of 16 micro-electrodes and stimulating at low 
(theta) frequencies is more effective than macrostimulation in controlling seizures in a 
rodent model of MTLE[7].  Asynchronous distributed multi-electrode stimulation 
(ADMES) can be delivered in a continuous fashion, but has the potential to be used in a 
responsive or optimized manner as well.  These stimulation modes require the ability to 
identify biomarkers, or neurophysiologic features identifiable on recording on neural 
activity, indicative of impending seizures to optimize stimulation.  The goal of the 
present study is to explore potential biomarkers that could distinguish between the inter-
ictal (between seizures), pre-ictal (before seizures) and ictal states (during seizures) to be 
used later for optimization of stimulation parameters in human subjects with implantable 
neurostimulation device.  
As a high volume epilepsy surgery center, we have a unique opportunity to study 
electrophysiology directly from the brain in human subjects with epilepsy using 
electrodes already in place for clinical purposes.  For many patients being considered for 
epilepsy surgery, invasive monitoring with stereo-EEG (SEEG) electrodes is needed to 
localize seizure onset zone. As part of routine clinical care, SEEG electrodes are used to 
monitor and record brain activity and for brain stimulation for the purpose of mapping 
brain function and eliciting seizures.  During SEEG in patients with mesial temporal lobe 
epilepsy, depth electrode arrays are routinely placed in the hippocampus.  We can utilize 
these implanted electrodes to both stimulate in an asynchronous manner and also 
simultaneously record local field potentials (LFPs) for analysis of biomarkers.
Informed by our non-human primate (NHP) data, we will identify electrophysiological 
biomarkers related to the pre-ictal state and determine the influence of specific patterns of 
stimulation on these biomarkers. The results obtained here will be used to inform an early 
feasibility study of ADMES neuromodulation in patients using an implantable 
neurostimulation device (for which a separate IRB proposal will be submitted).  

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Study Endpoints
Each biomarker (or log biomarker) determined in the parameter sweep experiment will be 
estimated and compared by epileptic state using repeated measures analyses implemented 
via the SAS Procedure MIXED. Free recall accuracy will be statistically compared using 
a paired t-test between the ADMES and non-stimulation lists to determine whether there is 
any effect of ADMES on long-term memory. 
Study Design and Methods
Electrode placement
Electrodes are implanted stereotactically to help localize the seizure focus. As a standard 
means to increase accuracy, the surgery is guided by contrasted MR images, with post-
operative reimaging for confirmation. The electrodes (Dixi Medical or Adtech) have 
platinum contacts for electrophysiological (electroencephalogram [EEG] and local field 
potential [LFP]) recording and for stimulation). An electrode may include macroelectrode 
contacts only or macro- and micro electrode contacts. All electrodes are FDA-approved 
equipment for recording intracranial EEG during presurgical evaluation.
Monitoring Participants
The epilepsy monitoring unit (EMU) at Emory University Hospital is a 10-room inpatient 
ward that is designed for inpatient video-EEG monitoring and is staffed by a 
multidisciplinary team of specialists, including attending physicians, fellows, psychiatrists, 
EEG technicians, nurses, and information-technology technicians from the Emory 
Healthcare Information Services (EHc-IS).The EMU contains 10 computers with monitors, 
one station per room, to visualize the real-time recording of EEG and video data. The data 
is automatically stored on a server in the EMU for secure storage and access. The EMU 
continuously monitors the daily progress and health of each patient server for secure 
storage and access. The EMU rotates personnel to monitor and care for each patient daily 
(24 hours per day) during the patient’s stay (on average 2-3 weeks) in the EMU.  A patient 
under presurgical evaluation is discharged from the EMU at the discretion of the treating 
physicians. Patients are discharged generally after 5 weeks with no seizures or if the patient 
has had at least 3-5 reliable seizures with ostensibly focal epileptic activity according to 
the EEG.
Data recording and processing
Equipment: All electrophysiological data will be collected through the EMU’s Xltek 
system or other devices that have been approved by the FDA to be sold for studies in human 
subjects or are equivalent to previously approved devices and have already been approved 
for use by the Emory IRB (IRB00076437-DARPA; e.g. Blackrock Microsystems 
Neuroport Data Acquisition System, Blackrock Cerestim R96 neurostimulator, and 
Medtronic handheld stimulators commonly used for clinical mapping). A summary of 
device testing and equivalence is attached for the Blackrock CereStim M96. In addition, a 
letter of non-significant risk determination is attached to the IRB amendment. Intracranial 
electrical stimulation will be delivered through these devices as well. All intracranial 

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electrodes are FDA-approved equipment for recording intracranial EEG during presurgical 
evaluation. We will collect data from macroelectrodes and from microelectrodes. Either 
AdTech Medical Instrument Corporation (Racine, WI) or Dixi Medical USA 
(Chaudefontaine, FR) manufactures and ships the intracranial EEG electrodes after 
sterilization. Such electrodes are currently in use at Emory University Hospital specifically 
for collection of intracranial EEGs, single-unit activity, and for intracranial stimulation. 
Microelectrode iEEG signals will be acquired using a separate acquisition system from 
Blackrock Microsystems (Salt Lake City, UT). In addition, the Blackrock custom cable & 
splitter box splits the signal between the Clinical EEG system and the Blackrock 
components. This custom EEG cable and splitter is introduced to allow the signal path from 
the subject’s electrodes to be split between the Blackrock recording and stimulation devices 
and the clinical EEG system. In this configuration, the ECoG signal processed and recorded 
by the Neuroport and analyzed by the Host PC can be used to control the timing of 
stimulation via the CereStim.  The two different arrangements are depicted in Figures 1 
and 2.
Intracranial Electroencephalographic (iEEG) Activity: This study analyzes routine 
diagnostic EEG data that is generated using intracranial electrodes. The number, type, 
orientation, and size of the iEEG electrodes depend on the anatomy and clinical 
considerations per patient. Typically there will be tens to hundreds of electrode contacts 
arranged as a depth, strip, and/or grid. An electrode may be relatively large 
(macroelectrode) or very small (microelectrode). Macroelectrode local field potentials 
(LFPs) consist of 0.1-1000 Hz signals obtained from iEEG contacts placed either within 
the brain (i.e. recorded from depth electrodes) or on the surface of the brain (i.e. recorded 
from subdural strip or grid electrodes). These signals will be acquired at 256 or 512 samples 
per second and 12-bit precision for electronic storage. Both the standard and investigational 
macroelectrode iEEGs are automatically stored to a 2-Tetabyte RAID server that is 
securely managed by Emory Healthcare Information Services (EHc-IS). The stored data is 
directly accessed via only one password-protected Epilepsy Monitoring Unit EMU 
computer that is securely managed by EHc-IS. Microelectrodes record signals at a 
sampling rate of up to 30,000 samples per second and 16-bit precision for electronic 
storage. These signals are then processed by applying a high-pass filter between 100 and 
750 Hz, in order to extract the extracellular action potential waveforms (single unit activity) 
from neurons located in the vicinity of the recording contact.
 

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Figure 1: Schematic for study device in System 1.0 configuration. Here, the testing 
computer interfaces with the existing clinical EEG system via the Sync Box and 
stimulates via the CereStim.

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Figure 2: Schematic for the study device in System 2.0 configuration. Here, a custom 
cable and splitter box connects the Blackrock NeuroPort and CereStim to the subject 
electrodes for data recording and stimulation.
Intracranial stimulation protocol
LFPs will be continuously collected from intracranial depth electrodes before, during, and 
after stimulation using our data acquisition and stimulation system (Blackrock 
Microsystems, Salt Lake City, UT). The goal will be to measure the effect of different 
combinations of stimulation parameters (amplitude, frequency, and pulse width) on 
electrophysiological neural features (spectral power, synchrony) shown to correlate with 
the pre-ictal state. Multiple stimulation parameter sweeps will then be performed to identify 
parameters that modify these biomarkers most effectively. These parameter sweeps will 
initially focus on the range of stimulation parameters that will be feasible in a planned 
subsequent study using the RC+S device (Medtronic, MN) under a subsequent IRB to be 
submitted. However, given the greater flexibility of the externalized Blackrock CereStim 
device, additional stimulation patterns may be evaluated if supported by the initial results. 
Connection of the stimulation and recording hardware (recording hardware takes a ‘split’ 
signal and also does not interrupt the clinical study) will be supervised and/or performed 
by a neurologist trained in electrophysiology, amplifiers and stimulators.  Charge density 
is calculated based on the surface area of the electrode contacts, and will not exceed the 30 
µC/cm2/phase safety limit within the parameter space[8]. All stimulations will be 
composed of a biphasic charge-balanced square wave without an inter-phase delay. In all 
cases, iEEG will be continuously monitored by a neurologist during the session for the 
presence of after-discharges and seizures. Patients are admitted to the intracranial 
monitoring unit to have seizures, so this can coincidentally occur during the stimulation 
session.  
The proposed intracranial stimulation parameters are both historically common and proven 
safe in epileptic populations. Stimulation will be current-regulated and charge-balanced, 
with biphasic rectangular pulses. The anticipated electrode impedence is 1-4 kΩ. 
Stimulation will be bipolar, with the electrodes placed 1.5 mm apart (surface area, 0.059 
cm). Prior to testing, current amplitude will be increased in a stepwise fashion in order to 
identify the threshold for afterdischarge (anticipated range 0.2-2 mA), and then decreased 
by 25% for the maximum amplitude for the duration of testing. The subjects will be blinded 
to stimulation condition. These parameters are similar to intracranial stimulation 
parameters used in other ongoing translational research protocols at Emory University 
Hospital over many years44,45.
Pre-stimulation threshold testing:
Before the session, the epilepsy monitoring staff and patient will be consulted to determine 
if the patient has had any clinical seizures in the previous 2 hours. If the patient has had a 
clinical seizure in the previous 2 hours, then the experiment will be delayed until a 2 hour, 

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seizure-free period has been met. For each session, we will ask the patient for verbal 
consent to testing. During the entirety of all sessions, a study neurologist, clinical 
neurophysiologist, or neurosurgeon will monitor the subject and view the real-time EEG 
for afterdischarges. If any afterdischarges are observed, the protocol will be immediately 
halted and the patient assessed. Once afterdischarges have stopped, stimulation current will 
be decreased by 25-30% and testing will resume. If afterdischarges occur again, all testing 
will be aborted on the patient. If at any time clinical seizures are elicited during stimulation, 
all testing of that patient will be aborted.
The goal of the first session will be to establish the range of safe stimulation parameters 
that can be tested in subsequent parameter sweeps. The procedure for safety threshold 
testing is as follows: 

Seven stimulation frequency pulse-width combinations will be tested: 
o
2 Hz, 450 µs
o
7 Hz, 450 µs
o
50 Hz, 450 µs
o
90 Hz, 100 µs
o
90 Hz, 450 us
o
125 Hz, 100 µs
o
125 Hz, 450 us

Each frequency/pulse width combination will be tested at 0.25 mA, and incremented 
by 0.25 mA until the patient reports adverse side-effects, undesired changes are 
observed in the real-time LFP, or 3.0 mA is reached. This limits the number of tests to 
5 frequency/pulse width combinations at 12 current amplitudes, for a maximum total 
of 60 stimulation patterns to be evaluated for safety.

The test of each stimulation pattern will consist of 5 seconds of stimulation, followed 
by 15 seconds of washout (20s total), repeated 3 times, for a total of 60 seconds per 
stimulation pattern. For lower frequencies, a longer stimulation train may be 
administered to increase likelihood of observing effects (e.g. 10 – 15 sec).  During 
memory tasks, stimulation trains up to 15 minutes will be used to provide sufficient 
time to observe any temporary effects of stimulation on memory tasks as has been 
previously reported.

The total test time will be approximately 60 minutes.

For the following parameter search, the maximum current threshold for each 
frequency/pulse width combination will be set to 80% of the current that induced 
patient-reported side-effects or undesired changes to the LFP. 

The clinician conducting the threshold testing is at liberty to test additional safe 
parameters, under the current safety limit, at their discretion. 

Lower current limits may be determined based on the neurologist’s discretion given 
what is known about the patient’s epilepsy.
Parameter search:
During subsequent sessions, the focus will be on collecting the data necessary to evaluate 
the effect of different stimulation patterns (combinations of stimulation parameters) on the 
neural signal. The default approach will be to conduct a randomized sweep of stimulation 
patterns. Randomized sweeps are typically superior to the more traditional grid search 

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approach, as a more diverse array of stimulation patterns can be tested. While a grid search 
lends itself to more classical statistical analysis (e.g. ANOVA), we’ve shown that the data 
collected using a random search can be analyzed using a non-parametric Gaussian process 
(GP) model. The stimulation parameter space will be discretized as:

Current – 0.1-3.5* mA with 0.1 mA increments (35 values)

Frequency – 2-125 Hz with 1 Hz increments (124 values)

Pulse width – 100-450† µs with 10 µs increments (35 values)

* The maximum current will be derived based on the results of the initial 
threshold testing

† The maximum pulse width is limited depending on the frequency
These three discretized parameters will be combined to produce input space consisting of 
a maximum 156,240 potential stimulation patterns, minus those that identified as unsafe 
by the initial threshold testing, and prohibited by the limitations of the hardware. 
The random sweep will be conducted using 180 non-repeated stimulations consisting of 5 
second of stimulation, followed by an average of 15 seconds of washout. For each 
stimulation, the duration of the washout will be selected from a uniform distribution on the 
interval [10 20] seconds. Data will be analyzed by measuring power spectral and time-
series features, and using computational tools to estimate biomarkers written in Matlab. 
This will be done offline following the session. 
An alternative approach will utilize a data-driven optimization algorithm. Data-driven 
optimization algorithms, particularly Bayesian optimization, can be used to efficiently 
search high-dimensional stimulation parameter spaces where the measured output is noisy, 
as is the case for neural modulation. However, successfully applying data-driven 
optimization is contingent on 1) having a desired electrophysiological objective to be 
optimized, and 2) properly selecting and configuring the algorithm. The first point, the 
objective function, would be a specific electrophysiological neural feature or biomarker 
that we want to modulate. Identifying such an objective will be dependent on both the 
preclinical findings of ADMES in independent non-human primate studies, as well as the 
results from the earlier randomized parameter sweeps (above). The second point, properly 
configuring the algorithm, is also critical. While a well-configured data-driven 
optimization algorithm can-out perform a random sweep combined with a GP model, a 
poorly-configured algorithm can perform much worse. As such, the data from the 
randomized parameter sweep will be used to construct simulation models. These will then 
be used to design a well-configured optimization algorithm to efficiently search for specific 
electrophysiological objectives. If there is sufficient evidence to use a data-driven 
optimization approach, it will be designed so that 1) it cannot use stimulation parameters 
outside safety thresholds identified during the initial testing, 2) can be terminated at any 
time at the discretion of the supervising clinician, and 3) if necessary, can require the 
approval of each stimulation pattern prior to delivering the stimulation. These experiments 
will use the stimulation/recording configuration depicted in Figure 2.
ADMES:

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The effects of ADMES (asynchronous distributed multi-electrode stimulation) on 
neurophysiological biomarkers will be tested. Stimulation parameters will be based on our 
extensive non-human primate studies, in which stimulation was cycled through 4 sets of 
contacts within one stimulation cycle (Figure 3). Additionally, we will test whether 
ADMES influences the encoding and retrieval of long-term memories. This will be 
accomplished by using a well-established free recall task [9]. 
We will test 3 distinct asynchronous multi-electrode stimulation patterns shown in Figure 
1:
Figure 3. Stimulation patterns. Each stimulation pattern is divided into an ordered set of 
programs (p1, p2, …). A program defines which contacts are stimulated and with which 
parameters (amplitude, pulse-width, polarity). This ordered set of programs is repeated at an 
overall group frequency. (A) Ring Bipolar is divided into four programs with an overall group 
frequency of 7Hz. In the NHP instantiation, cylindrical ring contacts were segmented into 3 
equally spaced equatorial contacts; in each program a set of three segmented contacts were 
stimulated simultaneously to create a ring of activation closely approximating the human 
contacts used in intracranial EEG. This ring is paired with an adjacent ring of contacts with the 
opposite polarity. All four programs are cycled through over 1/7s, with a fixed time interval 
between programs (~1/7/4s). (B) Wide Bipolar uses the two outer rings of each electrode to 
create two wide alternating fields of activation. The two programs are specified with a group 
frequency of 65Hz. This is intended to create a volume of tissue at the seizure focus that is 
activated at 130Hz. (C) The Dual Ring Bipolar pattern is identical to the Wide Bipolar, except the 
top and bottom two rings are combined into a “super-contact” (D) This instantiation, where 
individual segments are stimulated, is not being used in the ring contacts of the human study. 
The order of contacts stimulated is fixed, but arbitrary.

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
Ring Bipolar – 7 Hz stimulation with 4 rings per electrode created by shorting the three 
segmented contacts

Wide Bipolar – 65 Hz stimulation using top/bottom 2 shorted ring-contacts

Dual Ring Bipolar – 65 Hz stimulation using 2 large contact-groups per electrode 
created by shorting the top and bottom halves of the electrode 
Each of these stimulation patterns will consist of symmetric charge-balanced tri-phasic 
pulse-trains with anodic and cathodic phases of 200µs and an interphase gap of 53µs. The 
current controlled amplitude will be determined per-pattern according the safety 
considerations described above. Stimulation will be applied using an intermittent paradigm 
of 5 seconds of stimulation followed by 5 seconds without stimulation. This approach will 
be used so that if there were electrographic seizures they could be clearly identified 
between the stimulation artifacts. 
ADMES effects on memory: 
We have proposed an electric Wada test to be used to evaluate the safety of stimulation in 
the human following the parameters of the current UG3 grant.
This procedure will follow the protocol of the well-established Medical College of 
Georgia (MCG) Wada (behavioral) procedure used with the setting of the intracarotid 
amobarbital procedure (10). This protocol was designed to introduce novel objects, which 
could be dually encoded by visual and verbal means during a period of drug 
anesthesization, with an evaluation of recognition memory to occur after the effects of the 
drug had cleared. The period of delay tended to average 10 to 15 minutes in this chemical 
procedure. We will follow the exact same behavioral protocol while replacing the 
administration of drug with the administration of electrical stimulation. As we are more 
interested in determining any effect on function, we will apply stimulation during the 
entire test session (i.e., encoding through recall) rather than just during encoding. 
We will establish a baseline with each potential subject by testing them during a period 
free of electrical stimulation. They will be presented with a set of 8 real objects, 
presented one at a time in sequential order, while being provided with the name of each 
object orally in simultaneous fashion (e.g., “remember the fork” when being presented 
with an actual fork). After all 8 objects are presented, we will have the patient engaged in 
another task for 15 minutes, and then ask them to freely recall all 8 objects. Next, we will 
show them the 8 objects intermixed with 16 similar foils, and have them respond “yes” or 
“no” as to whether or not they have been shown each object. We are primarily interested 
in the recognition recall score, consistent with the use of the aforementioned chemical 
Wada. 
The same procedure will be used with a different set of objects during the application of 
stimulation. We will complete two trials at the highest tolerable frequency of stimulation 
using both asynchronous and continuous stimulation. The encoding phase will likely 
require approximately one minute. After the novel objects are presented to the subject, 
they will be asked to engage in additional tasks during the 15-minute delay period. We 

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will have them perform standard clinical tasks of attention and processing speed during 
the delay period (e.g., Digit Span, Coding tasks, verbal fluency), as these are tasks that 
could be affected by stimulation (i.e., tasks of general function that are affected by any 
general disruption in brain function). Following the delay period, the subject will be 
asked to recall the 8 target objects,  and their verbal responses will be recorded. We will 
calculate their total score and any false positive errors. Next, we will show the subject the 
8 objects intermixed with 16 similar foils, and we will have them respond “yes” or “no” 
as to whether or not they have been shown each object. This will allow us to calculate 
scores that reflect the total number of accurate identifications (i.e., total “hits” out of 8) a 
total number of false positive errors, and a corrected score (i.e., half a point will be 
deducted from the total hits for each false positive error made). 
We will create three sets of objects for this procedure, so that it can be repeated to obtain 
a baseline as well as to test the asynchronous and continuous stimulation parameters. 
Procedures Involved
Clinical assessments
Prior to enrollment in the study, all patients will have had a standard presurgical workup, 
including video EEG monitoring, brain MRI, PET scan, neuropsychological testing, and 
functional MRI or Wada (sodium amobarbital) test. As part of their presurgical workup, 
they will require an intracranial electrode study (stereoelectroencephalography, SEEG) for 
further seizure focus localization, with multiple hippocampal electrode arrays, either 
unilaterally or bilaterally.  
Patients will be admitted to the hospital for surgical implantation of depth electrodes. After 
electrode placement and confirmation of electrode location with imaging, patients will be 
monitored with continuous intracranial EEG recording in the Emory Epilepsy Monitoring 
Unit. Post-operative imaging (CT or MRI) is used to confirm location of the electrodes.  
Their seizure medications will be lowered, directed by the epilepsy team, in order to capture 
and characterize habitual seizures.  This “seizure capture” phase typically lasts 7-21 days, 
with minimum of 3-5 clinical seizures captured during this time.
Prior to the Testing Session 
We will schedule a time that is convenient for the patient to undergo testing, typically 
suggesting that a 1-2 -hour block of time is ideal.  On the day of proposed testing, we will 
again check with the clinical team and patient that the originally proposed time and date is 
still acceptable.
Patient Instructions
General Instructions. The patient is asked to get comfortable and if they need to use the 
restroom or need anything to drink.  The patient is asked to minimize head movement 
during the study, as well as to maintain wakefulness.  During the majority of the sessions 
during which patient participation is not needed, they can watch television, read or talk to 
friends or family members that they permit to remain in the room.  During stimulation, 
patient is continuously monitored clinically, as well as by EEG.  If the patient notes 
anything they are to verbalize this or raise a hand.  Stimulation is then immediately stopped 

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to discuss what was noted.  A decision is then made about whether to persist with 
stimulation of the present electrodes or move to the next.  The patient is able to stop the 
study at any time.  
The Testing Session
Not including the time to set-up equipment, the actual testing session is expected to last 
~1-2 hour and will not exceed four hours.  The patient can take breaks during the session 
for food, rest, drink or bathroom use.  The patient is at liberty to terminate the session at 
any time.  Brain stimulation will be performed as detailed above.
Number of Sessions
Patients will undergo three ~1-2-hour testing sessions occurring on subsequent days.  
Debriefing
The patient will be given the opportunity to ask questions of the team at any time, but will 
be invited to do so at the end of a session.  This way, they can learn about what was tested 
and how this knowledge can lead to better patient outcomes or increased knowledge of 
brain function.  We will not give medical advice during this de-brief and the study is not 
designed to provide information that is useful in relate to a specific patient’s care.  Where 
there is such information, this will be relayed to the clinical team. 
Data and Specimen Banking
No physical specimens will be obtained. Data will be kept on encrypted laboratory 
computers, securely locked in the Woodruff Memorial Research Building and behind the 
Emory University 'Firewall' maintained by Information Technology Services.  Data will 
consist of video-electrophysiological recordings and records from the testing session.  Data 
will only be accessed and used by study staff.  Study staff will de-identify the data by 
assigning each participant an alphanumeric ID (study number) as a reference. Any 
publication or presentation that uses the data from patients in this study is reported without 
identifying information.  Data will be kept for at least six years after creation, thus the 
duration of the IRB and then for as long as required by any funding obtained for the project.
Sharing Results with Participants
This work (with no identifying information) will be shared with the epilepsy community 
and the work will result in peer-reviewed publication and presentations targeted to the 
epilepsy community.  The epilepsy community consists not only of health care workers, 
but patients and their families, researchers, educators, administrators, public health and 
policy workers. Overall, we hope that the data obtained here will improve the care of 
patients treated with neuro-stimulation devices.

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Study Timelines
Duration of individual patient involvement is 3-1-2 hour sessions over the course of 1 
week. We estimate enrollment of patients to occur over the course of 1 year.  The total 
study is anticipated to take place over the course of 2 years including data analysis.  
Inclusion and Exclusion Criteria
Screening- Patients are known to the PIs in the context of their clinical work.
In order to be eligible to participate in this study, an individual must meet all of the 
following criteria:
Inclusion criteria
1. Provision of signed and dated informed consent form
2. Male or female, aged 18-65
3. Diagnosed with lesional or non-lesional mesial temporal (hippocampal) seizure 
onset confirmed on SEEG monitoring
4. Implanted with depth electrodes for localization of seizure onset with multiple 
hippocampal electrode arrays
Exclusion criteria
1. Any patient who is unwilling or unable to provide consent
2. Women who are pregnant 
3. Patients under 18 years
4. Incarcerated persons   
Vulnerable Populations
We are not studying a vulnerable group and will not include children, incarcerated persons, 
persons with cognitive disability or persons who are unable to give consent.
Local Number of Participants
Based on our power analysis, we estimate needing about 18 subjects for our analysis.  Other 
studies in our Unit have typically had consent rates of 80% for eligible patients.  We admit 
about 50 patients per year for intracranial EEG monitoring, with approximately 50% 
having mesial temporal lobe epilepsy.  
Recruitment Methods
All patients entering our Intracranial Monitoring Unit who meet inclusion criteria will be 
approached for potential participation after recovery from the implantation surgery (>= 72 
hours after implantation).  

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Patients with refractory suspected MTLE undergoing sEEG represent an accessible patient 
population from which participants may be recruited. As a high volume tertiary care 
epilepsy center (14 epileptologists, 3 nurse practitioners, and 2 epilepsy neurosurgeons), 
the Emory Epilepsy Center has unparalleled access to a large and continuously growing 
population of patients with refractory epilepsy. Emory is the only Level IV epilepsy center 
(including an active epilepsy surgery program) in the greater Atlanta area (a city of > 6 
million people). Atlanta has one of the largest African American populations of any 
metropolitan area in the United States. 36% of the patients seen in the Emory Epilepsy 
Clinic are African American, and 56% of the patients seen are women.
Based on our past clinical volume, we estimate that >20 patients with MTLE will undergo 
SEEG per year. Study subjects will be recruited from this pool of patients. Our recruitment 
and retention rates for current and recent research protocols in SEEG patients have been 
~80%. We are targeting to enroll 18 subjects, which should be feasible given our historic 
volume and recruitment rates. 
Withdrawal of Participants
If the patient requests to withdraw from the study, all research and clinical records 
maintained outside the clinical record will be erased, with documentation of the original 
consent and that the subject has withdrawn from the study. 
Risks to Participants
Referred Pain from Meningeal and Large Vessel Stimulation.  This is unlikely to occur 
during hippocampal stimulation, but can be minimized and is not uncomfortable when 
stimulation intensity is increased gradually. 
Seizure
The patient is admitted for the capture of spontaneous seizures.  Seizure timing is not 
predictable, so a spontaneous seizure may occur during the testing session.  Causing a 
seizure by stimulation is unlikely, but possible. This has typically only occurred during 
stimulation sessions, in our clinical experience, when high frequency stimulation is used 
in the seizure onset zone, or repeated stimulus pulses are delivered sequentially to the 
hippocampus in a patient in which seizures start in the hippocampus.  In a study of 770 
research stimulations, stimulation induced seizures were found to occur in 0.39%- 1.82% 
of sessions, with none were more severe than the patients typical clinic seizures and none 
adding morbidity or affecting the clinical course [10]. 
A neurologist or neurosurgeon is present at the bedside, as mentioned as above, during 
stimulation and can determine if there is a clinical need for an abortive seizure medication.  
In the unlikely event that a seizure occurs and becomes prolonged, lorazepam (1-2 mg IV) 
will be administered under the direction of a physician), as per standard epilepsy 

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monitoring unit protocol. Stimulation will be discontinued if an electroclinical seizure is 
triggered by stimulation or if requested by the patient.  
In the event that the seizure is clearly related to the stimulation itself, or cannot be clearly 
determined to be spontaneous, this will be reported as an adverse event; when the seizure 
is judged spontaneous, this is a routine part of clinical care and will not be considered an 
adverse event.  We expect that we will report rare events that we cannot determine 
definitively as related to stimulation or spontaneous, perhaps in the order of 2-3 such 
events. 
Memory testing
There are minimal risks to memory testing, except for some distress in the case of patient’s 
responding to their difficulty with the task. Again, if the patient is uncomfortable or 
distressed, the session will be aborted.
General overview of stimulation safety considerations 
The stimulation parameters that we will use have been informed by our previous human 
studies our nonhuman primate data and fall within the range of typically used clinical 
stimulation parameters.  When stimulation of the brain region within which seizures arise 
is performed, occasional epileptiform discharges can be seen.  These are not seizures, but 
single events lasting < 200 ms that are the sign of increased excitability of the brain.  These 
after-discharges can warn that seizure may occur with more intense stimulation.  To avoid 
seizures, a neurologist will always be performing the stimulation and watching the real 
time EEG for these discharges.  If a particular current intensity causes after-discharges, the 
current intensity of subsequent stimulations will be reduced.  
Electrical stimulation of brain, using our technique and stimulus parameters, has minimal 
risk. The main risk is that stimulation might trigger a seizure, but this is uncommon given 
guidance by study staff who are neurologists trained in human electrophysiology and brain 
stimulation, and, with our stimulation parameters (careful attention to current density and 
emphasis of low-frequency stimulation; avoidance or appropriate decrease of current 
density and use of only low frequency stimulation in the hippocampal formation).
In the present study, current density will be kept below the typical safety limit of SEEG 
stimulation of 30 µC/cm2/phase (thirty micro-Coulombs per square centimeter per phase), 
calculated based on current delivered per second and electrode surface area [8].  
Stimulation will be graded, starting at very low current density then gradually increased. 
During stimulation, the EEG will be observed by a trained neurologist physician with 
experience with reading intracranial EEG. If epileptiform discharges appear we will stop 
the stimulation run.  If these continue we will use the ictal disrupt feature.  We will then 
decrease the current and continue, but typically we will already have useful data at a lower 
current intensity.  In the unlikely event that a seizure occurs, and becomes prolonged, 
lorazepam (1-2 mg IV) will be administered under the direction of a physician (there will 
always be a physician present), as per standard epilepsy monitoring unit protocol. 

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There is no evidence or preclinical reason to believe that this stimulation work will affect 
patient likelihood of having spontaneous seizures - the object of the admission. This study 
does not add additional physical, psychological, financial, legal, or other risk to each 
human subject beyond the risks discussed above and the risks already associated with 
clinical video-intracranial-EEG monitoring. The risk of accidentally disclosing personally 
identifiable private information will be minimized by (1) the activities of Emory EHIS and 
(2) the de-identification of patient data in accordance with HIPAA guidelines before 
release of data, analyses, grants, talks or publications.
Risks associated with the custom cable and splitter box
Custom cables and splitter boxes have been developed with Blackrock Microsystems to 
split the signal between the clinical EEG system and  the Blackrock neural recording and 
stimulation devices. These components have been extensively tested to ensure that they 
provide uninterrupted physiological monitoring capabilities. However, as with any 
component, there is a very small risk of failure. 
Cable failure does not put the subject at risk of injury. However, it does introduce the risk 
of data loss. If the cable fails during the time when the subject is not having a seizure, 
then there is no risk to the subject. However, if a cable fails while the subject is having a 
clinically necessary seizure then this may extend the subject’s length of stay in the 
Epilepsy Monitoring Unit (EMU) until the subject has another seizure that can be 
localized. The risk of a cable failure that extends the subject’s stay in the EMU is 
anticipated to be very small. In addition, there is no reason to expect that the risk of the 
Blackrock cable failure is any greater than the risk of the standard clinical cable failing.
Potential Benefits to Participants
People with Epilepsy. This work will guide us in selecting neurostimulation parameters for 
patients undergoing asynchronous neurostimulation with implantable devices (to be 
examined in a subsequent early feasibility study).  The overall goal is to improve seizure 
outcomes for patients requiring neurostimulation. 
Science. There are several benefits to science, including clinical science with future 
benefits for medical care.  We will (a) improve understanding of the physiologic changes 
occurring during seizures (b) provide better parameters for electrophysiological 
stimulation using implantable devices. 
Society. We aim to provide a means to better understand and treat epilepsy, hoping to 
reduce the burden of epilepsy, a common disorder, in the community.  This will reduce the 
psychological, social, financial and productivity burden of epilepsy.  We will also 
communicate our findings to the greater epilepsy community, through publications in peer-
reviewed journals when impactful findings are obtained. 
Benefit to Subjects. The time with the study group will afford some added time for 
education about epilepsy, science and neurophysiology.  The data obtained from 
individual subjects will, unfortunately, not provide a direct clinical benefit.  Patients often 
report, however, that participating in research can be intrinsically rewarding, knowing 

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that the knowledge gained can help future patients with epilepsy.  Where some clinical 
information is gained, this will be relayed to the clinical team.
Data Management and Confidentiality
Plans to protect subjects’ privacy during their participation in the study
Our testing will only be performed in the patient’s single-patient private hospital room. 
Plans to establish and maintain confidentiality of subjects’ identifiable data
All data collection and monitoring will be in compliance with the Emory University 
Clinical Trials Guidebook. To adhere to HIPAA guidelines about confidentiality in 
collecting and disseminating human data, all data for a patient is de-identified before any 
non-clinician researcher obtains it for analysis.  The confidential data in this study will 
include medical records, neurological or psychological exams, medical imaging of the 
brain, EEG, video, and surgical outcomes at typical time points (e.g., 6 weeks, 6 months, 
1 year).  Study staff will de-identify the data by assigning each participant an alphanumeric 
ID (study number) as a reference.  The relationship between the encoded ID and all 
identifiable information about the participant (e.g., name, date of birth) will be known and 
accessible by only this person, within the limits possible by the contact of medical staff 
involved in the study who will likely recognize de-identified data, video and audio 
recordings.  Any publication or presentation that uses the data from patients in this study 
is reported using the study numbers for the patients, with video and audio, where shown, 
manipulated to obscure the participant’s identity.    
Provisions to Monitor the Data to Ensure the Safety of 
Participants
The proposed study is most appropriately considered the equivalent of a basic science 
interventional clinical trial. The Emory Brain Health Center Data Safety Monitoring Board 
will provide oversight and annual review of the safety and confidentiality components of 
the study. All serious adverse events and Unanticipated Problems will be reported to the 
DSMB within 10 days of learning of their occurrence, and any deaths will be reported 
within 24 hours. The DSMB includes physicians who are experienced in clinical research, 
a nurse, and administrative support. Statistical help is available as needed. Study clinicians 
serving on the DSMB will recuse themselves when the current studied is being reviewed 
by the DSMB.
Data and Safety Monitoring Plan
a.  Plans for assuring compliance with requirements regarding the reporting of adverse 
events:
Definitions:
1. Unanticipated Problems Involving Risk to Subjects or Others: any 
incident, experience, or outcome that meets all of the following criteria:

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
Unexpected in nature, severity, or frequency (i.e., not described in 
study-related documents such as the IRB-approved protocol or consent 
form)

Related/possibly related to participation in the research (i.e.,there is a 
reasonable possibility that the incident experience or outcome may 
have been caused by the research)

Suggests that the research places subjects or others at greater risk of 
harm

(including physical, psychological, economic, or social harm)
2.  Adverse Event (AE): any symptom, sign, illness, or experience that 
develops or worsens in severity during the course of the study. Intercurrent 
illnesses or injuries should be regarded as adverse events. Abnormal results 
of diagnostic procedures are considered to be adverse events if the 
abnormality:

Results in study withdrawal

Is associated with clinical signs/symptoms or a serious adverse event

Leads to additional treatment or to further diagnostic tests

Is considered by the investigator to be of clinical significance
3.  Serious Adverse Event: classified as serious or non-serious. A serious 
adverse event is any AE that is fatal, life-threatening, requires/prolongs 
hospital stay, or results in persistent or significant disability or incapacity. 
An important medical event is an event that may not be immediately life 
threatening, but is clearly of major clinical significance.
Investigators shall submit reports of the following problems to the 
institutional IRB within 10 working days from the time the investigator 
becomes aware of the event: 

Any adverse event (regardless of whether the event is serious or non-
serious, on-site or off-site) that occurs any time during or after the 
research study, which in the
opinion of the principal investigator, is:

Unexpected (its specificity and severity are not accurately reflected in 
the IRB- approved research protocol and IRB-approved informed 
consent document)

Related to the research procedures (in the opinion of the principal 
investigator, the event was more likely than not to be caused by the 
research procedures)
Reporting Deaths: deaths that occur during the course of a research study 
will be reported more rapidly, as follows:

Unexpected/unforeseen deaths will be reported within 24 hours

All other deaths, regardless of whether the death is related to study 
participation, will be reported within 72 hours
   Other Reportable Events:

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
Any AE that would cause the PI to modify the protocol or consent 
form, or would prompt other action by the IRB to assure protection of 
human subjects

Breach of confidentiality

Information that indicates a change to the risks or potential benefits of 
the research

Change to the protocol taken without prior IRB review to eliminate 
apparent immediate hazard to a research participant

Complaint of a participant when the complaint indicates unexpected 
risks or the complaint cannot be resolved by the research team

Protocol violation (an accidental or unintentional deviation from the 
IRB approved protocol) that in the opinion of the investigator placed 
one or more participants at increased risk, or affects the rights or 
welfare of subjects
b.  Monitoring the progress of trials and the safety of participants

The medical doctor for the patient holds primary responsibility for 
monitoring the safety of each subject both during study visits and in 
between study visits, if complications arise. All complications will be 
well documented, followed, and submitted to the Emory IRB and 
reported to the DSMB either annually or ad hoc.
The PIs, Dr. Gross and Bullinger, will be primarily responsible for monitoring patient 
safety. Additionally, because this work is conducted in the Intracranial Monitoring Unit 
(ICMU) while each participant is hospitalized, the ICMU staff (including members of this 
study) and Emory HealthCare IT maintain strict EHC standards for patient confidentiality, 
safety and data storage. Each time a patient is included in the study, the PI will discuss the 
patient with both clinical staff and the study personnel involved in research to ensure that 
there was no additional risk to the patient, no adverse event and that the patient was safe.  
If there are any concerns, these will be handled as required by the protocol. Any 
unanticipated problem or adverse event due to the study will be carefully documented, 
investigated and submitted to the Emory eIRB under Reportable New Information (RNI). 
The eRIB submission will also be shared with the DSMB.  Copies of each report and 
documentation of IRB notification and receipt will be kept in the PI’s study file.  
Monitoring of the following information, and other pertinent permissible data, for study 
participants will occur continuously for the purposes of the Study Objectives and Safety 
Monitoring:
•
Administrative and scheduling information
•
Proper attainment and storage of signed informed consents
•
Any adverse events
•
Withdrawals from the study
•
Experimental data
•
Original and processed neurophysiological recordings (including video)
•
Medical and surgical records before, during and after the present admission

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•
Any diagnostic testing pertaining to the patient’s epilepsy, neurological status and 
present admission. neurophysiology or neuroimaging of the brain
Reporting
If any expected or unexpected problem arises as a result of this study, then we will complete 
and submit a report to the eIRB portal as a Reportable New Information (RNI) in 
compliance with the Emory University Clinical Trials Guidebook. Any RNI will be 
reported to the DSMB at the time of the site awareness concurrent to IRB submission.  
Since currently there is no sponsor for the protocol, there is no additional requirement for 
reporting beyond those of the Emory IRB.
Site Monitoring Plan
Monitoring of study data and study regulatory documents will be conducted periodically 
to ensure that the study is taking place in accordance with the approved study protocol 
including study procedures, study intervention, and data collection processes. 
The monitoring plan includes:
1. PI-requested monitoring visit(s) by the Clinical Trials Audit and Compliance 
(CTAC) Department: A CTAC initial audit will be scheduled after 2 subjects have 
been consented in the study and have completed the study procedures. Additional 
CTAC audits may be requested during the course of the study and at study close-
out.
2. Self-monitoring: the study coordinators will conduct an annual self-monitoring 
visit using CTAC’s self-monitoring tool. Findings  will be discussed with the study 
PIs and reported to CTAC. The scope of the review will include regulatory 
documents, including IRB fillings, and subject-related data sources to ensure 
compliance with established study protocol and Emory policies. Every effort will 
be made to ensure that reviewers involved in self-monitoring activities are not 
involved in data collection or reporting.
Findings from the internal audits and self-monitoring activities will be shared with the PIs, 
with CTAC and with IRB, as appropriate. Findings leading to corrective action plans will 
also be discussed with the PIs, and may be reported to the DSMB, CTAC and Emory’s 
IRB, if and when appropriate. 
Provisions to Protect the Privacy Interests of Participants
All data is encrypted and stored on Emory University Computers that are behind the Emory 
Firewall.  All computers used for analysis are also hardware encrypted and password 
protected in accord with Emory HealthCare IT policies. Each patient is given a unique 
identifier by the study staff for the purposes of communication: Any publication or 
presentation that uses the data from patients in this study is reported using the study 
numbers for the patients.  While not presently anticipated, before any researcher not on the 
protocol uses any data whatsoever, complete deidentification will occur.  In this case, the 

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patients’ unique identifiers will be used that can only be linked to identifying information 
by the study staff (all of which are included on this IRB). 
Economic Burden to Patients
There is no cost to the patient.  No reimbursement will be given for this study. 
Consent Process
We will only obtain informed consent after admission and after the patient has recovered 
from surgery.  While typically lucid the day after surgery, there is often quite marked 
headache after electrode implantation that takes 48-72 hours to settle.  We will plan to 
approach patients after at least 72 hours of admission and to return at a later time if they do 
not feel up to hearing about the study.  Informed consent will be obtained by a member of 
the research staff: Drs. Gross, Bullinger, Mahmoudi or Marc Connolly. 
We request a HIPAA partial waver to know which patients are admitted to the hospital.  
The neurologists and neurosurgeons that are participating will know this in the course of 
clinical practice (we all attend weekly surgical conference), but in order to be certain about 
these details when we are not directly involved in clinical care of each patient, we request 
a partial waver. We can then contact the clinical team to coordinate consenting of the 
patient.  
We are not studying a vulnerable group and will not include patients with cognitive 
disability that preclude autonomous consent and/or participation, as described above.
Informed consent will be validated by: allowing time for questions, having the patient 
verbally summarize the material, asking subjects to answer a few questions to gauge 
understanding and then asking the patient if they understand all components of the study 
to the extent that they can then consent. 
Setting
Data collection for this study will take place within the Emory University Epilepsy 
Monitoring Unit (EUH 3G) where patients are electively hospitalized for the clinical 
purpose of recording seizures and identifying the brain location of seizure onset. This 
study will not interfere with or extend the duration of their clinical stay. No physical 
specimens will be obtained. Data will be kept on encrypted laboratory computers, 
securely locked in the Woodruff Memorial Research Building and behind the Emory 
University 'Firewall' maintained by Information Technology Services.  

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Resources Available
As a high volume tertiary care epilepsy center (14 epileptologists, 3 nurse practitioners, 
and 2 epilepsy neurosurgeons), the Emory Epilepsy Center has unparalleled access to a 
large and continuously growing population of patients with refractory epilepsy. Based on 
our past clinical volume, we estimate that >20 patients with MTLE will undergo SEEG 
per year. Study subjects will be recruited from this pool of patients. Our recruitment and 
retention rates for current and recent research protocols in SEEG patients have been 
~80%. We are targeting to enroll 18 subjects, which should be feasible given our historic 
volume and recruitment rates. 
Patients included in this study are admitted to Emory University Hospital for clinical 
purposes by the functional neurosurgery team.  Patients are monitored with continuous 
EEG in our Epilepsy Monitoring Unit (EMU).  Emory has an 11 bed EMU.  The EMU is 
staffed by 2 physician epileptologists, 2 or more epilepsy/clinical neurophysiology 
fellows and 1 nurse practitioner at any given time. 24 hour inpatient support for 
intracranial monitoring patients is provided by the neurosurgery and general neurology 
teams in addition to nursing staff.  The epilepsy monitoring unit consists of a centralized 
monitoring pod which is continuously monitored by EEG technicians.  
References
1.
Nair, D.R., Management of Drug-Resistant Epilepsy. Continuum (Minneap Minn), 
2016. 22(1 Epilepsy): p. 157-72.
2.
Loring, D.W., It's about time: long-term memory outcome following temporal 
lobectomy. Epilepsy Curr, 2007. 7(2): p. 38-40.
3.
Heck, C.N., et al., Two-year seizure reduction in adults with medically intractable 
partial onset epilepsy treated with responsive neurostimulation: final results of the 
RNS System Pivotal trial. Epilepsia, 2014. 55(3): p. 432-41.
4.
Fisher, R.S., Direct brain stimulation is an effective therapy for epilepsy. 
Neurology, 2011. 77(13): p. 1220-1.
5.
Velasco, A.L., et al., Electrical stimulation of the hippocampal epileptic foci for 
seizure control: a double-blind, long-term follow-up study. Epilepsia, 2007. 48(10): 
p. 1895-903.
6.
Morrell, M.J. and R.N.S.S.i.E.S. Group, Responsive cortical stimulation for the 
treatment of medically intractable partial epilepsy. Neurology, 2011. 77(13): p. 
1295-304.
7.
Desai, S.A., et al., Asynchronous Distributed Multielectrode Microstimulation 
Reduces Seizures in the Dorsal Tetanus Toxin Model of Temporal Lobe Epilepsy. 
Brain Stimul, 2016. 9(1): p. 86-100.
8.
Gordon, B., et al., Parameters for direct cortical electrical stimulation in the 
human: histopathologic confirmation. Electroencephalogr Clin Neurophysiol, 
1990. 75(5): p. 371-7.
9.
Sederberg, P.B., et al., Theta and gamma oscillations during encoding predict 
subsequent recall. J Neurosci, 2003. 23(34): p. 10809-14.

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10. 
Loring DW, Meador KJ, Lee GP, King DW. Amobarbital effects and lateralized 
brain function: The Wada test: Springer-Verlag; 1992.
11. 
Goldstein HE, Smith EH, Gross RE, et al. Risk of seizures induced by intracranial 
research stimulation: analysis of 770 stimulation sessions. J Neural Eng. 
2019;16(6):066039. Published 2019 Nov 11. doi:10.1088/1741-2552/ab4365