Electrophysiologic Studies of Cognition in Epilepsy Patients
Phase: NA
Conditions: Drug-resistant Epilepsy
Sponsor: Icahn School of Medicine at Mount Sinai

Electrophysiologic Studies of Cognition in Epilepsy Patients
Correct NCT05769634 (incorrect on next page) 
Principal Investigator: Allison Waters
Document Date: 05/13/2025

CONFIDENTIALITY STATEMENT
This document is confidential communication. Acceptance of this document constitutes agreement by the 
recipient that no unpublished information contained herein will be published or disclosed without prior 
approval of the Principal Investigator or other participating study leadership and as consistent with the 
NIH terms of award. 
Effective Date: 5/13/2025
End Date:6/3/2025

Electrophysiologic Studies of Cognition in Epilepsy Patients
Version 1
Protocol 22-00529
17 March 2022
Table of Contents
STATEMENT OF COMPLIANCE .......................................................................................................................................4
INVESTIGATOR’S SIGNATURE ........................................................................................................................................5
1
PROTOCOL SUMMARY...........................................................................................................................................6
1.1 Synopsis .............................................................................................................................................................7
1.2 Schema ..............................................................................................................................................................8
1.3 Schedule of Activities.........................................................................................................................................9
2
INTRODUCTION......................................................................................................................................................9
2.1 Study Rationale................................................................................................................................................10
2.2 Background......................................................................................................................................................10
2.3 Risk/Benefit Assessment..................................................................................................................................10
2.3.1
Known Potential Risks
10
2.3.2
Known Potential Benefits.........................................................................................................................12
2.3.3
Assessment of Potential Risks and Benefits.............................................................................................12
3
OBJECTIVES AND ENDPOINTS ..............................................................................................................................12
4
STUDY DESIGN .....................................................................................................................................................13
4.1 Overall Design..................................................................................................................................................13
4.2 Scientific Rationale for Study Design ...............................................................................................................15
4.3 Justification for Intervention ...........................................................................................................................15
4.4 End-of-Study Definition ...................................................................................................................................15
5
STUDY POPULATION ............................................................................................................................................16
5.1 Inclusion Criteria..............................................................................................................................................16
5.2 Exclusion Criteria .............................................................................................................................................16
5.3 Strategies for Recruitment and Retention.......................................................................................................16
6
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S).......................................................................17
6.1 Study Intervention(s) or Experimental Manipulation(s) Administration.........................................................17
6.1.1 Study Intervention or Experimental Manipulation Description..................................................................17
6.2 Lost to follow up..............................................................................................................................................17
6.3 Measures to Minimize Bias: Randomization and Blinding...............................................................................17
6.4 Study Intervention/Experimental Manipulation Adherence ...........................................................................17
7
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .............................................................................................................................18
7.1 Discontinuation of Study Intervention/Experimental Manipulation...............................................................18
7.2 Participant Discontinuation/Withdrawal from the Study................................................................................18
8
STUDY ASSESSMENTS AND PROCEDURES............................................................................................................18
8.1 Endpoint and Other Non-Safety Assessments.................................................................................................18
8.2 Safety Assessments..........................................................................................................................................19
8.3 Adverse Events and Serious Adverse Events ...................................................................................................19
8.3.1
Definition of Adverse Events....................................................................................................................19
8.3.2
Time Period and Frequency for Event Assessment and Follow-Up .........................................................20
8.3.3
Adverse Event Reporting..........................................................................................................................20
8.3.4
Serious Adverse Event Reporting.............................................................................................................21
8.3.5
Reporting Events to Participants..............................................................................................................21
8.3.6
Events of Special Interest.........................................................................................................................21
8.3.7
Reporting of Pregnancy 21
9
STATISTICAL CONSIDERATIONS.......................................................................................................................21
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Electrophysiologic Studies of Cognition in Epilepsy Patients
Version 1
Protocol 22-00529
17 March 2022
9.1 Statistical Hypotheses......................................................................................................................................21
9.2 Sample Size Determination..............................................................................................................................22
9.3 Populations for Analyses .................................................................................................................................22
9.4 Statistical Analyses...........................................................................................................................................22
9.4.1
General Approach
22
9.4.2
Analysis of the Primary Endpoint(s).........................................................................................................23
9.4.3
Analysis of the Secondary Endpoint(s).....................................................................................................24
9.4.4
Safety Analyses
25
9.4.5
Baseline Descriptive Statistics..................................................................................................................25
10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ......................................................25
10.1 Regulatory, Ethical, and Study Oversight Considerations................................................................................25
10.1.1
Informed Consent Process...................................................................................................................25
10.1.2
Study Discontinuation and Closure......................................................................................................26
10.1.3
Confidentiality and Privacy ..................................................................................................................26
10.1.4
Future Use of Stored Specimens and Data ..........................................................................................27
10.1.5
Key Roles and Study Governance ........................................................................................................27
10.1.6
Safety Oversight
31
10.1.7
Clinical Monitoring
31
10.1.8
Data Handling and Record Keeping .....................................................................................................31
10.1.9
Protocol Deviations
32
10.1.10
Publication and Data Sharing Policy ....................................................................................................32
10.1.11
Conflict of Interest Policy.....................................................................................................................33
10.2 Protocol Amendment History..........................................................................................................................33
11
REFERENCES....................................................................................................................................................34
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1
STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Council on Harmonisation Good Clinical Practice (ICH 
GCP) and the following: 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 21 CFR Part 50, 
21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812). 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible for the 
conduct, management, or oversight of NIH-funded clinical trials have completed Human Subjects Protection and ICH 
GCP Training.
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2
INVESTIGATOR’S SIGNATURE
The signature below constitutes the approval of this protocol and provides the necessary assurances that 
this study will be conducted according to all stipulations of the protocol, including all statements 
regarding confidentiality, and according to local legal and regulatory requirements and applicable US 
federal regulations and ICH guidelines, as described in the Statement of Compliance above.
Principal Investigator or Clinical Site Investigator:
Signed:
Date:
2/22/2022
Name*: Ignacio Saez
Title*: Assistant Professor
Investigator Contact Information
Affiliation: Icahn School of Medicine at Mount Sinai
Address: 1000 10th Ave. Rm 10-41A
Telephone: (212)523-8829
Email: ignacio.saez@mssm.edu
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3
1
PROTOCOL SUMMARY
1.1
SYNOPSIS 
Title:
Electrophysiologic studies of cognition in epilepsy patients
Study Description:
In this study, we seek to study how brain activity contributes to the 
generation of actions, emotions, memories, and other thought processes. 
To do that, we propose to examine brain activity recorded in patients 
undergoing neurosurgical interventions for treating epilepsy. Specifically, 
we leverage the fact that intractable epilepsy patients are surgically 
implanted with electrodes that allow recording the brain’s electrical 
activity. Each electrode provides a readout of electrical activity in a 
different brain area, and therefore a way to measure brain activity in a very 
precise way, both anatomically and temporally, something that is very 
difficult to achieve otherwise in human subjects. We combine these 
recordings of electrical activity with tasks designed to test different 
aspects of behavior and thought, such as memory, decision-making, 
spatial navigation, etc. These take the form of short computer games that 
the patients will play while their brain activity is recorded using the 
clinically implanted electrodes. We will subsequently analyze the brain 
data, together with the patients’ behavior and information about the 
location of each electrode, to derive information on how brain activity in 
different brain areas is related to behavior. In some cases, we will use 
special electrodes that allow very precise examination of neural activity 
(i.e. examine activation of single neurons, compared to large populations 
of neurons using other approaches) or use small amounts of electrical 
currents to stimulate specific brain areas to test their contribution to 
behavior. This will provide us with a more detailed understanding of the 
neurobiology of thought and provide causal observations of the 
contributions of individual brain areas. In a subset of patients that are 
clinically determined to undergo treatment resection, we will collect tissue 
samples for molecular analyses. This combination of electrophysiological 
recordings and behavioral tasks provide a unique opportunity to 
understand the contribution of brain processes to normal thoughts and 
behavior, as well as how these are affected in disease states (i.e. epilepsy, 
depression).
Objectives*:
Primary Objective:
Study the neurophysiological basis of human cognition and actions.
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4
Endpoints*:
The 
primary 
endpoint 
of 
this 
research 
is 
to 
investigate 
electrophysiological correlates of human cognitive and perceptual 
processes. The approach involves the analysis of the brain's electrical 
activity during computer-controlled cognitive/perceptual tasks, to 
determine how behaviors that occur during these tasks correlate with 
changes in electrical activity measured inside the human brain and on the 
scalp.
The secondary endpoint of this research is to examine changes in neural 
activity and behavior in response to neurostimulation.
The tertiary endpoint of this research is to characterize the genetic and 
molecular composition of human brain tissue to reveal important 
information about genetic differences in epileptic tissue and correlate 
electrophysiological and molecular biological measures to brain function 
and clinical diagnoses.
The knowledge gained from these experiments will further our 
understanding of the brain’s electrical activity and its relation to human 
cognition and disease. This increased knowledge base may lead to 
insights regarding better treatments for cognitive deficits and to improve 
epilepsy surgery and other therapies for seizure and other disorders. 
Further, uncovering the electrophysiological signatures of cognitive 
function through functional mapping, which enables the surgeon to avoid 
the resection of brain regions that could be especially crucial to cognitive 
function, may be improved, reducing the risk of post-surgical cognitive 
impairment following resection.
Study Population:
Epilepsy patients undergoing invasive monitoring.
Description of 
Sites/Facilities Enrolling 
Participants:
Mount Sinai Health System Hospitals and Epilepsy outpatient clinics.
Study Duration*:
An initial period of 10 years, to be extended as data collection continues.
Participant Duration:
Length of duration of intracranial EEG recordings in the Epilepsy 
Monitoring Unit (EMU; typical EMU stays range between 5-14 days) plus 
up to 12 months post-discharge. 
1.2
SCHEMA 
Study Design: 
Research will be conducted at Mount Sinai West and Mount Sinai Hospital. Patients will be identified and recruited 
in either of these settings. Electrophysiological recordings will take place during patient stay in the Epilepsy 
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5
Monitoring Unit (EMU) of either site. Select tasks may need to be collected before hospital admission or after 
discharge; these will be carried out either in person during a patient visit to the hospital or remotely through a 
computer screen in the patients’ preferred setting (i.e. at their homes) through a computer browser.
Mount Sinai may act as the coordinating institution across several research institutions involved in research. In such 
case, all sites will carry out research following all NIH and IRB guidelines and regulations. We will establish a research 
reliance and/or data transfer agreements with Mount Sinai as necessary.
1.3
SCHEDULE OF ACTIVITIES 
Patients will participate in the study for the duration of their hospitalization (typically 5-14 days in the EMU; 1 day 
for participation in placement of the microelectrodes during surgery). In some cases, patients will be asked to 
complete one or several remote behavioral tests (computer games) before they are admitted or after they are 
discharged from the hospital. In the case of pre-operative testing, the available time window will occur between 
consenting and EMU stay, typically a few weeks. Consent will take place preoperatively or on surgery day. If patients 
undergo resective surgery and consent to research use of resected tissue, this portion will happen at the time of 
resection, determined on clinical grounds. For post-operative testing, patients will be asked to carry out behavioral 
testing one or several times over the 12 months following EMU discharge.
Pre-
operative
Surgery  
Day
Epilepsy 
monitorin
g unit stay 
(typically 
5-14 days)
Resective 
surgery (if 
applicable)
Post-
discharge 
(up to 12 
months)
Informed Consent
X
X
Demographics
X
Clinical history
X
X
X
X
Obtain tissue
X
Outcome Evaluation
Quality of Life 
Questionnaire
X
X
Task Administration
X
X
X
Adverse Events 
Reporting
X
X
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2
INTRODUCTION
2.1
STUDY RATIONALE 
The study aims at understanding the neural substrates of language, attention, motor control, emotion and memory 
processing; as well as developing techniques to improve neurosurgical treatment of seizures and brain 
abnormalities. These approaches will assess the functional connectivity and communication between cortical 
regions involved in human cognitive processing. It will provide neuroanatomical, electrophysiological 
neurostimulation and behavioral information about the neural circuits involved in decision-making, attention, motor 
control, emotion and memory. This will ultimately help us improve clinical treatment of neurosurgical patients.
2.2
BACKGROUND 
Although one can crudely measure the human brain’s electrical signals by recording from the scalp, the ability to 
observe and measure oscillations generated in local regions of the brain requires recordings taken from electrodes 
implanted in the brain (i.e., invasive EEG, or iEEG recording). Such iEEG recordings are often clinically required in the 
surgical treatment of severe medication-resistant epilepsy (i.e., seizure disorders that are not controlled by standard 
drug therapies). For these patients, surgery is potentially curative; the goal in planning surgery is to precisely localize 
the brain areas responsible for seizure activity. This can be accomplished by monitoring iEEG recordings over a period 
of several days to several weeks.
Intracranial EEG monitoring furthermore enables the study of single-neuron activity using hybrid “micro-macro” 
electrodes that contain additional microwire bundles exiting from the tip of the standard clinical electrodes. This 
minor modification provides a rare and important opportunity to study the human nervous system as a single-cell 
resolution in awake, behaving humans. This paradigm has led to key insights into epileptic seizure generation and 
propagation, as well as human cognition. 
In addition, electrical brain stimulation is a routine procedure in the EMU for localization of brain function and is 
frequently performed in patients with intracranial electrodes. By studying how electrical stimulation elicits changes 
in oscillatory activity related to epilepsy or cognition, we may be able to causally discern the specific brain circuits 
involved. Electrical stimulation also provides the opportunity to measure changes in neurotransmitter concentration 
via voltammetry techniques that have been utilized in rodents for 25 years, and human subjects more recently, and 
can assess how critical neurotransmitters such as dopamine, serotonin, and norepinephrine fluctuate in relation to 
human cognitive performance. 
iEEG recordings therefore offer a rare and valuable opportunity to record neurophysiological activity directly from 
the human brain, compare these results with those from animal models and to extend these insights into unniquelyl 
human cognitive capabilities (for example in decision-making or abstract reasoning). iEEG recordings have already 
been used to greatly enhance our knowledge of the physiology of human cognition by allowing investigating local 
cortical dynamics in an awake human, how different cortical areas interact to generate cognition and actions, to 
assess the formation and propagation of seizures, and to carry out causal interrogations of brain activity (Saez 2018, 
Sani 2018, Helfrich 2018, Kahana 1999, Fried 2014, Parvizi 2013, Desmurget 2009).
In addition, resective surgeries, which are a possible treatment outcome post-iEEG evaluation, offer a possibility to 
recover human tissue for subsequent molecular analysis and characterization. This offers unique possibilities to 
characterize the genetic and molecular composition of human brain tissue, which could reveal important 
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7
information about genetic differences in epileptic tissue, and allow correlating electrophysiological and molecular 
biological measures.
2.3
RISK/BENEFIT ASSESSMENT 
2.3.1
KNOWN POTENTIAL RISKS 
EMU patients will be under standard neurology and nursing care with video/medical monitoring in the EMU. Note 
that these patients typically have their medications tapered during their stay in order for them to have seizures, 
which is the goal of the clinical monitoring. In the event of a seizure, standard protocols will be followed on the unit. 
Again, patients are supposed to have multiple seizures during this stay in the EMU. A member of the study team will 
always be present during the testing required for this study, including testing that involves stimulation.

Cognitive testing: all cognitive and memory tests are designed to be minimally difficult. Some subjects may find 
the tests to be stressful, tiring, or boring. Cognitive testing will not interfere with their epilepsy monitoring or 
treatment. Standard medical care and safety protocols during EMU admission will not be altered by participation 
in this study. If an intervention is medically required due to the occurrence of seizures or post-ictal complications 
(including but not limited to the administration of sedating or anticonvulsant medications, resuscitative 
measures including supplemental oxygen, or patient restraint for safety in the setting of post-ictal agitation), 
the cognitive testing will be aborted and/or deferred until a time when the patient’s medical condition permits 
continuation of the testing. Procedures to mitigate risks of cognitive testing: session times will be minimized, 
and assessments may take place over more than once session, if needed and appropriate. Participants may also 
take breaks, as needed. Subjects have the right to refuse to answer questions they feel are too distressing, as 
well as to terminate any one part or the whole of their participation at any time. 

Single neuron recordings: we will use augmented macro-micro electrodes that include, in addition to the macro 
contact sites routinely used for clinical recordings, micro contact filaments to allow electrophysiological 
recordings that can isolate individual neurons. There is no additional risk of intracerebral hemorrhage or tissue 
injury compared with the standard clinical macro electrodes. There are no reports of any ill effects from these 
FDA-approved electrodes for clinical EEG recording. Recordings from the microelectrode filaments that protrude 
from the macro electrode shaft do not interfere with the usual clinical recordings and have the potential to 
significantly improve some aspects of mapping seizures and cognition. Every study examining the design and 
safety of such micro-macro depth electrodes has found them to be as safe and effective as standard depth 
electrodes for intracranial monitoring (House 2006, Van Gompel 2008, Waziri 2009, Hefft 2013, Misra 2014, 
Carlson 2018). Their use requires no extra surgical procedures. Procedures to mitigate risks of single neuron 
recording: we will only use single-unit recording electrodes in locations targeted for clinical reasons. The 
locations and number of sEEG electrodes will therefore be based on clinical necessity and will not be changed 
due to participation in this study. Only a subset of sEEG electrodes (typically 1-4) will be replaced by macro-
micro electrodes.

Brain stimulation: we do not anticipate any significant increase in risk, since we will be using FDA-approved 
electrodes and stimulating according to clinical protocols. Stimulation will be carried out using macro electrodes 
only, even if the patient consented to microelectrode implantation. It is possible that brain stimulation could 
produce a seizure that causes injury. We will monitor the occurrence of seizures producing injury in all enrolled 
patients. Patient safety will be tracked by the PI and research staff in real time and reported to the Mount Sinai 
IRB according to the guidelines in HRP-214. Procedures to mitigate stimulation testing risks: to minimize the risk 
of triggering a seizure through stimulation, we will limit stimulation to levels routinely used by the clinical team 
for functional mapping (≤6mA). Stimulation testing will only be carried out once the patient has been cleared 
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8
for explantation by the clinical team, to minimize risks of elicited seizures prolonging the patients’ medical stay. 
Stimulation will only occur using macroelectrodes.

Privacy: the risk of loss of private information, however small, is always present when PHI is shared by a patient, 
as well as when data is shared among study personnel and collaborators. However, we will take every precaution 
to prevent this. Each participating patient will be assigned a unique identification number and there will be no 
reference personal identifiers in any subsequent publication. All personal identifiers will be destroyed upon 
completion of the research and the required storage period. Data files will be stored on a secured server, which 
will be password-protected and access to data files will be given only to IRB approved research personnel. The 
main risks of audio and video recordings performed in this protocol are associated with patient privacy. Patients 
will be fully informed that their face and voice will be identifiable to the team members analyzing the data. 
While recordings will only be associated with a participant’s study ID, it is not possible to fully de-identify facial 
images. Procedures to mitigate privacy risks: The risk of disclosure of PHI will be adequately conveyed to 
participants in the informed consent document for this study. The study investigators and research staff will 
abide by all policies and procedures set forth by Mount Sinai and in accordance with Good Clinical Practices with 
respect to the proper storage and transfer of PHI and other subject data. Only the minimal amount of patient 
information, including that which is personally identifiable, will be accessed in the conduction of this study.

Tissue resection:  tissue resection will be carried out adhering to clinical protocols, with all research activities 
being carried out on the resected tissue. Therefore, no additional risks are estimated.

Unforeseeable risks: this study may involve risks that are currently unknown and unforeseeable. Procedures to 
Mitigate Unforeseeable Risks: All new information, including new risks and that which may affect a person’s 
decision to continue study participation, will be disclosed as it becomes available. 
2.3.2
KNOWN POTENTIAL BENEFITS 
We anticipate no direct benefit to enrolled patients. This fact will be communicated to the patients. However, this 
research may benefit future patients through a better understanding of the activity of brain regions involved in 
cognition and disease.
2.3.3
ASSESSMENT OF POTENTIAL RISKS AND BENEFITS 
Through the risk mitigation strategies outlined above, risk to the patients is kept to a minimum, whereas there is 
large potential for improving our understanding of brain function and disease. 
3
OBJECTIVES AND ENDPOINTS 
OBJECTIVES
ENDPOINTS
JUSTIFICATION 
FOR ENDPOINTS
PUTATIVE 
MECHANISMS 
OF ACTION
Primary
Investigate the neurophysiological 
correlates of human cognitive processes. 
The approach involves the analysis of the 
brain's electrical activity during computer-
controlled cognitive/perceptual tasks, to 
determine how behaviors that occur during 
these tasks correlate with changes in 
electrical activity measured inside the 
human brain and on the scalp.
The primary endpoint for 
each task tested will be the 
number of estimated 
subjects required for 
appropriate powerful 
statistical testing –an 
estimated 10-20 subjects 
depending on the 
Achieving 
appropriate 
statistical power 
for each task.
Measuring 
neuronal 
activity in 
neuronal 
populations.
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9
OBJECTIVES
ENDPOINTS
JUSTIFICATION 
FOR ENDPOINTS
PUTATIVE 
MECHANISMS 
OF ACTION
anatomical coverage of 
individual patients.
Secondary
Investigate the causal involvement of 
individual brain areas in cognitive processes 
through targeted electrical stimulation.
The primary endpoint for 
each task tested will be the 
number of estimated 
subjects required for 
appropriate powerful 
statistical testing –an 
estimated 10-20 subjects 
depending on the 
anatomical coverage of 
individual patients.
Achieving 
appropriate 
statistical power 
for each task.
Modulation of 
neuronal 
activity and 
behavior 
through neural 
stimulation.
Tertiary
Characterize the genetic and molecular 
composition of human brain tissue to reveal 
differences in genetic expression and its 
relationship to electrophysiological and 
clinical measures.
The primary endpoint will 
be the number of 
estimated subjects 
required for appropriately 
powerful statistical testing 
for each clinical diagnosis, 
comorbidity or 
electrophysiological metric 
under study–an estimated 
20 subjects per set.
Achieving 
appropriate 
statistical power 
for transcriptomics 
studies.
Gene 
transcription 
patterns in 
resected tissue.
4
STUDY DESIGN
4.1
OVERALL DESIGN
Overview: this is a prospective observational study. We will recruit adult patients who are undergoing intracranial 
electroencephalographic (iEEG) or regular EEG monitoring as part of a standard clinical procedure for the treatment 
of pharmacologically resistant epilepsy. iEEG monitoring is used by physicians to pinpoint seizure foci and to map 
areas of the brain that give rise to seizures. In addition, this method is used for brain stimulation mapping in order 
to characterize areas that are critical for cognitive function. Patients will be from the clinical population at MSSM 
undergoing monitoring. Potential study subjects are discussed at epilepsy Surgical Conferences and the clinical team 
will identify and flag candidates that meet the inclusion criteria. Subjects will be approached prior to surgery or upon 
arrival in the epilepsy monitoring unit the day after the electrode implantation surgery, and will be informed that 
they will receive the same standard of care whether or not they choose to participate in the research. Informed 
consent will be obtained from all participants. No patient will be excluded on the basis of race, gender or ethnicity. 
The main goal of the current project is to study the neurophysiological basis of human cognition across brain areas, 
which will be accomplished through behavioral testing, electrophysiological recordings and brain stimulation.
Behavioral testing: The main objective of this project is to record neurophysiological activity during cognitive and 
behavioral tasks during the patients’ EMU stay. Patients will primarily complete behavioral tasks for the duration of 
their EMU stay, for as long as they’re willing to participate. We will present them with cognitive tasks while we record 
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10
iEEG, so that we can help define critical brain areas for decision-making, memory, and other cognitive processes. 
The same electrodes used clinically will be used for the cognitive tasks. We will present these patients with images 
or video clips on a computer monitor, sounds through headphones, or taps to different fingers. They will be asked 
to pay attention to and remember the different pictures, sounds or taps. They also may be asked to press a button 
in response to certain stimuli or make movements with their hands, make a verbal response, or make a series of 
choices involving uncertain outcomes (e.g., money). In some cases, audio recording may be conducted as part of the 
experimental procedure, with the patient speaking into a microphone and the speech recorded. The patient may be 
asked to say out loud individual phonemes, words, or complete sentences out loud. If a verbal response is recorded, 
the recordings will be assigned a subject identifier number that is also assigned to other data from the experiment. 
Conducting and administering cognitive and memory tests poses no clinical or safety risks to the patient.  All tests 
will be scheduled around patient clinical needs and will interfere in no way with patient clinical schedule and events. 
Typically, recording sessions will take about 60-90 minutes, for a total of 2-5 hours total. The patient can stop the 
recording session at any time and for any reason.
Remote testing: In some instances, patients will be asked to complete behavioral tests (i.e. computer games) prior 
to or after their hospital stay, as specified above (Section 1.2). These are necessary in some cases in which the 
scientific validity of the research requires preliminary training or testing, or subsequent re-testing or validation. 
Patients will complete remote testing accomplished in-person during hospital visits or through remote testing in 
internet-connected devices (e.g. laptop or tablet). The patient will be given the option to complete testing in either 
modality. If the patient prefers the remote option, s/he will be offered a research-owned device in which to carry 
out testing, or be instructed on how to access the task through a computer program (i.e. a browser). If the patient 
chooses the device, s/he will be allowed to keep it until their involvement with the research program is complete.
Electrophysiological recordings: Study subjects will be patients with intractable medication resistant epilepsy who 
are candidates for scalp EEG or iEEG monitoring, meaning they will have electrodes surgically inserted either 
subdurally (grids/strips) or into the brain (depth electrodes). These electrodes are part of their standard clinical 
treatment, and electrode locations will not be altered in any way for this research. During recordings, we may add a 
connector from our behavioral testing computer to the clinical recording computer (Saez 2018); this device will have 
no effect on patient clinical monitoring or outcome and it is solely intended to allow time synchronization of our 
testing computer with the recording computer, and it has been approved for use by clinical engineering. Neurologists 
and nurses will be available and on-call should any other clinical safety issues arise as part of the patient’s stay in the 
hospital. Electrophysiological recordings will be carried out using the clinical recording system, and in some cases 
additionally using a research dedicated system.
Video recordings: Video recording during invasive epilepsy is part of standard of care treatment. We will record video 
of the patient during their hospital stay, and in some instances analyze it to contribute to research analyses, for 
example to verify patient’s behavior during different times of the day or facial expression during tasks.
Modified electrodes: For single neuron recordings, we will use augmented macro-micro electrodes that include, in 
addition to the macro contact sites routinely used for clinical recordings, micro contact filaments to allow 
electrophysiological recordings that can isolate individual neurons. There is no additional risk of intracerebral 
hemorrhage or tissue injury compared with the standard clinical macro electrodes. There are no reports of any ill 
effects from these FDA-approved electrodes for clinical EEG recording. Recordings from the microelectrode 
filaments that protrude from the macro electrode shaft do not interfere with the usual clinical recordings and have 
the potential to significantly improve some aspects of mapping seizures and cognition. Every study examining the 
design and safety of such micro-macro depth electrodes has found them to be as safe and effective as standard 
depth electrodes for intracranial monitoring (House 2006, Van Gompel 2008, Waziri 2009, Hefft 2013, Misra 2014, 
Effective Date: 5/13/2025
End Date:6/3/2025

11
Carlson 2018). Their use requires no extra surgical procedures. The locations and number of sEEG electrodes will be 
based on clinical necessity and will not be changed due to participation in this study. Only a subset of sEEG electrodes 
(typically 1-4) will be replaced by macro-micro electrodes. Thus, these micro-macro electrodes provide unique and 
safe opportunities to study the human brain at single-neuron resolution during the performance of cognitive tasks. 
If the patient consents to the use of microelectrodes and chooses to withdraw from study at any time, the 
microelectrodes will be removed during the explantation procedure of the standard of care electrodes to minimize 
risk to the patient.
Brain Stimulation: Electrical brain stimulation is a routine procedure in the EMU for localization of brain function and 
is frequently performed in patients with intracranial electrodes. We plan to use similar focal currents, using 
macroelectrodes to stimulate the brain, during cognitive tasks to help localize and define cognitive networks. The 
patient's baseline performance on specific tasks will be established on trials without stimulation and compared to 
trials with stimulation in specific regions and statistically analyzed. For stimulation, we may employ the stimulation 
hardware routinely used for clinical mapping (e.g. Nicolet cortical stimulator) or an equivalent research device (e.g. 
ATLAS Stim Headbox - High Density, part number: 31-0601-0132) using identical stimulation parameters as specified 
below. The electrical current will be kept at or below the same safe levels as used in standard clinical cortical 
mapping. Safety limits have been established for decades (McCreery, et al. 1990; Gordon et al., 1990, Shannon 1992). 
Here, we will apply stimulation while subjects perform cognitive tasks at levels far below the safety limits identified 
by histological analysis for stimulation protocols (McCreery, et al. 1990; Gordon et al., 1990). Stimulation studies will 
be performed using currents not exceeding 10mA, below the accepted safety limits for charge density (Shannon 
1992), and in line with previous studies. There is no evidence that stimulation of the type to be performed in this 
study causes any patient risk. The only significant change to the patient’s routine in the proposed studies is that 
brain stimulation will be performed for longer periods and sometimes in different locations than required for 
standard evaluation. Patients will be asked frequently if they would like to continue or stop testing, and testing will 
be halted at any signs of patient discomfort or fatigue. Electrical stimulation also provides the opportunity to 
measure changes in neurotransmitter concentration via voltammetry techniques that have been recently developed 
for safe use in human subjects (Kishida 2018).
Resected tissue analysis: in some cases, the determined clinical strategy for intractable epilepsy patients involves 
removal of epileptiform clinically determined to be the focal origin of seizure activity. This is an effective treatment 
strategy, which is employed in a subset of patients that undergo iEEG monitoring, and which is determined strictly 
on clinical grounds. This provides a valuable research opportunity to characterize the resected tissue with molecular 
and genetic tools (e.g. in situ gene expression) in a way that, like the electrophysiological component of this study, 
is not otherwise possible. 
4.2
SCIENTIFIC RATIONALE FOR STUDY DESIGN
iEEG recordings taken during treatment for intractable epilepsy have already been used to greatly enhance our 
knowledge of the physiology of human cognition. First, iEEG recordings sample from smaller brain volumes than 
scalp-recorded EEG or magnetoencephalographic (MEG) signals, are not subject to distortions produced by the 
human skull, and are relatively impervious to movement artifacts because of their high signal- to-noise ratio. iEEG 
recordings also offer far better temporal resolution than functional magnetic resonance imaging (fMRI). In addition 
to providing an opportunity to investigate the local cortical dynamics in an awake human, iEEG allow us to study 
how different cortical areas interact to produce dedicated functions, to assess the formation and propagation of 
seizures, and to causal interrogations of brain activity. We will be using the same electrodes placed for clinical 
purposes, and will not remove, replace, or add additional electrodes unless it is clinically indicated or as 
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12
contemplated below. The resulting datasets will provide a depiction of brain activity with superb anatomical and 
temporal resolution and a high signal to noise ratio typically unavailable in studies of human brain function. Similarly, 
the tissue analysis portion of the study, which provides a unique possibility to study the genetic and molecular 
composition of human brain tissue, will be only carried out when there is a clinical determination to use resection 
as a treatment.
4.3
JUSTIFICATION FOR INTERVENTION
Leveraging existing clinical interventions will allow us to carry out detailed electrophysiological and molecular 
studies on human brain activity at a level of temporal and anatomical resolution otherwise unavailable to 
neuroscientific research.
4.4
END-OF-STUDY DEFINITION
Study completion can happen through one of the several mechanisms:

Completion of study procedures 

Withdrawal of participant consent 

Withdrawal of participant by study investigator 

Clinical safety endpoints
Procedures for Subjects to Request Withdrawal: Procedures to withdraw from the protocol are conveyed to 
participants in the informed consent document, which requires the formal withdrawal of consent in writing to the 
Principal Investigator of the study. Subjects will be advised that information already collected in the study may not 
be removed from the research study database and will continue to be used to complete the research analysis. 
Patients may also withdraw permission for the use and disclosure of any of protected information for research 
purposes by notifying the Principal Investigator in writing. However, the Principal Investigator may still use the 
information that was already collected if that information is necessary to complete the research study and/or data 
analyses. As this is not a treatment study, study withdrawal will not impact subjects’ ongoing clinical care.  
Procedures for Investigator to Withdraw Subjects: Participants will be notified that the Principal Investigator has the 
right to withdraw any subject from the protocol at her discretion without patient consent, which is conveyed in the 
informed consent document. Potential reasons for participant withdrawal include: termination of the research, 
subject non- compliance with study protocol (particularly that which compromises patient safety or renders data 
collected to be unusable), or patient inability to complete study procedures as required (which renders data 
collected to be unusable). 
Clinical safety endpoints: We will immediately terminate a patient’s participation in the study if this is deemed 
necessary by the clinical team. In addition, the PI will monitor the study for any adverse events (AEs), although we 
do not anticipate any given the nature of the study. Adverse events, any untoward medical occurrence in a subject 
during participation in the study including include any sign, symptom, abnormal assessment (laboratory test value, 
vital signs, electrocardiogram finding, etc.) or combination thereof, will result in termination of the patients’ 
participation in the study. The AE will be documented by the research team and reported to the IRB using IRB 
communication channels. If action is deemed appropriate to ensure patient safety by the IRB following AE review, 
the research team will implement these changes in all future participants.
5
STUDY POPULATION
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13
5.1
INCLUSION CRITERIA
We will enroll patients who have pharmacologically resistant epilepsy who are undergoing invasive 
electroencephalogram (iEEG) monitoring as part of their standard care.
In order to be eligible to participate in this study, an individual must meet all of the following criteria:

Is able to provide written informed consent.

Is a candidate to receive iEEG for Epilepsy.

Is willing and able to comply with all study-related appointments and procedures.

Has English language proficiency or an available translator for all study procedures.

Is over the age of 10.
No patient will be excluded on the basis of race, gender, or ethnicity. Underage subjects (children 10 years and 
older) will be considered for inclusion after obtaining both patient and parental consent. Consent will be obtained 
when a minor enrolled in the study attains 18 years of age.  
5.2
EXCLUSION CRITERIA
An individual who meets any of the following criteria will be excluded from participation in this study:

Has cognitive or physical impairments that would limit their ability to participate in testing.

Is unable to consent.

Is pregnant (Note: Pregnant women are not candidates for intercranial EEG monitoring).

Is a prisoner.

Is under the age of 10.
5.3
STRATEGIES FOR RECRUITMENT AND RETENTION
This protocol will recruit patients who are undergoing intracranial electroencephalographic (iEEG) monitoring as part 
of a standard clinical procedure for the treatment of pharmacologically resistant epilepsy. Potential iEEG surgical 
candidates present to Mount Sinai epilepsy clinic at a rate of approximately 30-40 a year. Of these, based on past 
data we expect about 50-75% to be capable of participating in the tasks based on our inclusion criteria, for an 
expected data collection rate of about 20 EMU patients/year. We plan to collect 200 patients over the course of the 
first 10 years of study.

How participants will be identified: Epilepsy patients are discussed at weekly epilepsy clinical meetings in 
which the clinical team will identify candidates that meet the inclusion criteria. Epilepsy monitoring unit 
(EMU) patients will be approached prior to surgery or upon arrival in the EMU and will be informed that 
they will receive the same standard of care whether they choose to participate in the research or not. 
Informed consent will be obtained from all participants. Future recruitment materials will be submitted for 
IRB review as a protocol modification, as needed.

Consenting of underage participants: consent will be obtained from the patient and an accompanying 
parent or legal guardian. When the minor turns 18, they will be asked to consent again. 

Who will initially approach potential participants: Study Personnel, Treating Physician, Principal Investigator 
of referring protocol.
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14

Patient Incentives: Patients will be compensated for completing tasks. Most tasks will offer a flat 
compensation for completion (typically $10). When required by the research, an additional variable 
payment will be added. This is essential for the scientific validity of some tasks that are designed to test 
brain responses to reward (e.g. decision-making tasks), on which reward must be tied to performance. 
Despite this constrain, we will guarantee the fairness of the tasks by having a minimum $10 payment for 
completion regardless of performance. Payment will be provided as a gift card after the end of the study. 
We will only provide compensation for non-military personnel. If patient is underage (<18 yo), payment will 
be provided to parents or legal guardians.

Costs: All costs associated with this study are paid for by research funds. The cost of macro-micro electrodes 
and study-specific cognitive testing will be provided by the study and not charged to the patient nor 
insurance. The patient’s surgery and other standard medical care including their stay in the EMU will be 
billed to the patient and or insurance.
6
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S)
6.1
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) ADMINISTRATION
6.1.1 STUDY INTERVENTION OR EXPERIMENTAL MANIPULATION DESCRIPTION
N/A.
6.2
LOST TO FOLLOW UP
This study does not involve any follow-up after completion.
6.3
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING
N/A.
6.4
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION ADHERENCE
N/A.
7
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
DISCONTINUATION OF STUDY INTERVENTION/EXPERIMENTAL MANIPULATION
N/A.
7.2
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY
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15
Participants are free to withdraw from participation in the study at any time upon request without penalty. Their 
withdrawal from the study will not affect their clinical care. If subjects withdraw from the research for whatever 
reason, the recorded data will be kept, unless specifically asked by the subject to be withdrawn. Patients can 
withdraw from the study at any time and for any reason.
8
STUDY ASSESSMENTS AND PROCEDURES
8.1
ENDPOINT AND OTHER NON-SAFETY ASSESSMENTS
The following non-safety assessments with take place as part of this study:
Screening and evaluation: After providing study-specific informed consent, potential participants will be formally 
evaluated for eligibility and study inclusion. Participants will provide demographics and contact information. Per the 
informed consent document, additional information will be collected from the electronic medical record, including 
diagnoses, current medications, medical / treatment history, neuroimaging studies (pre/postoperative MRI, CT), and 
others as applicable.
Assessment battery: participants may complete self-report cognitive and psychological assessments at each study 
visit (including for example scales of depression, apathy, anxiety, and obsessiveness/compulsivity such as the Beck 
Depression Inventory and Beck Anxiety Inventory). Each of these assessments takes approximately 5 minutes to 
complete, and this part of the study is anticipated no last more than 30 minutes. Additional disorder-specific 
assessments may be used at research visits to quantify clinical symptoms unique to each patient’s 
neuropsychological assessment.
If the suicide item of the DI questionnaire (question #9) is rated 2 or greater (regardless of total score), the study 
member will notify the PI, who will contact the referring physician within 24 hours. If any subject is in acute distress 
at the time of intake, their doctor will be contacted immediately, for care as needed.
Additional measures of psychopathology, affect, anhedonia, motivation, personality, and motor function may be 
performed when requested by a referring study PI or clinician. Assessments will be performed by a licensed clinical 
psychologist, physician, or trained member of the research staff in accordance with administration standards for 
each measure. These may be obtained from the electronic medical record if performed as part of routine care, if 
available.
Access to medical records: As part of recruitment and research efforts, the research team will review mental health 
and psychotherapy records prior to consent. This is necessary to identify patients who should be excluded from the 
study as per our inclusion/exclusion criteria, and also because this information will be important for the scientific 
validity of our findings. For example, co-morbid pathologies such as anxiety or depression, which are common in 
intractable epilepsy patients, can strongly affect behavior in some of the cognitive tasks and behaviors under 
examination, and knowing whether a previous diagnosis exists and its severity is essential for interpretation of the 
data.
8.2
SAFETY ASSESSMENTS
We will continue to track patient safety data as usual for all patients in the epilepsy monitoring unit. We maintain 
an electronic database in which we record complications. We will report any new information or safety events per 
Mount Sinai IRB.
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16
To protect participants against fatigue, frequent breaks will be offered during every session. Research sessions will 
be immediately interrupted for any health-care-related needs. Involved physician and nursing personnel, as well as 
the research team will carefully attend to the comfort of every participant. Participants will be made aware of their 
right to discontinue a session at any time, without repercussion. 
Provisions for Research Related Harm or Injury: The subject should promptly tell the person in charge of the research 
if they believe that they have been injured because of taking part in this study. If a subject is injured as a result of 
study participation, Mount Sinai will provide necessary medical treatment. Depending on the circumstances, the 
costs of the treatment may be covered by Mount Sinai Health System or may be billed to the insurance company 
just like other medical costs. Mount Sinai does not normally provide any other form of compensation for injury.  
8.3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
8.3.1
DEFINITION OF ADVERSE EVENTS
An adverse event (AE) is any untoward medical occurrence in a subject during participation in the clinical study or 
with use of the experimental agent being studied. An adverse finding can include a sign, symptom, abnormal 
assessment (laboratory test value, vital signs, electrocardiogram finding, etc.), or any combination of these.
A serious adverse event (SAE) is any adverse event that results in one or more of the following outcomes:

Death

A life-threatening event

Inpatient hospitalization or prolongation of existing hospitalization

A persistent or significant disability/incapacity

An important medical event based upon appropriate medical judgment
CLASSIFICATION OF AE SEVERITY
AEs will be labeled according to severity, which is based on their impact on the patient, using a 1-4 scale. An AE will 
be termed “mild” (1) if it does not have a major impact on the patient, “moderate” (2) if it causes the patient some 
minor inconvenience, “severe” (3) if it causes a substantial disruption to the patient’s well-being and “life-
threatening” (4) if it causes complications that can result in death.
8.3.1.1
RELATIONSHIP TO STUDY INTERVENTION/EXPERIMENTAL MANIPULATION
AEs will be categorized according to the likelihood that they are related to the study intervention using a 0-5 scale. 
Specifically, they will be labeled definitely unrelated (0), unlikely (1), potentially related (2), probably related (3) or 
definitely related (4) to the study intervention.

Definitely Unrelated (0) – The AE is completely independent of study procedures administration, and/or 
evidence exists that the event is definitely related to another etiology.

Unlikely to be related (1) – A clinical event, including an abnormal laboratory test result, whose temporal 
relationship to study procedures administration makes a causal relationship improbable (e.g., the event did 
not occur within a reasonable time after administration of the study procedures) and in which other drugs 
or chemicals or underlying disease provides plausible explanations (e.g., the participant’s clinical condition, 
other concomitant treatments). 
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17

Potentially Related (2) – There is some evidence to suggest a causal relationship (e.g., the event occurred 
within a reasonable time after administration of study procedures). However, other factors may have 
contributed to the event (e.g., the participant’s clinical condition, other concomitant events). Although an 
AE may rate only as “possibly related” soon after discovery, it can be flagged as requiring more information 
and later be upgraded to “probably related” or “definitely related”, as appropriate. 

Probably Related (3) – There is evidence to suggest a causal relationship, and the influence of other factors 
is unlikely. The clinical event, including an abnormal laboratory test result, occurs within a reasonable time 
after administration of the study procedures, is unlikely to be attributed to concurrent disease or other 
drugs or chemicals, and follows a clinically reasonable response on withdrawal. 

Definitely Related (4) – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test result, occurs 
in a plausible time relationship to study procedures administration and cannot be explained by concurrent 
disease or other drugs or chemicals. The response to withdrawal of the study procedures should be clinically 
plausible. The event must be pharmacologically or phenomenologically definitive.
8.3.2
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of study 
personnel during study visits and interviews of a study participant presenting for medical care, or upon review by a 
study monitor. All AEs, not otherwise precluded per the protocol, will be captured on the appropriate case report 
form (CRF). Information to be collected includes event description, time of onset, clinician’s assessment of severity, 
relationship to study procedures (assessed only by those with the training and authority to make a diagnosis), and 
time of resolution/stabilization of the event. All AEs occurring while on study will be documented appropriately 
regardless of relationship. All AEs will be followed to adequate resolution.
Any medical or psychiatric condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any time during the 
study, it will be recorded as an AE.  Changes in the severity of an AE will be documented to allow an assessment of 
the duration of the event at each level of severity to be performed. Documentation of onset and duration of each 
episode will be maintained for AEs characterized as intermittent.
The PI’s team will record events with start dates occurring any time after informed consent is obtained until the last 
day of participation in the hospital stay portion of the study.  Events will be followed for outcome information until 
resolution or stabilization.
8.3.3
ADVERSE EVENT REPORTING 
The PI will monitor the study for any AEs, although we do not anticipate any given the nature of the study. Adverse 
events will be documented by the research team and reported to the IRB using IRB communication channels. If 
action is deemed appropriate to ensure patient safety by the IRB following AE review, the research team will 
implement these changes in all future participants. In addition, if necessary (i.e. multiple AEs are reported) the PI 
and the research team will maintain a log of all AEs.
SAEs that are unanticipated, serious, and possibly related to the study intervention will be reported to the 
Independent Monitor and IRB in accordance with requirements.
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18

Unexpected fatal or life-threatening AEs related to the intervention will be reported within 7 days. Other 
serious and unexpected AEs related to the intervention will be reported within 15 days.

Unrelated SAEs will be handled in a less urgent manner but will be reported to the Independent Monitor, 
IRB and other oversight organizations in accordance with their requirements.
8.3.4
SERIOUS ADVERSE EVENT REPORTING 
In consultation with the PI, a trained member of the study team will be responsible for conducting an evaluation of 
a serious adverse event and shall report the results of such evaluation to the NIH and the reviewing Institutional 
Review Board (IRB) as soon as possible, but in no event later than 10 working days after the investigator first learns 
of the event.
DESIGNATION OF AN INDEPENDENT MONITOR
The Independent Monitor for this study is Dr. Sophia Ryan (Dept. of Neurology, Icahn School of Medicine). Dr. Ryan 
is not associated with this research project and thus works independently of the study team. Dr. Ryan is not a part 
of the key personnel involved in this project, and is qualified to review the patient safety data generated by this 
study because of her expertise in Neurology.
8.3.5
REPORTING EVENTS TO PARTICIPANTS 
N/A.
8.3.6
EVENTS OF SPECIAL INTEREST 
N/A.
8.3.7
REPORTING OF PREGNANCY 
N/A - pregnant women are excluded from the study.
9
STATISTICAL CONSIDERATIONS 
9.1
STATISTICAL HYPOTHESES
Primary endpoints: Investigate the neurophysiological correlates of human cognitive processes. We hypothesize that 
modulations in neural activity, as recorded by electrophysiological or electrochemical techniques, will be associated 
with different cognitive aspects of the behavioral tasks that the patients will complete. Specifically, we expect that 
cognitive brain functions will localize to a variety of brain areas, including temporal and prefrontal regions, with 
electrophysiologic signatures in the theta (4-8Hz) and high-gamma (70-200 Hz) frequency ranges. Scientists have 
theorized that cyclic changes in the brain’s electrical activity (brain oscillations) play a fundamental role in memory 
function. Studies have focused on the theta (slow) rhythm which oscillates in the 4-8Hz frequency range and high 
gamma activity which appears in the 70 to 200 Hz frequency range because these neural signatures appear 
prominently during a wide range of cognitive tasks and are hypothesized to be the cause of all neural activity - our 
thoughts, feelings and perceptions. The relationship between brain oscillations and neuronal activity is largely 
unexplained so our study aims to investigate the correlation between brain oscillations and the neuronal activity of 
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19
human cognition. We will also investigate the contribution and information processing capabilities of individual 
neurons.
Secondary endpoints: investigate the causal involvement of individual brain areas in cognitive processes through 
targeted electrical stimulation. We hypothesize that modulation of brain electrical activity through targeted 
stimulation will reversibly affect patient behavior. Specifically, we expect that stimulation of prefrontal cortical areas 
(i.e. orbitofrontal cortex) will result in changes in associated behavior (for example, in choices during decision-
making behavior) that will be sampled through behavioral tasks.
Tertiary endpoints: characterize the genetic and molecular composition of human brain tissue to reveal important 
information about genetic differences in epileptic tissue and correlate electrophysiological and molecular biological 
measures to brain function and clinical diagnoses. We hypothesize that there will be significant association between 
expression of individual genes (e.g. related to synaptic function such as neurotransmitter receptors, voltage-gated 
ion channels, GPCRs) and (1) clinical diagnosis (e.g. epilepsy type, psychiatric comorbidities) and (2) 
neurophysiological activity (e.g. theta [4-8Hz] or high-gamma [70-200 Hz] frequency power, oscillatory coherence, 
etc.) as recorded in the deep temporal lobe area prior to resection.
9.2
SAMPLE SIZE DETERMINATION
The primary analyses will compare the difference in neural activity at individual electrodes depending on behavioral 
or computational regressors or classifications. Based on previous studies, we expect sample sizes of 10-20 patients 
to be sufficient to examine activation in individual brain regions of interest. With an estimated average of 2-4 iEEG 
electrodes per region per patient, this will result in sample sizes of 20-80 electrodes. Given that prior studies show 
only a subset of electrodes is active in response to specific conditions of regressors, with activation rates ranging 
between 5-30%, a difference of 10 µV2/Hz in power activation in a specific frequency band (e.g. high gamma), this 
sample size will have >90% power to detect this difference using a two-sided test at ⍺=0.05.
Conversely, the main outcome measure for stimulation experiments will often be behavioral parameters, i.e. risk 
attitudes during decision-making tasks. Assuming a difference of 10 points in risk preferences (in line with prior 
results) scores, this sample size will have > 85% power to detect this difference using a two-sided test at ⍺=0.05.
9.3
POPULATIONS FOR ANALYSES
There is no patient segmentation, and all patients that complete a specific behavioral task will be included in 
analyses.
9.4
STATISTICAL ANALYSES
9.4.1
GENERAL APPROACH
To identify association between behavioral and neural metrics, we will use a regression approach where the 
dependent variable was defined as the analytic amplitude of the neural time series. For trial-based analyses, the 
neural time series is subsequently divided into event-related epochs, normally averaging neural activity using a 
rolling window at (e.g. 200ms width, with 50ms increments). To identity task-selective channels, we performed 
separate linear regressions of average neural activity on each behavioral regressor of interest. Given the inter-trial 
variability in response latencies, this analysis may be performed separately time-locked to each behavioral event of 
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20
interest (i.e. task presentation, patient response). We use the resulting R2 (variance in the neural data that can be 
explained by the behavioral regressors of interest, % explained variance, %EV) as a metric of the quality of the fit. 
This approach is insensitive with respect to time of task-related activation and to the direction of encoding (i.e., 
increases or decreases in neural activity). Electrodes will be classified as task active for any given regressor if they 
show a significant correlation (p < 0.05) at 5 or more consecutive time windows at any point during the epochs. False 
positive rate will be determined using a permutation strategy. For each regression, we will shuffle the relationship 
between behavioral labels and neural activity 1,000 times, and take the resulting distribution as the null for that 
particular regressor-electrode combination. In the case of single neuron analyses or voltammetry recordings, we will 
use the spiking activity or recorded neurotransmitter concentration as the variable of interest in a similar fashion.
In the case of multiple regressors of interest, we will verify that the encoding profile of individual electrodes is not 
affected by regressor collinearity, for example by using a stepwise regression model. In summary, the analysis for 
each electrode proceeded as follows: first, we will carry out multiple individual linear regressions for all regressors. 
To leverage the time profile of the signals without imposing restrictions on activation timing, an aggregate statistic 
was calculated as the sum of F-stats for the longest stretch of consecutive significant (linear regression p < 0.05) 
windows. We will repeat this procedure 10,000 times after shuffling the behavioral labels, and take the proportion 
of permuted fits with a sum-of-F-stat higher than that in the original dataset was taken as the permutation p value. 
This p value will be further corrected for multiple comparisons using a Bonferroni correction (across n electrodes); 
regressors that did not survive multiple comparisons will be considered not active. Subsequently, we will seek to 
identify the set of regressors that best explain neural activity variance by performing a model selection procedure 
on the surviving regressor set. We will first select the regressor that explains the most variance in the neural data 
(maximum peak %EV) as the base model, then create an alternative complex model by incorporating the second 
regressor that most improved the model. These two models will be compared using an ANOVA test; if the complex 
model results in a significantly improved fit (ANOVA p < 0.05), we will reject the basic model. This process will be 
iteratively repeated by adding new regressors, sorted by residual %EV improvement, until the model cannot be 
further improved (ANOVA p > 0.05). Finally, we will estimate the proportion of electrodes encoding each variable 
across all electrodes, regardless of the order in which they were incorporated into the model. To verify that the 
results were not driven by inter-subject or inter-electrode variability, we may conduct mixed-effects model analysis 
using the concatenated HFA for all electrodes as dependent variable, round-by-round regressors of interest (risk, 
regret, etc.) as fixed effects, and patient and electrode ID as nested mixed-effects. 
In the case of behavioral analyses (i.e. for secondary endpoints), behavioral metrics or latent model parameters will 
be estimated from the behavioral data. To compensate for potential variability across patient behavioral strategies 
and behavior, we will whenever possible employ a within-subject analysis by completing a baseline behavioral task 
pre-stimulation (either before or during hospital admission). If possible, we will also test for lingering behavioral 
effects by carrying out behavioral testing post-stimulation.
9.4.2
ANALYSIS OF THE PRIMARY ENDPOINT(S)
The main goal of the study is to understand the neurophysiological basis of human cognition. This will require 
integrated analysis of clinical, neurophysiological, anatomical, video and behavioral datasets.
Analysis of Electrophysiological Data: Some of the analysis will be performed at Mount Sinai, and some will be 
performed at collaborating sites. Any data sent to other sites will be de-identified. Typically, iEEG recordings are 
amplified x10000, analog filtered (0.01-1000 Hz) with > 1kHz digitization rate, re-referenced to a common average 
or bipolar reference scheme offline and high-pass filtered at 0.1-1 Hz with a symmetrical (phase true) finite impulse 
response (FIR) filter (35 dB/octave roll-off). Channels with a low signal-to-noise ratio (SNR) are identified and deleted 
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21
(i.e., 60 Hz line interference, electromagnetic equipment noise, amplifier saturation, poor contact with cortical 
surface). Additionally, channels are visually inspected by a neurologist or research team member to exclude epochs 
of aberrant or noisy activity (typically < 1% of data points). A photodiode recorded screen updates in the behavioral 
task, recorded in the electrophysiological system as an analog input and used to synchronize behavioral and 
electrophysiological data. In some cases, different synchronization (through an audio feed into an analog channel or 
through TTL pulses) may be carried out. Data analysis is carried out in MATLAB and R using custom scripts and 
electrophysiological analysis toolboxes (e.g. Fieldtrip). Data for each channel is down sampled to 1KHz and filtered 
into high-frequency activity (HFA; 70–200 Hz) using a two-way, zero phase-lag, finite impulse response band pass 
filter to prevent phase distortion. Alternatively, time-frequency representations are created using wavelets, or 
equivalent methods, using linearly or logarithmically spaced frequencies, which allows for comparisons between 
time-varying high-frequency and low-frequency signals on an equal footing. This is especially important for iEEG 
signals, which are generally nonstationary and have time-varying phase components. We will also measure 
coherence and phase synchronization to quantify the degree to which oscillatory effects are synchronized across 
brain regions.  
When analyzing physiological data recorded at many electrode sites for effects at many frequencies, it is necessary 
to correct for multiple comparisons. Using standard statistical methods, such as a t-test or a Wilcoxon rank-sum test, 
and setting an arbitrary p-value threshold for the significance of the difference between two conditions does not 
account for the possibly high number of false positives by chance. Therefore, to generate an unbiased empirical 
estimate of the Type I error rate, we will use a bootstrap procedure, a method often used to handle correlations 
among statistical comparisons of electrophysiological measures. The bootstrap procedure first entails generating a 
large number (>1000) of random samples of the experimental data by randomly swapping items from each of the 
categories being compared. The same randomization is used across electrodes to control for between-electrode 
correlations. By running the statistical tests on each of the shuffled datasets one generates a distribution of statistics 
from which one can then determine the statistical threshold that would achieve a given Type I error rate.  
Analysis of video data: A video recording of the patients will be obtained, either through the standard video-EEG 
procedure included as part of the standard of clinical care or through a dedicated research video camera in the same 
room. The video data may be analyzed to identify patient behavioral or mood states (e.g. sleep, awake, 
communication, laughing, etc.). These analyses will be carried out either by research personnel or using dedicated 
software. The resulting datasets will be kept in a secure location together with the electrophysiological and other 
data from the patient. 
Electrode Localization: For the proposed research, electrode locations are determined using co-registered 
postoperative CTs and preoperative MRIs by an indirect stereotaxic technique (Talairach & Tournoux, 1988). After 
normalization, locations can be reported by means of stereotaxic (Talairach) coordinates. This format uses three 
numbers (X, Y, Z) to describe the distance from the Anterior Commissure (the “origin” of Talairach space). The X, Y, 
Z dimensions refer to left- right, posterior-anterior, and ventral-dorsal, respectively (i.e., 38 X 64 X 58 mm refers to 
a point in the right-posterior-dorsal region of the brain). Region-of-interest analyses can be conducted and better 
compared across participants by normalizing the brain using Talairach coordinates. The Talairach atlas serves as a 
reference so that one may know what region of the “idealized” brain is being described. These techniques are 
commonly used at Mount Sinai now and may aid in clinical patient care by providing accurate anatomical localization 
for individual electrodes.
9.4.3
ANALYSIS OF THE SECONDARY ENDPOINT(S)
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22
The secondary endpoints will involve analysis of behavioral modulation resulting from electrical modulation of 
neuronal activity. As such, they will be task specific, but in most instances this will entail estimation of a behavioral 
(for example, proportion of remembered items in a memory task) or computational (derived from behavior through 
the application of computational models) metric of interest in pre-stimulation (baseline) and stimulation conditions. 
We will carry out within-patient comparisons to account for inter-patient variability, and in most instances will carry 
out two-tailed statistical tests (e.g. two-tailed t-test) to compare individual behavioral/computational estimates.
9.4.4
ANALYSIS OF THE TERTIARY ENDPOINT(S)
The tertiary endpoints will involve analysis of genetic expression data and comparison across comorbidities or 
electrophysiological features of interest. For example, we will plan to examine differences in genetic expression 
profiles across depression comorbidity status (e.g. depressed/non-depressed) and severity (e.g. Beck Depression 
Inventory score). We will perform multivariate analyses between transcriptomic expression data and clinical scores 
or electrophysiological features (e.g. individual frequency band oscillatory power) as appropriate and use 
permutation/bootstrapping methods to assess statistical significance.
9.4.5
SAFETY ANALYSES
N/A.
9.4.6
BASELINE DESCRIPTIVE STATISTICS
For all analyses, we will keep track of the patients’ demographic information (age, sex, handedness, neuropsychiatric 
test results) and include these as covariates in analyses as necessary.
10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS
10.1.1 INFORMED CONSENT PROCESS
EMU subjects will be approached prior to surgery or upon arrival in the epilepsy monitoring unit and will be informed 
that they will receive the same standard of care whether or not they choose to participate in the research. Patients 
who consent upon arrival to the EMU will not be eligible to participate in the microelectrode portion of the study 
because their electrodes would have been already placed at that point but could participate in the other portions of 
the study. Informed consent will be obtained from all participants. The subjects will be asked to consent to the 
following (note: patients can consent to one or more of these portions, without consenting to all of them): 

Collection of electroencephalographic (EEG) and invasive EEG (iEEG), Radiology Studies and Clinical history.

Cognitive testing.

Use of Microelectrodes in addition to standard electrodes. 

Brain stimulation mapping in addition to what is required clinically. 

Use of resected tissue.
 Non-English speaking patients will only be allowed to participate in the presence of a translator.
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23
10.1.1.1 CONSENT/ASSENT 
AND 
OTHER 
INFORMATIONAL 
DOCUMENTS 
PROVIDED 
TO 
PARTICIPANTS
Research staff will communicate with treating clinicians/ISMMS researchers to inform them about the protocol, who 
will identify potential participants and ascertain his/her interest in the study. Individuals who are potentially eligible 
(see Inclusion-Exclusion criteria) and agree to consider participating in the study will be consented by a member of 
the research team. All personnel involved in recruitment will have undergone all appropriate HIPAA and CITI training, 
as per institutional policy. 
Participant Screening: If an individual is interested in pursuing study participation, he/she would be invited to meet 
with the research team, provide written informed consent, and be formally evaluated for study inclusion. Study 
inclusion/exclusion criteria will be reviewed with participants. Patients will provide demographics and contact 
information, a list of current medications, and information regarding his/her epilepsy status. In addition, this 
information may be retrieved from the participant’s medical record, as well as previous neuroimaging studies 
(pre/postoperative MRI, CT) and neuropsychological assessment. Subjects will only be consented by study staff who 
are not providing clinical care, to avoid undue pressure to participate. All personnel involved in evaluation and 
enrollment will have undergone all appropriate HIPAA and CITI training. 
This study will only enroll patients who have the capacity to provide informed consent. Capacity to consent will be 
made by the individual conducting the informed consent discussion with the participant. If a subject cannot comply 
with the consent process or there is a question on the part of the assessor as to the fitness of the individual to 
participate in the research as prescribed, the subject will be excluded from study participation and not be permitted 
to sign the informed consent document. In the case of underage (<18) iEEG patients, assent will be obtained from 
the participant and consent from at least one parent. 
This protocol will not exclude participants based upon race nor sex/gender. Patients will have to exhibit English 
language proficiency; otherwise, a qualified translator (i.e. a bilingual member of the research team, or a qualified 
translator) must be present for consent and all study procedures. In this case, study assessments will be presented 
in the relevant language.
Consent forms describing in detail the study intervention, study procedures, and risks will be given to the participant 
and written documentation of informed consent will be completed prior to starting the study intervention.  The 
following consent materials are submitted with this protocol:

Consent form for adult patients (>18 years of age).

Consent form for underage patients’ parents or legal guardians. (<18 years of age).
10.1.2 STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. Written 
notification, documenting the reason for study suspension or termination, will be provided by the suspending or 
terminating party to the funding agency. If the study is prematurely terminated or suspended, the Principal 
Investigator (PI) will promptly inform study participants, the Institutional Review Board (IRB), and sponsor/funding 
agency and will provide the reason(s) for the termination or suspension. Study participants will be contacted, as 
applicable, and be informed of changes to study visit schedule. Circumstances that may warrant termination or 
suspension include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to participants   
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24

Insufficient compliance of study staff to the protocol (i.e., significant protocol violations)

Data that are not sufficiently complete and/or evaluable
The study may resume once concerns about safety, protocol compliance, and data quality are addressed, and satisfy 
the funding agency, sponsor, IRB, Food and Drug Administration (FDA), or other relevant regulatory or oversight 
bodies (OHRP, DSMB).
10.1.3 CONFIDENTIALITY AND PRIVACY 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, the safety 
and oversight monitor(s), and the sponsor(s) and funding agency. This confidentiality is extended to the data being 
collected as part of this study. Data that could be used to identify a specific study participant will be held in strict 
confidence within the research team. No personally-identifiable information from the study will be released to any 
unauthorized third party without prior written approval of the sponsor/funding agency. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor or funding agency, representatives of the 
Institutional Review Board (IRB), regulatory agencies or representatives from companies or organizations supplying 
the product, may inspect all documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
clinical study site will permit access to such records.
The study participant’s contact information will be securely stored at each clinical site for internal use during the 
study. At the end of the study, all records will continue to be kept in a secure location for as long a period as dictated 
by the reviewing IRB, Institutional policies, or sponsor/funding agency requirements.
Some study participant research data, which is for purposes of statistical analysis and scientific reporting, may be 
transmitted to and stored at NIH repositories. This will not include the participant’s contact or identifying 
information. Rather, individual participants and their research data will be identified by a unique study identification 
number. The study data entry and study management systems used by clinical sites and by NIH research staff will be 
secured and password protected.
Measures Taken to Ensure Confidentiality of Data Shared per the NIH Data Sharing Policies: it is NIH policy that the 
results and accomplishments of the activities that it funds should be made available to the public 
(see https://grants.nih.gov/policy/sharing.htm). The PI will ensure all mechanisms used to share data will 
include proper plans and safeguards for the protection of privacy, confidentiality, and security for data dissemination 
and reuse (e.g., all data will be thoroughly de-identified and will not be traceable to a specific study participant). 
Plans for archiving and long-term preservation of the data will be implemented, as appropriate. 
Certificate of Confidentiality: to further protect the privacy of study participants, the Secretary, Health and Human 
Services (HHS), has issued a Certificate of Confidentiality (CoC) to all researchers engaged in biomedical, behavioral, 
clinical or other human subjects research funded wholly or in part by the federal government.  Recipients of NIH 
funding for human subjects research are required to protect identifiable research information from forced disclosure 
per the terms of the NIH Policy (see https://humansubjects.nih.gov/coc/index). As set forth in 45 CFR Part 
75.303(a) and NIHGPS Chapter 8.3, recipients conducting NIH-supported research covered by this Policy are 
required to establish and maintain effective internal controls (e.g., policies and procedures) that provide reasonable 
assurance that the award is managed in compliance with Federal statutes, regulations, and the terms and conditions 
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25
of award. It is the NIH policy that investigators and others who have access to research records will not disclose 
identifying information except when the participant consents or in certain instances when federal, state, or local law 
or regulation requires disclosure. NIH expects investigators to inform research participants of the protections and 
the limits to protections provided by a Certificate issued by this Policy.
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA 
Data collected for specific tasks in this study will be analyzed and stored at the NIMH Data Archive (NDA). After the 
study is completed, the de-identified, archived data will be transmitted to and stored at the NDA, for use by other 
researchers including those outside of the study. Permission to transmit data to research repositories will be 
included in the informed consent.
If tissue resection analyses are carried out, the resected biological tissue will be stored until the molecular and 
genetic characterization is carried out (typically 2-3 weeks).
10.1.5 KEY ROLES AND STUDY GOVERNANCE
Principal Investigator
Ignacio Saez, PhD
Academic Title: Assistant Professor
Department: Neuroscience, Neurosurgery, and Neurology
Mailing Address: 1000 10th Ave. Rm 10- 41A NY, NY 
Phone: 212-523-8278
Email: ignacio.saez@mssm.edu
Co-Investigator
Helen Mayberg, MD
Academic Title: Professor
Department: Neurology, Neurosurgery, Neuroscience, Nash Family Center 
for Advanced Circuit Therapeutics
Mailing Address: 
Phone: 212-523-8276
Email: helen.mayberg@mssm.edu
Co-Investigator
Fedor Panov, MD 
Academic Title: Associate Professor 
Department: Neurosurgery
Mailing Address:  1000 10th Ave, Suite 10G-80
Phone: (212) 636-3240
Fax: (212) 523-6115
Email:  fedor.panov@mountsinai.org
Co-Investigator
Lara V. Marcuse, MD 
Academic Title: Associate Professor
Department: Neurology
Mailing Address: 1 Gustave L. Levy Place, Box 1052 NY,NY
Phone: 212-241-2627
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26
Fax: 646-537-9690
Email: lara.marcuse@mssm.edu
Co-Investigator
Saadi Ghatan, MD 
Academic Title: Professor of Neurosurgery & Pediatrics
Department: Neurosurgery (Site Chair)
Mailing Address: 1000 10th Ave, 10G
Phone: 212-636-3233
Email: saadi.ghatan@mountsinai.org
Co-Investigator
Madeline Fields, MD 
Academic Title: Associate Professor
Department: Neurology
Mailing Address: 1 Gusttave L. Levy Place, Box 1052, NY, NY
Phone: 212-241-2627
Fax: 646-537-9690
Email: madeline.fields@mssm.edu
Co-Investigator
Ki Sueng Choi, MD 
Academic Title: Assistant Professor
Department: Diagnostic, Molecular and Interventional Radiology 
Mailing Address: 1000 10th Ave, Rm 10G-41
Phone: 212-523-8756
Email: kisueng.choi@mssm.edu
Co-Investigator
Martijn Figee, MD, PhD
Academic Title: Associate Professor 
Department: Psychiatry, Neurosurgery, Neurology, Neuroscience
Mailing Address: 1000 10th Ave, Rm 10G-44
Phone: 212-523-8681
Email: martijn.figee@mssm.edu
Co-Investigator
Stephen Heisig
Academic Title: Research Scientist
Department: Neurology
Mailing Address: 
Phone: 914-310-2744
Email: stephen.heisig@mssm.edu
Co-Investigator
Shannon O’Neill, PhD 
Academic Title: Assistant Professor
Department: Psychiatry
Mailing Address: 1000 10th Ave, 10G-44A
Phone: 212-523-6449
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27
Email: shannon.oneill@mountsinai.org
Co-Investigator
Allison Waters, PhD 
Academic Title: Assistant Professor 
Department: Psychiatry, Neuroscience
Mailing Address: 1000 10th Ave, 10-42
Phone: 212-523-8832
Email: allison.waters@mssm.edu
Co-Investigator
James Young, MD, PhD
Academic Title: Assistant Professor
Department: Neurology
Mailing Address: Annenberg Building, 1468 Madison Ave, 2, 210
Phone: 212-241-2627
Fax: 646-537-9690
Email: james.young@mssm.edu
Co-Investigator
Xiaosi Gu, PhD 
Academic Title: Associate Professor
Department: Psychiatry, Neuroscience
Mailing Address: Mount Sinai Doctors Long Is. 55 W 125th St, 13, 1302
Phone: 212-585-4670
Email: xiaosi.gu@mssm.edu
Co-Investigator
Daniela Schiller, PhD 
Academic Title: Associate Professor 
Department: Psychiatry, Neuroscience
Mailing Address: Hess CSM Building, 1470 Madison Ave, 9, 111
Phone: 212-824-8977
Email: daniela.schiller@mssm.edu
Co-Investigator
Peter H. Rudebeck, PhD 
Academic Title: Associate Professor
Department: Neuroscience, Psychiatry
Mailing Address: Hess CSM Building, 1470 Madison Ave, 10, 112
Phone: 212-824-9307
Email: peter.rudebeck@mssm.edu
Co-Investigator
Erin L. Rich, MD, PhD
Academic Title: Associate Professor
Department: Neurosciences
Mailing Address: Hess CSM Building, 1470 Madison Ave, 10,115
Phone: 212-824-9304
Email: erin.rich@mssm.edu
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28
Additional Research Personnel: Research staff affiliated with this protocol have combined expertise in neuroimaging 
analysis, biomedical engineering (signal processing, hardware development, software programming), iEEG and single 
neuron data collection and analysis, diagnostic and clinical assessments of neurological and psychiatric populations, 
and clinical trial development and administration. In addition, the current research team has developed methods to 
acquire, manage, and analyze data collected specifically from individuals with implanted invasive electrodes. 
Assurance of Staff Familiarity with the Protocol: While conducting research under this protocol, all members of the 
research team participating in this study must have complete and up-to-date Collaborative IRB Training Initiative 
(CITI) and HIPPA training, and all must be familiar with relevant study procedures and documents commensurate 
with his/her role on the project. Further, weekly C-ACT laboratory and clinical meetings will include thorough 
discussion of pertinent study-related issues, and the multidisciplinary, team-based approach to research and clinical 
matters which is the foundation of the Center will ensure continuity of care and additional monitoring of subjects 
for potential adverse events.
10.1.6 SAFETY OVERSIGHT
Study will be monitored internally by clinician members of the study team. As an added precaution, we will have an 
independent Medical Research Monitor available for consultation and safety oversight. As Medical Research 
Monitor, Dr. Sophia Ryan will be available for consultation to provide expert medical recommendations in case of 
any serious adverse events. Dr. Ryan is a trained Neurologist, Chief of Inpatient General Neurology and Medical 
Director of Quality and Safety at Mount Sinai West Hospital. Dr. Ryan is independent of the research team and she 
will promptly report any adverse events to the IRB. Additionally, Dr. Ryan will also review the case details of any 
adverse event and determine whether any modifications to the protocol are needed in order to further minimize 
risks.
10.1.7 CLINICAL MONITORING
Study will be monitored internally by clinician members of the study team.
10.1.8 DATA HANDLING AND RECORD KEEPING 
We will maintain appropriate medical and research records for this trial, in compliance with ICH GCP and regulatory 
and institutional requirements for the protection of confidentiality of participants. As part of participating in a NIH-
sponsored or NIH-affiliated study, we will permit authorized representatives of the NIH, sponsor, and regulatory 
agencies to examine (and when permitted by applicable law, to copy) clinical records for the purposes of quality 
assurance reviews, audits, and evaluation of the study safety, progress, and data validity.
10.1.8.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
De-identified intracranial and/or scalp EEG data, radiology studies, pathology reports, cognitive testing results, video 
recordings, Epilepsy Surgical Conference notes, Operative notes and Tissue samples (if resections are carried out) 
will be obtained. All data will be stripped of identifying information and stored with an identifier as a reference. 
Names and participant numbers will only appear together on a single list stored in a password-protected file, and 
will only be accessible to the research team. Access to all files is and will continue to be restricted to the Principal 
Investigator and the research team.
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29
How Media Will Be Stored to Ensure Confidentiality: the data will be stored securely on encrypted servers behind 
the Mount Sinai firewall, which comply with all applicable Mount Sinai policies and procedures including HIPPA and 
IT data integrity and security. Data and PHI accessed from local workstations are within the Mount Sinai network 
and are housed behind the institutional firewall. Remote access from offsite will employ VPN. All other personal 
identifying information (e.g. participant name, medical record number, etc.) will be removed from audiovisual data. 
Video recordings will only be identified by study-specific subject ID. However, as videos will include full face images 
of research participants, it is not possible to fully de-identify this media. This risk to participant privacy is clearly 
conveyed to potential research subjects in the informed consent document.  
How PHI will be protected from improper use or disclosure: all PHI, including subject audiovisual recordings, will be 
stored in secured locations. Electronic PHI will be kept stored on a physically secured server in a password protected 
database which adheres to all Mount Sinai data security standards. Access to PHI will be limited to research staff and 
collaborators who require this information to conduct study-related tasks and data analyses. Data will be coded and 
identified only by study-specific ID. Information containing PHI, including audiovisual recordings, will be stored 
separately from other deidentified research data. The code which links study ID with patient identity via direct 
identifiers will be stored separately from other study data in a physically and/or electronically secure location, with 
access limited to certain research staff requiring this information to ensure quality of clinical care, regulatory 
compliance, and research operations.  
Steps that will be taken to secure the data during storage, use, and transmission: whenever possible, PHI will be 
separated from other data, and deidentified data will be accessed by study personnel or transmitted to study 
collaborators who do not require personal identifiers to perform protocol-related activities. Data transmitted 
outside of the Mount Sinai network will be encrypted. When not in use, data, including PHI, will be kept in locked 
files in the C-ACT offices. Data will be accessed from password protected workstations and servers, which have been 
configured to limit physical and electronic access by unauthorized persons.  
10.1.8.2 STUDY RECORDS RETENTION 
PHI (research/HIPAA records) will be stored for 6 years after the close of the study (per the Mount Sinai Investigator 
Manual). De-identified data will be stored indefinitely. If patients elect to withdraw from the study, they will be 
advised that information already collected in the study may not be removed from the research study database and 
will continue to be used to complete the research analysis. Patients may also withdraw permission for the use and 
disclosure of any protected information for research purposes by notifying the Principal Investigator in writing. 
However, the Principal Investigator may still use the information that was already collected if that information is 
necessary to complete the research study and/or data analyses. This is conveyed to potential participants in the 
study informed consent document.  
Tissue samples will be kept until the molecular analysis are carried out, typically a few days and no more than a 
month. The techniques we are proposing are destructive, so the tissue will be destroyed during experimentation.
10.1.9 PROTOCOL DEVIATIONS  
The PI will monitor the study for any adverse events (AEs), although we do not anticipate any given the nature of 
the study. Adverse events will be documented by the research team and reported to the IRB using IRB 
communication channels. If action is deemed appropriate to ensure patient safety by the IRB following AE review, 
the research team will implement these changes in all future participants.
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30
In addition, if necessary (i.e. multiple AEs are reported) the PI and the research team will maintain a log of all AEs 
using the format specified in Appendix (AE log table).
SAEs that are unanticipated, serious, and possibly related to the study intervention will be reported to the 
Independent Monitor and IRB in accordance with requirements:

Unexpected fatal or life-threatening AEs related to the intervention will be reported within 7 days. Other 
serious and unexpected AEs related to the intervention will be reported within 15 days.

Unrelated SAEs will be handled in a less urgent manner but will be reported to the Independent Monitor, 
IRB and other oversight organizations in accordance with their requirements.
10.1.10
PUBLICATION AND DATA SHARING POLICY 
This study will be conducted in accordance with the following publication and data sharing policies and regulations:
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the published 
results of NIH funded research. It requires scientists to submit final peer-reviewed journal manuscripts that arise 
from NIH funds to the digital archive PubMed Central upon acceptance for publication. This study will comply with 
the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical 
Trials Registration and Results Information Submission rule. As such, data from tasks classified as clinical trials will 
be registered at ClinicalTrials.gov, and results from this trial will be submitted to ClinicalTrials.gov. In addition, every 
attempt will be made to publish results in peer-reviewed journals.  Data from this study may be requested from 
other researchers 5 years after the completion of the primary endpoint by contacting PI Saez.  Considerations for 
ensuring confidentiality of these shared data are described in Section 10.1.3.
10.1.11
CONFLICT OF INTEREST POLICY
Dr. Fedor Panov (a co-investigator in this study) receives financial compensation as a lecturer for Zimmer, the 
company that manufactures the device used to implant the intracranial electroencephalogram (EEG). Dr. Panov also 
receives financial compensation as a lecturer for Neuropace, a company that manufactures implantable devices used 
in the treatment of epilepsy.
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31
10.2 PROTOCOL AMENDMENT HISTORY
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page. 
Version
Date
Description of Change 
Brief Rationale
2
3 April 2025
The protocol has been modified to 
include collection of resected tissue 
samples from patients who undergo 
resective surgery. Additionally, 
approved stimulation hardware has 
been expanded to include an 
equivalent research device (e.g. 
ATLAS Stim Headbox - High Density, 
part number: 31-0601-0132).
Collection and molecular 
analysis of resected tissue 
would offer unique possibilities 
to characterize the genetic and 
molecular composition of 
human brain tissue, which 
could reveal important 
information about genetic 
differences in epileptic tissue, 
and allow correlating 
electrophysiological and 
molecular biological measures. 
Inclusion of additional 
stimulation hardware would 
streamline the stimulation 
research protocol. 
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32
11
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