A Randomized Controlled Pilot Study of TMS Enhancement of Associative Memory Networks in Healthy Subjects and Epilepsy Patients
Phase: NA
Conditions: Epilepsy
Sponsor: NYU Langone Health

 
 
Official Title: 
A Randomized Controlled Pilot Study of TMS Enhancement of 
Associative Memory Networks in Healthy Subjects and Epilepsy 
Patients   
NCT Number: 
NCT02749422 
Study Number: 
15-00732 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
• 
June 6, 2017  
 
 

 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
 
 
 
 
 
TITLE: 
 
A randomized controlled pilot study of TMS enhancement of associative memory networks in healthy 
subjects and epilepsy patients. 
 
Principal Investigator:   
         Anli Liu MD MA 
Assistant Professor of Neurology 
NYU School of Medicine 
Comprehensive Epilepsy Center 
223 East 34th Street 
New York, NY 10016 
 
Co-Principal Investigator:  
        Heath Pardoe PhD 
        Assistant Professor of Neurology 
        NYU School of Medicine 
        Comprehensive Epilepsy Center 
        223 East 34th Street 
        New York, NY 10016 
 
NYU Co-Investigators:   
        Ruben Kuzniecky MD  
        Professor of Neurology 
        NYU School of Medicine 
        Comprehensive Epilepsy Center 
        223 East 34th Street 
        New York, NY 10016 
 
 
        Daniel Friedman MD 
 
        Assistant Professor of Neurology 
        NYU School of Medicine 
        Comprehensive Epilepsy Center 
        223 East 34th Street 
        New York, NY 10016 
 
        Orrin Devinsky MD  
        Professor of Neurology 
        NYU School of Medicine 
        Comprehensive Epilepsy Center 
        223 East 34th Street 
        New York, NY 10016 
 
 
 
 
 
       Milton Biagioni, MD 
NYU School of Medicine, Department of Neurology - Division of 
Movement Disorders  
Assistant Professor, Research 
240 East 38th Street, 20th Floor 
New York, NY 10016 
Clinical Research 

A randomized controlled pilot study of TMS enhancement of associative memory networks in healthy 
subjects and epilepsy patients. 
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Phone: 212-263-4838 
Fax: 212-263-7721 
 
Anita Shankar, MA 
NYU School of Medicine 
        Comprehensive Epilepsy Center 
        223 East 34th Street 
        New York, NY 10016 
 
 
 
 
 
       Hamzeh Migdadi, MD 
NYU School of Medicine, Department of Neurology - Division of 
Movement Disorders  
Assistant Professor, Research 
240 East 38th Street, 20th Floor 
New York, NY 10016 
 
 
Funding Sponsor: 
FACES 
Study Product: 
Magstim Rapid 2 
Protocol Number: 
s15-00732 
IDE Number: 
n/a 
 
 
Initial version: 11/16/2015 
Amended: 
05/25/2016 
Amended: 
06/22/2016 
Amended: 
09/26/2016 
Amended: 
03/30/2017 
Amended:  
05/11/2017 
Amended: 
05/19/2017 
 
 

A randomized controlled pilot study of TMS enhancement of associative memory networks in healthy 
subjects and epilepsy patients. 
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authorized in writing by the study sponsor 
 
 
Table of Contents 
 
STUDY SUMMARY ..............................................................................................................................5 
1 
INTRODUCTION ............................................................................................................................2 
1.1 
BACKGROUND ..................................................................................................................................... 2 
1.2 
TMS.................................................................................................................................................. 2 
1.3 
RESEARCH RISKS & BENEFITS ................................................................................................................. 3 
1.4.1 
Risks of Device ......................................................................................................................... 3 
1.4.2 
Other Risks of Study Participation ........................................................................................... 4 
1.4.3 
Potential benefits ..................................................................................................................... 4 
2 
STUDY OBJECTIVES .......................................................................................................................4 
2.1 
PRIMARY OBJECTIVE ............................................................................................................................. 4 
2.2 
SECONDARY OBJECTIVE(S) ..................................................................................................................... 4 
3 
STUDY DESIGN AND PROCEDURES ................................................................................................5 
3.1 
GENERAL DESIGN ................................................................................................................................. 5 
3.2 
PRIMARY STUDY ENDPOINTS.................................................................................................................. 6 
3.3 
SECONDARY STUDY ENDPOINTS.............................................................................................................. 6 
4 
SUBJECT SELECTION AND WITHDRAWAL .......................................................................................7 
4.1 
INCLUSION CRITERIA ............................................................................................................................. 7 
4.2 
EXCLUSION CRITERIA ............................................................................................................................ 8 
4.3 
SUBJECT RECRUITMENT AND SCREENING ................................................................................................. 8 
4.4 
EARLY WITHDRAWAL OF SUBJECTS ......................................................................................................... 8 
4.4.1 
When and How to Withdraw Subjects .................................................................................... 8 
5 
STUDY DEVICE ..............................................................................................................................9 
5.1 
DESCRIPTION ...................................................................................................................................... 9 
5.2 
TREATMENT REGIMEN .......................................................................................................................... 9 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ..................................................................... 9 
5.4 
IMPLANTATION OF STUDY DEVICE ........................................................................................................... 9 
5.5 
PRIOR AND CONCOMITANT THERAPY .................................................................................................... 10 
5.6 
RECEIVING, STORAGE, DISPENSING AND RETURN .................................................................................... 10 
5.6.1 
Receipt of Study Device ......................................................................................................... 10 
5.6.2 
Storage ................................................................................................................................... 10 
6 
STATISTICAL PLAN ...................................................................................................................... 10 
7.1 
SAMPLE SIZE DETERMINATION ............................................................................................................. 10 
7.2 
STATISTICAL METHODS ....................................................................................................................... 10 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ................................................................................................ 10 
7 
SAFETY AND ADVERSE EVENTS ................................................................................................... 10 
7.1 
DEFINITIONS ..................................................................................................................................... 10 
7.2 
RECORDING OF ADVERSE DEVICE EFFECTS .............................................................................................. 11 
7.3 
REPORTING OF ADVERSE DEVICE EFFECTS AND UNANTICIPATED PROBLEMS................................................. 11 
7.3.1 
Investigator reporting: Notifying the study sponsor ............................................................. 11 
7.3.2 
Investigator reporting: Notifying the IRB ............................................................................... 12 
7.4 
STOPPING RULES ............................................................................................................................... 13 
7.5 
MEDICAL MONITORING ...................................................................................................................... 13 
7.5.1 
Data Monitoring Committee .................................................................................................. 14 

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8 
DATA HANDLING AND RECORD KEEPING .................................................................................... 14 
8.1 
CONFIDENTIALITY ............................................................................................................................... 14 
8.2 
SOURCE DOCUMENTS ......................................................................................................................... 15 
8.3 
CASE REPORT FORMS ......................................................................................................................... 15 
8.4 
RECORDS RETENTION ......................................................................................................................... 15 
9 
STUDY MONITORING, AUDITING, AND INSPECTING................................................................... 15 
9.1 
STUDY MONITORING PLAN ................................................................................................................ 15 
9.2 
AUDITING AND INSPECTING ............................................................................................................... 15 
10 
ETHICAL CONSIDERATIONS ....................................................................................................... 16 
11. STUDY FINANCES ...................................................................................................................... 16 
11.1 
FUNDING SOURCE ............................................................................................................................ 16 
11.2 
CONFLICT OF INTEREST ..................................................................................................................... 16 
12 
PUBLICATION PLAN .................................................................................................................. 16 
14 
REFERENCES ............................................................................................................................. 17 
 
 
 

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List of Abbreviations 
 
EEG – electroencephalography 
 
TMS-Transcranial Magnetic Stimulation 
 
fMRI – functional magnetic resonance imaging 
 
 
Study Summary 
Title 
A randomized controlled pilot study of TMS enhancement of associative 
memory networks in healthy subjects and epilepsy patients. 
 
Protocol Number 
s15-00732 
Methodology 
Randomized, single-blinded, controlled phase 1 trial 
Study Duration 
2 years 
Study Center(s) 
NYU Langone Medical Center 
 
Objectives 
To explore whether rTMS, guided by fMRI based resting state networks, can 
be a safe and effective method of enhancing associative memory 
performance. 
Number of Subjects 
20 healthy subjects 
20 Temporal Lobe epilepsy patients 
Diagnosis and Main 
Inclusion Criteria 
Healthy subjects will be 1) 18-40 years, 2) fluent in English, 3) be right-
handed, 4) Score at least 26 out of 30 on the Montreal Cognitive Assessment 
(MOCA), and 5) be able to provide informed consent.  
 
Epilepsy subjects will be 1) 18 - 40 yrs,  2) fluent in English,  3) Right-handed, 
4) Score at least 26 out of 30 on the Montreal Cognitive Assessment 
(MOCA). Healthy subjects will be matched to age, handedness, and 
education compared to epilepsy subjects. 5) Must be able to provide 
informed consent, 6) Demonstrate evidence of verbal memory dysfunction, 
7) Have TLE, and 8) Well controlled epilepsy. 
Study Product and 
Planned Use 
MagStim RapidStim2 
 
 
 
Reference therapy 
No currently available therapy 

A randomized controlled pilot study of TMS enhancement of associative memory networks in healthy 
subjects and epilepsy patients. 
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Statistical 
Methodology 
The primary outcome measure will be improvement in an associated 
memory task (verbal word pairs).  A secondary outcome measure will be 
increased fMRI-based functional connectivity between the hippocampus and 
cortical regions. Changes in hippocampal-cortical functional connectivity will 
be identified using voxel-wise paired T-tests (pre-post TMS).  
 

A randomized controlled pilot study of TMS enhancement of associative memory networks in healthy 
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1 
INTRODUCTION 
1.1 
Background 
Memory difficulty, slowed processing, and attention deficits are the most common complaints of epilepsy 
patients (Dodrill 2004).  Current models of cognitive dysfunction rely mostly on patients with mesial 
temporal lobe epilepsy (TLE) and suggest that deficits are widely distributed.  TLE affects not only memory, 
but also intelligence quotient, executive functions, language, and sensorimotor function (Oyegbile, Dow 
et al. 2004, Hermann, Lin et al. 2009). Similarly, instead of localized brain changes, functional and 
structural MRI reveal that these patients display widespread dysfunction and atrophy in the bilateral 
frontal, temporal, and parietal lobes, as well as the thalamus, basal ganglia, and cerebellum (Dabbs, Jones 
et al. 2009, Meador and Hermann 2010, Vlooswijk, Jansen et al. 2010).  However, it is unclear whether 
treating more transient variables, such seizure frequency and interictal activity, plays a role in improving 
cognition (Aldenkamp and Arends 2004, Aldenkamp, Arends et al. 2010). 
 
Our current therapies for these cognitive comorbidities are limited.  Currently there are no proactive 
means of addressing memory dysfunction.  Many anti-epileptic medications have undesirable mood and 
cognitive side effects.  Many anti-depressants interact with anti-epileptic medications, have undesirable 
side effects, take a significant amount of time to reach therapeutic effect, or may themselves lower the 
seizure threshold.  Finding safe, alternative methods of addressing the affective and cognitive aspects of 
epilepsy is therefore of tremendous clinical significance. 
 
This project seeks to develop a technology with significant therapeutic potential for memory remediation: 
non-invasive transcranial magnetic stimulation (TMS).  A recent study demonstrated that targeted TMS 
increased functional connectivity among cortical-hippocampal networks in healthy subjects (Wang, Rogers et 
al. 2014). Moreover, the enhancements of connectivity correlated with improved memory performance.  We 
propose to extend these findings to a clinically-relevant population; specifically, to develop an intervention 
(repetitive TMS) and approach (resting state fMRI guided) that could be used for memory remediation in 
epilepsy patients. 
 
This will be a randomized, controlled, and single-blinded cross-over pilot study. The purpose of this study 
is to demonstrate feasibility and explore the neurophysiologic and clinical effects of repetitive transcranial 
magnetic stimulation (TMS) interventions in epilepsy patients and healthy controls. The inclusion of a 
control group will be used to see whether epilepsy patients, who suffer from a higher degree of comorbid 
memory difficulty presumably from entorhinal-hippocampal dysfunction, can benefit from a TMS 
intervention can benefit as much as a healthy matched population.  
1.2 
TMS. 
Transcranial Magnetic stimulation (TMS) is a non-invasive method of neurostimulation and 
modulation, in which an applied magnetic field may induce a secondary electric field in the brain.  
The field may be of sufficient magnitude and density to depolarize neurons; when TMS is applied 
in repetitive trains (rTMS), modulation of cortical excitability can occur beyond the duration of the 
train of stimulation. 
 
The Magstim Rapid2 used to produce rTMS in this study is considered a nonsignificant risk device 
because: 
• 
It is non-invasive and does not pose a serious risk of the healthy, safety or welfare of a subject if 
used under appropriate safety guidelines, delineated below. 
• 
Is not purported for supporting or sustaining human life 

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• 
Is not intended to be substantially important in diagnosing, curing, mitigating or treating disease 
• 
 
Does not otherwise pose a potential for risk to the health, safety or welfare of a subject (please see 
detailed evidence below provided under research risks and benefits for common and rare risks). 
 
Safety guidelines have been delineated since 2009 by the Safety of TMS Consensus Group(Rossi, 
Hallett et al. 2009). Multi-session rTMS at higher intensities, higher frequencies, and longer 
durations for depression have been tested in thousands of patients without significant adverse 
events and been approved FDA approved as an option for treating medication-refractory 
depression, as well as for presurgical motor mapping. The rTMS protocol described in this study 
complies with these current safety guidelines for TMS.  Specific risks to an epilepsy patient 
population, as well as appropriate safety guidelines, will be discussed below.  
 
 
1.3 
Research Risks & Benefits 
1.3.1 
Risks 
According to the Safety of TMS Consensus Group (2009), the following side effects and risks have been 
reported.  
 
  Common: 
• 
Headache and Neck Pain: The most common side effect of TMS is focal discomfort at the area of 
stimulation, as well as headache and neck pain of muscular origin. This pain typically lasts up to 
a few hours after the session and can be relieved with over the counter pain 
medications.(Daskalakis, Paradiso et al. 2004). 
• 
Tinnitus, Hearing Loss: Tinnitus is occasionally reported after a TMS session. Hearing loss has 
been reported in one patient whose earplug became dislodged during the session.  
Rare: 
• 
Seizures: Low-frequency rTMS, as administered in this study, has been used for inhibition of 
seizure activity. However, high-frequency rTMS, used for depression treatment, may rarely 
provoke seizure activity. TMS-induced seizures are almost always self-limited and are not 
reported to produce permanent sequelae. Seizure risk is related to intensity of stimulation, as 
well as use of neuroleptics, antidepressants, or other medications which may lower the seizure 
threshold.(Rossi, Hallett et al. 2009). 
 

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• Epilepsy, or a history of recurrent unprovoked seizures, is considered a relative contraindication to 
most TMS studies given the risk of provoking a seizure.  However, a recent meta-analysis of safety of 
rTMS in epilepsy(Bae, Schrader et al. 2007) indicated a 1.4% crude per subject risk of seizure and no 
cases of status epilepticus.   In another recent safety review, there were no TMS-triggered seizures 
among 152 patients with epilepsy who underwent weekly rTMS application at <1Hz frequency in 
trials investigating applications to reduce seizure frequency (Theodore, Hunter et al. 2002, Tergau, 
Neumann et al. 2003, Fregni, Otachi et al. 2006, Cantello, Rossi et al. 2007, Joo, Han et al. 2007, 
Santiago-Rodriguez, Cardenas-Morales et al. 2008). Furthermore, the use of high frequency/high 
intensity rTMS was unsuccessful at activating epileptogenic foci, with the exception of a subgroup of 
patients with progressive myoclonic epilepsy (Tassinari, Rubboli et al. 2005).   One case series of two 
patients with epilepsia partialis continua receiving high frequency rTMS (100 Hz, 20 Hz), there were 
no adverse effects (Rotenberg 2009). In other studies investigating rTMS in patients with a history of 
higher seizure risk, including chronic stroke, was safe (Fregni and Pascual-Leone 2006).  However, 
rTMS trains which are generally safe for healthy volunteers (20-25 Hz, 110-130% MT) are able to 
induce peripheral manifestations including spread of cortical excitability, which has led to the 
recommendation of more rigorous monitoring of patients at higher risk.  
 
• 
Changes in memory, attention, cognition, or psychiatric condition: TMS could cause occasional 
changes in memory, attention and other cognitive functions. However, none of these effects 
have been reported to be lasting, they are very mild, and they seem to be extremely rare. There 
have been reports of patients with an underlying depression or mood disorder developing mania 
after TMS. Hallucinations, delusions, personality changes, anxiety and agitation have been 
reported. Psychotic symptoms and suicidal ideation have never been described in normal 
subjects during or after rTMS. In all these cases, these psychiatric side effects induced by TMS 
did not last and went away by itself or with medication. 
 
• 
Dental Pain: Rarely, dental pain has been reported during TMS stimulation. This may indicate 
that the patient has a cavity, but will not cause lasting pain after stimulation has been stopped.  
 
• 
Motor Symptoms: Rare cases of transient worsening in motor task performance or increased 
tremor have been reported in Parkinson's patients.  
 
• 
Syncope, which has been reported as a rare risk.  
 
Given the potential for exacerbation of seizures during rTMS, one of the investigators who has specialty 
expertise in recognizing and managing seizures- Dr. Liu, Kuzniecky, or Friedman- will be onsite during the 
TMS sessions for epilepsy patients.  Because the risk of seizures is extremely low in healthy controls, 
sessions will be supervised by Dr. Milton Biagioni.  All physicians performing TMS procedures are either 
trained epileptologists, or have documented training in the first aid for seizure management and attend 
a quarterly training “TMS Seizure Recognition and First Aid Seizure Management Drill”. In addition, 
subject will be screened for any adverse effects, such as skin rashes, headache, or tinnitus, and 
necessary referrals and arrangements will be made. If any other unanticipated adverse events occur, the 
patient will be withdrawn from further participation in the study.  
 
1. In parallel with recording the primary outcome, we will monitor for increase in seizure severity 
attributable to rTMS by identifying all instances of generalized tonic clonic seizures after rTMS 

A randomized controlled pilot study of TMS enhancement of associative memory networks in healthy 
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treatments. Instances where seizure frequency increased after rTMS will be reported to the IRB 
within 72 hours of data analysis. 
2. If a self-limited, short (<5 min) focal seizure with alteration of consciousness occurs, treatment 
will stop for that day.  Subjects will be monitored clinically by an epilepsy physician (Dr. Liu) 
during the entire course of treatment and for 30 minutes afterwards, to ensure that the patient 
returns to baseline clinical status. Subjects will be followed up by phone call 24 hours later.  
3. If a secondarily generalized (convulsion starting in one area of body and then spreading to other 
areas) or 2 focal seizures with alteration of awareness occurs during treatment, the patient will 
be withdrawn from further participation in the study. .  If a seizure occurs and lasts for more 
than 5 minutes, or if there are 2 seizures occurring within 30 minutes without return to clinical 
baseline, the patient will be assisted to the NYU emergency room for further monitoring and 
care. Subjects will be followed up by phone call 24 hours later. 
4. In case of, erythema, transient itching or rashes of the skin under the electrodes necessary 
referrals and arrangements will be made.  
5. If any other unanticipated adverse events occur, the patient will be withdrawn from further 
participation in the study. 
 
1.3.2 
Other Risks of Study Participation 
There is the potential for loss of confidentiality for subjects participating in this study. However, every 
effort will be made to protect the confidentiality of subjects. After enrollment, patient identifiers will be 
linked to sequential numerical codes (Subject PO1, P02, etc.). The detailed results of the research will be 
kept in a separate research file maintained by and accessible to only the investigators in a locked cabinet 
in Dr. Liu's office. The numerical code key will also be maintained in a locked cabinet in Dr. Liu's office 
and accessible only to investigators. 
 
1.3.3 
Potential benefits 
Given that TMS will be applied based on the subject’s fMRI resting state connectivity, there is potential 
for improvement of verbal associative memory function. However, it is more likely that subjects may not 
benefit individually from this study, but that knowledge gained from this study will benefit others in the 
future.  
 
2 
STUDY OBJECTIVES 
The goal is to use targeted repetitive TMS (rTMS) to: 1) improve associative memory function in 16 healthy 
subjects and 16 temporal lobe epilepsy (TLE) patients, and 2) enhance hippocampal-neocortical functional 
connectivity. It is hypothesized that rTMS targeted to a superficial cortical node with high resting state 
functional connectivity with the hippocampus will enhance functional networks involved in memory 
consolidation and improve memory performance in both healthy subjects and TLE patients. 

A randomized controlled pilot study of TMS enhancement of associative memory networks in healthy 
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3. STUDY DESIGN 
3.1 General Design  
The study will last between 4-6 weeks: one week with involve stimulation to the left lateral parietal site 
(treatment) and one week with stimulation to the motor cortex (control), separated by two weeks of rest 
(Fig. 1).  Each stimulation week will include a baseline (day 1) and post-treatment (day 7) measurements, 
including fMRI, associative memory testing, IQ testing, and a seizure diary.  Epilepsy subjects will be asked 
to maintain a seizure diary for 1 week prior to the first stimulation week, and for 1 week after the second 
stimulation week.  
 
1. fMRI acquisition.  MRI scans will be performed on a Siemens Prisma 3T scanner without contrast.  
There will be a total of 4 scans performed: 1) Baseline resting state fMRI which will be performed within 
7-10 days prior to the first session of TMS for each condition (Visit 2, 9), (2) followup fMRI will be 
performed after the last session of rTMS  for each condition (Visit 8, 15).  The resting state fMRI 
acquisition will consist of 197 contiguous echo planar imaging volumes with the following parameters: 
TR = 2000 ms, TE = 25 ms, flip angle = 90 degrees, 39 slices, matrix = 64 x 64, field of view = 192 mm, 
with a resulting voxel size of 3 mm isotropic. Subjects will be instructed to lie still with their eyes trained 
on a cross-hair displayed on an LED display. A whole brain T1-weighted 1 mm isotropic MRI scan will also 
be acquired for inter-subject coregistration and display of results.  
 
A target stimulation site will be determined for each of the 32 subjects using resting state fMRI 
performed at the beginning of Weeks 1 and 3.  For each subject, a left lateral parietal cortical target will 
be identified by carrying out a seed-based resting state functional connectivity analysis. The anterior left 
hippocampus will be used as the seed region. This stimulation location was marked in stereotactic space 
and then transformed into the original structural MRI space and overlaid on the structural MRI to 
provide localization during rTMS. 
 
Resting state fMRI will also be performed at the end of Weeks 2 (Visit 8) and 5 (Visit 15) to assess for 
stimulation-induced changes in connectivity.   
 
2. rTMS.  Subjects will have rTMS applied using a Magstim Rapid 2 system. A 70 mm Figure of 8 coil 
will be used. A motor threshold will be determined for each subject at the baseline study visit, and 
defined as the minimum stimulator output required to generate a 50 mV threshold response in the 
abductor pollicis brevis  (APB) for at least 50% of trials.  rTMS will be applied for 5 daily sessions at 80% 
Fig. 1. General Study Design. Week 1 (not shown): Epilepsy Subjects only will 
be asked to start a seizure diary.  Week 2 (both healthy and epilepsy 
subjects). Each subject will receive baseline fMRI, EEG, and cognitive tests 
(light blue), followed by 5 daily sessions of rTMS to parietal cortex (red), then 
repeat fMRI, EEG, and cognitive tests.  Week 3-4 two week washout period. 
Week 5: each subject will receive a baseline fMRI, EEG and cognitive tests, 
followed by 5 daily sessions of rTMS delivered to the motor cortex (dark 
blue), then follow-up testing. Subjects will be assigned to the stimulus 
condition in a randomized and counterbalanced manner.  They will then have 
a follow up fMRI, EEG, and cognitive tests. Week 6 Epilepsy subjects will be 
asked to continue a seizure diary.  
Week 2 
Week 5

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motor threshold for 20 min of 20 Hz stimulation for 2  sec followed by 28 sec of no stimulation (Wang, 
Rogers et al. 2014), or a comparable high frequency stimulation protocol.  Subjects will be closely 
monitored for seizure occurrence and side-effects.  After a break of two weeks, to allow for washout 
effects, subjects will receive 5 daily rTMS sessions (same intensity as described above) to the motor 
cortex (control condition).  
 
3. Cognitive Testing. Two associative memory tasks (a word-face task and a word-pairs task) will be 
administered before, at treatment mid-point, and after each condition. A standardized 
neuropsychological battery (WASI IQ Testing, Verbal List Learning) will also be administered to control 
for non-specific cognitive enhancements with neurostimulation. 
 
The Wang and Voss 2014 study which is the model for our proposed study used a face-word recognition 
task, which included 20 arbitrarily paired face-word dyads. They then used functional MRI to determine 
the left lateral parietal cortical node which demonstrated greatest functional connectivity to the left 
hippocampus for each subject, and delivered a series of high frequency rTMS sessions or sham rTMS 
sessions to the subjects.  Real stimulation to the left lateral parietal node increased accurate recall of 
face-word pairs, whereas sham rTMS did not.  Their findings suggest that stimulation of a  
Superficial node in a hippocampal-neocortical network can produce a memory enhancing effect.   
  
In the study S15-00732, we are proposing to replicate and extend the Wang and Voss 2014 findings to a 
healthy population and epilepsy population.  We will utilize a similar face-word paradigm as Wang and 
Voss (20 pairs), as well as an unassociated word-pairs protocol.  The face-word pairs task is described in 
more detail in a supplementary document.  During each testing session (baseline, mid-treatment, and 
post-treatment), different sets of word-face pairs are presented to control for practice effect.  
 
The unrelated word-pairs tasks is a verbal associative paradigm which has also been used in memory 
consolidation studies  (Marshall, Molle et al. 2004, Marshall, Helgadottir et al. 2006, Antonenko, 
Diekelmann et al. 2013), and a paradigm which we have been testing and refining for the last year for 
S14-00609 Mechanisms and Enhancement of Memory Consolidation During Sleep.  In this task, we 
present 20 unrelated word pairs to subjects and test for delayed recall and recognition.  Patients with 
epilepsy often demonstrate declarative memory consolidation, or difficulty with explicit encoding and 
recall of episodic and semantic information. Adding a verbal word-pair associative task would allow us to 
understand whether enhanced function of a left hippocampal-cortical functional network is domain-
specific. We predict that epilepsy patients, who will be screened to demonstrate a baseline level of 
verbal memory dysfunction (defined as 1 SD below normative values on the Rey Auditory Verbal 
Learning Task, a verbal list learning task), will demonstrate enhanced verbal associative memory 
function from rTMS delivered to the left parietal lobe only and not from rTMS delivered to the motor 
cortex. 
 
Task Piloting: Before enrollment begins, we will pilot the word-pair and word-face tasks to assess for 
behavioral performance and variance. Pilot subjects will be recruited on www.mturk.com, and will be 
redirected to the memory tasks hosted on NYUMC’s license of Qualtrics.com. All data is encrypted by 
Qualtrics and stored securely as per HITECH requirements. No identifying information will be collected 
from pilot subjects, and they will be informed of this before completing the tasks. We will recruit 
participants to complete a testing block will be comprised of 2-3 tasks, which will take approximately 10 
minutes. Participants will be compensated $1 per completed set. Therefore, participants will perform 
tasks for 20-30 minutes and be paid between $4-5. The task performance data is the only data that will 

A randomized controlled pilot study of TMS enhancement of associative memory networks in healthy 
subjects and epilepsy patients. 
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This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
 
be collected, and will be identified by a participant number assigned by Qualtrics.com that is not linked 
to the pilot subjects.  Feedback from the pilot tasks will be used to ensure that test blocks are at the 
appropriate difficulty level.  
 
Dr. Anli Liu will be overseeing the psychometric assessments for the current study S15-00732. 
Dr. Liu has completed post-doctoral training in cognitive and behavioral neurology at Harvard Medical 
School (2011-2012), where she completed PhD level coursework in Cognitive Neuroscience and gained 
significant clinical experience in the evaluation of patients with cognitive disorders (including memory, 
attentional, language complaints).  In addition, she has completed a Masters Degree in Cognition and 
Education at UC Berkeley.  During medical school at UCSF, she spent two years as a research assistant 
under the supervision of Dr. Bruce Miller at the Memory and Aging Center, where she conducted 
prospective research on visual processing in Alzheimer’s and Frontotemporal Lobar Dementia 
patients.  Her clinical practice at NYU currently specializes in the management of the cognitive co-
morbidities of patients with epilepsy.  Moreover, for the last 3 years at NYU, she has been lead 
investigator on two prospective studies involving noninvasive neurostimulation and memory function in 
healthy subjects and patients with epilepsy (including S12-03395 Efficacy of TDCS for Treatment of 
Working Memory Dysfunction in Patients with Temporal Lobe Epilepsy and S14-00609 Mechanisms and 
Enhancement of Memory Consolidation During Sleep).  Through her clinical practice and research 
experience, she is extremely familiar with psychometric assessments of attention, working memory, 
associative memory consolidation, and visual memory.  She will either directly administer or  
supervise the administration of psychometric testing for this study.   
 
4. EEG.  Subjects will have a 20 minute routine EEG performed before and after the stimulation 
sessions, at visits 3, 7, 10 and 14. 
 
5. Seizure and Clinical Diary. Epilepsy subjects will be asked to maintain a daily seizure diary for 1 week 
prior to the first stimulation, through the 4 weeks of the study, and 1 week after the last stimulation 
session. 
 
Table 1. Study Schedule 
 
 
 
 
Week  
1 
Week  
2 
 
 
 
 
 
 
Week  
3 
Week 
4 
Week  
5 
 
 
 
 
 
 
Week 
6 
Visit  
1 
Visit    
2 
Visit 
 3 
Visit 
 4 
Visit 
 5 
Visit 
6 
Visit 
7 
Visit 
8 
 
 
Visit  
9 
Visit 
10 
Visit 
11 
Visit 
12 
Visit 
13 
Visit 
14 
Visit 
15 
 
Screening & 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
fMRI 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
TMS 
Stimulation 
 
 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
 
Cognitive 
Testing 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
EEG 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
Seizure 
Diary 
(Epilepsy 
Only) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hours 
0.5 
2 
2.5 
1 
2 
1 
2 
3 
0 
0 
2 
2.5 
1 
2 
1 
2 
3 
0 

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3.2  Primary Study Endpoint.  
The primary study endpoint will be improvement in a face-object pair association task post stimulation 
compared to pre-stimulation baseline in both epilepsy subjects and healthy controls.  
 
3.3  Secondary Study Endpoints.  
The secondary study endpoint will be improvement in a word-pair association task post stimulation 
compared to pre-stimulation baseline in both epilepsy subjects and healthy controls. We will also 
examine changes in hippocampal-cortical functional connectivity between baseline assessment and 
resting state fMRI assessment following TMS.   
 
4. SUBJECT SELECTION AND WITHDRAWAL 
We will recruit 40 subjects, including 20 epilepsy patients and 20 healthy controls. Patients will be 
maintained on constant anticonvulsant doses for the duration of the trial, unless there is a strong medical 
need to change them. This study will include both inpatients and outpatients. Patients will  
 
HEALTHY SUBJECTS.  Twenty (20) healthy controls will be recruited.  It is expected that 20% of recruited 
subjects will not meet I/E criteria or will not finish all study related tasks, which will result in 16 subjects per 
study group completing all study related tasks.  
 
Inclusion Criteria: 
1) 18 - 40 yrs,  
2) fluent in English,   
3) Right-handed 
4) score at least 26 out of 30 on the Montreal Cognitive Assessment (MOCA). Healthy subjects will be 
matched to age, handedness, and education compared to epilepsy subjects.  
5) Must be able to provide informed consent. 
 
Exclusion Criteria: 
1) Any history of a neurological or psychological/psychiatric disorder 
2) Chronic or progressive medical condition 
3) Any history of severe traumatic brain injury or skull defect 
4) Metal or devices in the head, including neurostimulators of metal foreign bodies 
5) Any other implanted metal device, including pacemaker, spinal cord stimulator, VNS. 
6) Any other ferromagnetic substance in the body (including tattoos, dental prosthetics, etc).  
7) Taking a medication which may lower the seizure threshold within the 4 weeks prior to the start of 
the study, including use of neuroleptic (esp. clozapine), antibiotic (penicillin, cephalosporins), and 
bronchodilating medications.  
8) Pregnancy 
9) Previous Transcranial Magnetic Stimulation 
10) An inability to refrain from psychoactive drug use during the study visits and the 48 hours prior 
 
EPILEPSY SUBJECTS Twenty patients with well-controlled temporal lobe epilepsy (TLE) will be recruited. In 
addition to the above inclusion and exclusion criteria, epilepsy subjects must additionally be screened for the 
following criteria.  Again, it is expected that 20% of recruited subjects will not meet I/E criteria or will not finish 
all study related tasks, which will result in 16 epilepsy subjects completing all study related tasks.  

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Only epilepsy patients with capacity for informed consent will be considered for inclusion.  The capacity of the 
patient will primarily be determined via consultation with the patient’s primary epileptologist.  If the primary 
epileptologist is a member of the study team, then another clinician who is knowledgeable of the patient’s 
clinical condition (a neuropsychiatrist, neuropsychologist, nurse practitioner, or adult epileptologist) will be 
consulted for an independent assessment regarding the decision making capacity of the individual, reflecting 
an appropriate level of understanding of the risks and benefits of any given medical procedure.  
Generally speaking, a patient who is deemed to have capacity to make their own medical decisions will be 
deemed to have capacity to consent for this study.  In addition, the PI will call the patient after the initial 
informed consent and before each week of study involvement (Weeks 2 and 4) for repetitive teaching and 
confirmation of patient understanding of study activities.  If there is a question of changed capacity during the 
course of the study, the patient’s epileptologist and/or a will be consulted for an independent assessment.   
Because only patients deemed to have capacity will be included, a surrogate decision maker will not be 
consulted, however, any family members involved in the clinical care of the patient will be allowed to 
participate in the consenting process. If the subjects are deemed to lose capacity during the course of the 
study, they will be withdrawn. 
 
Inclusion Criteria: 
1)  18 - 40 yrs,  
2)  fluent in English,   
3)  Right-handed 
4)  Score at least 26 out of 30 on the Montreal Cognitive Assessment (MOCA). Healthy subjects will 
be matched to age, handedness, and education compared to epilepsy subjects.  
5)  Must be able to provide informed consent. 
6) Demonstrate evidence of verbal memory dysfunction, which is defined as performance 1 SD 
below normative values in the Rey Auditory Verbal Learning Task (RAVLT)] or comparable task 
(such as the RBANS test), or evidence of left mesial temporal dysfunction on the WADA test 
(defined as ≤8/12 on the memory task with a right hemispheric injection).  
7) Have TLE.  A diagnosis of TLE will be made if the patient has at least 2 of the following features: 
a) characteristic semiology b) characteristic interictal or ictal pattern seen on EEG and/or c) 
concordant MRI brain or PET scan abnormality.   
8) Well-controlled epilepsy will be defined by stable seizure frequency in the 2 months prior to 
study participation.  Stable seizure frequency will be defined as ≤1 non-disabling seizure (auras 
or SPS only) per month and no generalized-tonic clonic seizures for >1 year.  
Exclusion criteria: 
1) Any history of severe traumatic brain injury or skull defect 
2) Metal or devices in the head, including neurostimulators of metal foreign bodies 
3) Any other implanted metal device, including pacemaker, spinal cord stimulator, VNS. 
4) Any other ferromagnetic substance in the body (including tattoos, dental prosthetics, etc).  
5) Taking a medication which may lower the seizure threshold within the 4 weeks prior to the start of 
the study, including use of neuroleptic (esp. clozapine), antibiotic (penicillin, cephalosporins), and 
bronchodilating medications.  
6) Subjects must NOT have an epileptogenic focus near the proposed stimulation site [ie. left 
lateral parietal region (P3)  
7) Pregnancy 
8) Previous Transcranial Magnetic Stimulation 
9) An inability to refrain from psychoactive drug use during the study 
 

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4.3 Subject Recruitment and Screening 
We will announce the opening of the trial with a group email sent to the NYU Comprehensive Epilepsy 
Center, as well as maintain regular communication with epilepsy attending physicians about potentially 
eligible subjects.  For potentially eligible epilepsy patients under the care of one of the investigators, a 
research team member will approach potential subjects during their clinic visit and provide Dr. Liu's 
contact information, and advise that if the patient agrees, Dr. Liu will contact him/her. If the patient is 
under the care of a physician who is not an investigator, then the treating physician will be asked to 
introduce the study and obtain the patient’s permission to be contacted by a study team member for 
further information.  
 
We will recruit healthy controls through a combination of flyers and web-announcements.  
 
All potential subjects will be pre-screened for eligibility either over the telephone, through an online 
OpenRedcap form, or in person. The telephone recruitment script and OpenRedcap form are included as 
supporting documents. When possible, i.e., when potential subjects are identified, he or she will meet 
with Dr. Liu or a study team member in person to review the study and further screen the participant, 
including special considerations regarding fMRI and TMS.  We will seek a waiver of documentation of 
consent for this prescreening process, as it is minimal risk. The PI or one of the co-investigators will 
conduct pre-screening for eligibility for the study. Information collected about the patient will be 
immediately discarded if the patient is ineligible for the study or the person chooses not to participate in 
the study.  If the patient is deemed eligible for the study, the information will be kept in a subject binder 
in a locked filing cabinet or protected in the Redcap database. After consent, subjects will complete a 
screening form about drug and medication use in order to determine eligibility. Subjects will also complete 
a demographics questionnaire. These forms are included as supporting documents.  
 
4.4 Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
This study is expected to end after all participants have completed all visits, and all information has been 
collected.  Under the following circumstances the subject's participation will be terminated by the 
investigator without regard to the participant's consent: 
• 
The study is cancelled by the principal investigator 
• 
The subject experiences an increase in seizure frequency at 50% above seizure frequency 
baseline, or a GTC during stimulation week.  
• 
The subject not able to attend the study visits required by the study. 
• 
The subject fails to follow the study requirements. 
• 
The subject needs a treatment or medication that may not be taken while on the study or 
the Principal Investigator feels it is in the best interest of you/your child to be taken of this 
study. 
• 
If a subject becomes pregnant. Participants will be asked to take a pregnancy test before 
receiving stimulation to ensure they are not pregnant. 
• 
If a subject decides not to continue participation in the study (by choice) 
 
4.4.2 Data Collection and Follow up for Withdrawn Subjects.  
The PI will call all withdrawn subjects at 1 week after withdrawal, to ensure that there are no ongoing 
clinical or safety issues related to study participation. 
 

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5.STUDY DEVICE 
5.1 Description 
The Magstim Rapid 2 is a machine which provides repetitive magnetic stimulation, which induces a 
secondary electrical currents in tissue using a non-invasive stimulating coil at frequencies up to 36 Hz. 
The stimulating coil is placed near the intended site of stimulation to trigger pulses and initiate brief 
magnetic pulses. The stimulation produces biphasic pulses from 1 Hz to 60 Hz at varying stimulation 
intensities, to produce a peak magnetic field from 0.5-2 Tesla at 100% of machine output.   The Magstim 
Rapid2 is currently FDA approved for the treatment of major depression and peripheral nerve 
stimulation, however is not currently approved for treating memory dysfunction.   
 
5.2 Treatment Regimen 
Repetitive TMS (rTMS) will be applied to the stimulation location (determined by fMRI based connectivity 
to a hippocampal seed region, as described In the protocol section) using a Magstim Rapidstim 2 device. 
A 70 mm figure of 8 coil will be used. Motor threshold was determined for each subject during the baseline 
visit of each study week, defined as the minimum stimulator output value required to generate 
contraction of the abductor pollicis brevis (APB) for at least 5 of 10 consecutive pulses (measured via Emg 
using a contraction threshold of 50 mV). For the stimulation condition, high frequency rTMS will be applied 
at 80% motor threshold (MT) to the stimulation location for 20 minutes of consecutive blocks of 20 Hz 
pulses for 2 seconds followed by 28 seconds of no stimulation, or a comparable high frequency protocol 
(between 5-20 Hz).  This protocol is similar to a previously published protocol Wang and Voss 2014), 
except that the stimulation intensity will be reduced to 80% to reduce the risk of seizure exacerbation.  
 
For the control stimulation, rTMS will be applied to another superficial cortical location determined to 
have low functional connectivity to the hippocampus. Subjects will be blinded to stimulation condition 
(which stimulation site is expected to result in a behavioral effect), and will not be aware of the different 
hypothesis regarding the effects of stimulation of the different locations.  
 
5.3 Method for Assigning Subjects to Treatment Groups 
All subjects will undergo both treatment and control stimulation arms, but will be assigned in a 
randomized and counterbalanced manner at the beginning of the study.  Randomization assignments will 
be maintained by Dr. Daniel Friedman, and will be communicated to Dr. Liu or other co-investigators 
directly involved in the administration of TMS to the subject.   However, co-investigators involved in 
neuropsychological testing and fMRI analysis (Dr. Pardoe), and study subjects will remain blinded to their 
randomization assignment.  
 
5.4 Prior and Concomitant Therapy.   Epilepsy patients enrolled in this study will continue to receive 
standard of care for their management of their partial onset epilepsy, and their medications will remain 
unchanged during participation.  
 
5.5 Receiving, Storage, Dispensing and Return 
The Transcranial Magnetic Stimulation (TMS) machine is stored at 240 East 38th Street, 20th Floor, NY 
10016. The room is locked at the end of the day and open only by authorized personnel who have access 
to the door key. The TMS device will only be operated by qualified research staff personnel.  Training 
will be supervised by Dr. Milton Biagioni, Assistant Professor in the Department of Neurology, Division of 
Movement Disorders, who has extensive experience in using TMS for both clinical and research 
indications.  Dr. Biagioni will be responsible for ensuring that members of the research team 

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demonstrate competency in performing TMS before enrolling subjects. In addition, Dr. Liu (PI) has 
completed a fellowship in cognitive neurology at Beth Israel Deaconess-Harvard Medical School, where 
she trained in the research lab of Dr. Alvaro Pascual Leone, an international leader in noninvasive brain 
stimulation.  Dr. Liu has significant scientific and practical experience in methods of noninvasive brain 
stimulation, including transcranial electrical stimulation (TES) and transcranial magnetic stimulation 
(TMS).  She is the principal investigator on four other IRB-approved studies utilizing non-invasive 
stimulation techniques at NYU School of Medicine. One of them will be present for the first five enrolled 
research subjects. 
 
6. Statistical Plan 
6.1 Sample Size Determination 
Sample size is based on the assumption that the memory performance change, defined as the difference 
in recall performance on a word-pair associates task after the assigned condition minus the recall 
performance before assigned condition, will be higher in each treatment condition (parietal rTMS), than 
in the control condition (motor cortex rTMS).  Assuming an improvement of 30% above baseline 
memory performance in the treatment arm, and no change in performance in the control arm (which is 
a large effect size, with F=1.3), with a standard error of 10%, confidence level of 95%, and power of 0.80, 
each condition will have a sample size of 16 (Wang, Rogers et al. 2014).  Assuming a 20% drop out rate, 
we will need 20 study subjects per study arm.  Therefore, we expect to recruit a total of 40 subjects for 
this study.   
 
6.2 Statistical Methods 
All data will be checked for completeness, out-of-range values, and distributional form. Analyses to 
measure relationships between TMS conditions (parietal vs motor cortex) and outcome measures 
(memory performance and fMRI based functional connectivity) will include a repeated measures 
ANCOVA with condition (parietal vs motor cortex) as the main within-subject variable, and order of 
stimulation as the main between-subject variable. Linear regression will be used to test relationships 
between memory performance change, degree of change in functional connectivity, and EEG variables. 
For group-wise comparisons we will also use t-test comparisons with diagnosis (healthy or epilepsy) as 
the independent variables and change in memory performance and functional connectivity as 
dependent variables.  
 
6.3 Subject Population(s) for Analysis 
All patients will be analyzed according to an intention-to-treat analysis.  
 
7. Safety and Adverse Events 
7.1Definitions 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
• Unexpected in nature, severity, or frequency  (i.e. not described in study-related documents such 
as the IRB-approved protocol or consent form, the investigators brochure, etc.) 
• Related or possibly related to participation in the research (i.e. possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research) 
• Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm). 
 

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Unanticipated Adverse Device Effect  
An Unanticipated Device Effect is any serious adverse effect on health or safety, or any life-threatening 
problem or death caused by, or associated with a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the investigational plan or application 
(including a supplementary plan or application), or any other unanticipated serious problem associated 
with a device that relates to the rights, safety, or welfare of subjects. 
 
Serious injury 
Any injury or illness that is any one of the following:  
• life-threatening 
• results in permanent impairment of a body function or permanent damage to body structure 
• necessitates medical or surgical intervention to preclude permanent impairment of a body 
function or permanent damage to a body structure 
 
Adverse Event 
(a) In parallel with recording the primary outcome, we will monitor for increase in seizure severity 
attributable to TMS by identifying all instances of generalized tonic clonic seizures after TMS treatments. 
Instances where seizure frequency increased after TMS will be reported to the IRB within 72 hours of 
data analysis. 
 
(b) If a self-limited, short (<5 min) partial seizure or evolution into generalized tonic clonic seizure occur, 
treatment will stop for that day. 
 
(c) If a secondarily generalized (convulsion starting in one area of body and then spreading to other 
areas) or 2 partial seizures occur during treatment, the patient will be withdrawn from further 
participation in the study. 
 
(d) If any other unanticipated adverse events occur, the patient will be withdrawn from further 
participation in the study. 
 
7.2 Recording of Adverse Device Effects 
 
At each contact with the subject, the investigator will record information on adverse device effects by 
specific questioning and, as appropriate, by examination.  Information on all adverse device effects 
should be recorded immediately in the source document, and also in the appropriate adverse effect 
module of the case report form (CRF).  All clearly related signs, symptoms, and abnormal diagnostic 
procedures results should recorded in the source document, though should be grouped under one 
diagnosis. 
 
All adverse device effects occurring during the study period will be recorded.  The clinical course of each 
event should be followed until resolution, stabilization, or until it has been determined that the study 
treatment or participation is not the cause.  Serious adverse device effects that are still ongoing at the 
end of the study period must be followed up to determine the final outcome.  Any serious adverse 
device effects that occur after the study period should be recorded and reported promptly (see section 
8.3 below). 
 

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The minimum initial information to be captured in the subject’s source document concerning the 
adverse device effect includes:  
• 
Study identifier 
• 
Study Center 
• 
Subject number 
• 
Device model and serial number 
• 
A description of the event 
• 
Date of onset 
• 
Investigator assessment of the association 
between the event and study treatment 
• 
Current status 
• 
Whether study treatment was discontinued 
• 
Whether the event is serious and reason for 
classification as serious 
 
7.3 Reporting of Adverse Device Effects and Unanticipated Problems 
7.3.1 Investigator reporting: Notifying the study sponsor 
The following describes events that must be reported to the study sponsor in an expedited fashion. 
 
Reportable events: 
• 
Unanticipated adverse device effect, regardless of seriousness or severity 
• 
Unanticipated problems related to study participation  
 
• 
Deviations from the study protocol 
Deviations from the protocol must receive both Sponsor and the investigator’s IRB approval 
before they are initiated. Any protocol deviations initiated without Sponsor and the 
investigator’s IRB approval that may affect the scientific soundness of the study, or affect the 
rights, safety, or welfare of study subjects, must be reported to the Sponsor and to the 
investigator’s IRB as soon as a possible, but no later than 5 working days of the protocol 
deviation. 
• 
Withdrawal of IRB approval 
An investigator shall report to the sponsor a withdrawal of approval by the investigator’s 
reviewing IRB as soon as a possible, but no later than 5 working days of the IRB notification of 
withdrawal of approval. 
 
7.3.2 Investigator reporting: Notifying the IRB 
Federal regulations require timely reporting by investigators to their local IRB of unanticipated problems 
posing risks to subjects or others.  The following describes the NYULMC IRB reporting requirements, 
though Investigators at participating sites are responsible for meeting the specific requirements of their 
IRB of record.  
 
Report Promptly, but no later than 5 working days: 
Researchers are required to submit reports of the following problems promptly but no later than10 
working days from the time the investigator becomes aware of the event: 
• Unanticipated problems including adverse events that are unexpected and related 
– Unexpected: An event is “unexpected” when its specificity and severity are not accurately 
reflected in the protocol-related documents, such as the IRB-approved research protocol, any 
applicable investigator brochure, and the current IRB-approved informed consent document 
and other relevant sources of information, such as product labeling and package inserts.  
– Related to the research procedures: An event is related to the research procedures if in the 
opinion of the principal investigator or sponsor, the event was more likely than not to be 
caused by the research procedures.  
– Harmful: either caused harm to subjects or others, or placed them at increased risk 

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• Unanticipated adverse device effect:  Any serious adverse effect on health or safety or any life-
threatening problem or death caused by, or associated with, a device, if that effect, problem, or 
death was not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary plan or application, or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or 
welfare of subjects. 
 
Other Reportable events: 
The following events also require prompt reporting to the IRB, though no later than10 working days: 
• Complaint of a research subject when the complaint indicates unexpected risks or the complaint 
cannot be resolved by the research team. 
• Protocol deviations or violations (includes intentional and accidental/unintentional deviations 
from the IRB approved protocol) for any of the following situations:  
– one or more participants were placed at increased risk of harm 
– the event has the potential to occur again 
– the deviation was necessary to protect a subject from immediate harm 
• Breach of confidentiality 
• Incarceration of a participant when the research was not previously approved under Subpart C 
and the investigator believes it is in the best interest of the subject to remain on the study. 
• New Information indicating a change to the risks or potential benefits of the research, in terms 
of severity or frequency. (e.g. analysis indicates lower-than-expected response rate or a more 
severe or frequent side effect; Other research finds arm of study has no therapeutic value; FDA 
labeling change or withdrawal from market) 
 
Reporting Process 
The reportable events noted above will be reported to the IRB using the form: “Reportable Event Form” 
or as a written report of the event (including a description of the event with information regarding its 
fulfillment of the above criteria, follow-up/resolution and need for revision to consent form and/or 
other study documentation). 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the Clinical 
Investigator’s study file. 
 
7.4 Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site.  This 
safety monitoring will include careful assessment/follow-up and appropriate reporting of adverse events 
as noted above, as well as the construction and implementation of a site data and safety-monitoring 
plan (see Data Monitoring Committee below).   
 
7.5. Data Monitoring Plan and Committee 
 
Stopping Rules: Should a safety concern arise, the study will be voluntarily paused until further review. 
Specific events that may prompt a study pause are: exacerbation of seizure intensity or frequency, 
syncope, and/or exacerbation of underlying neurologic symptoms. 
 
(a) If a self-limited, short (<5 min) partial seizure or evolution into generalized tonic clonic seizure occur, 

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treatment will stop for that day for that subject. 
 
(b) If a secondarily generalized (convulsion starting in one area of body and then spreading to other 
areas) or 2 partial seizures occur during treatment, the patient will be withdrawn from further 
participation in the study. 
 
(C) If >50% of epilepsy patients have a >=50% increase in seizure frequency above baseline, then the 
study will stop.  
 
The primary responsibility of data safety monitoring will lie with Dr. Liu, although all co-investigators of 
her research team will comprise a Data Monitoring Committee and have responsibility for carrying out 
the DSMP.  Data Monitoring Committee will meet in person or have telephone conversations every 2 
months, and informally meet on an as needed basis.  All Committee members have extensive experience 
in clinical neurophysiology as well as design and implementation of clinical trials, will participate: 
 
NYU PI: Anli Liu MD MA 
Assistant Professor of Neurology 
NYU School of Medicine 
Comprehensive Epilepsy Center 
223 East 34th Street 
New York, NY 10016 
 
NYU Co-PI: Heath Pardoe PhD 
Assistant Professor of Neurology 
NYU School of Medicine 
Comprehensive Epilepsy Center 
223 East 34th Street 
New York, NY 10016 
 
NYU Co-Investigator: 
Ruben Kuzniecky MD  
Professor of Neurology 
NYU School of Medicine 
Comprehensive Epilepsy Center 
223 East 34th Street 
New York, NY 10016 
 
NYU Co-Investigator: Daniel Friedman MD  
Assistant Professor of Neurology 
NYU School of Medicine 
Comprehensive Epilepsy Center 
223 East 34th Street 
New York, NY 10016 
 
NYU Co-Investigator: 
Orrin Devinsky MD 
Professor of Neurology 

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NYU School of Medicine 
Comprehensive Epilepsy Center 
 
 
7. Data Handling and Record Keeping 
All collected information will be secured in a locked office on a computer with password protection.  No 
individual who is not part of this protocol will be given access to this information. 
1. Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements 
of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a 
signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why.  Only site PIs and study team members will 
have access to PHI.  Outside collaborators will only have access to patient’s de-identified data. 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization.  For 
subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain 
permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study 
period. 
 
Data will be coded in an anonymous fashion, according to enrollment order (eg P001, P002, etc). 
2. Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are contained in 
source documents.  Examples of these original documents, and data records include: hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, 
and at medico-technical departments involved in the clinical trial. 
3. Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  All data 
requested on the CRF will be recorded.  All missing data must be explained.  If a space on the CRF is left 
blank because the procedure was not done or the question was not asked, write “N/D”.  If the item is 
not applicable to the individual case, write “N/A”.  All entries should be printed legibly in black ink. For 
clarification of illegible or uncertain entries, print the clarification above the item, then initial and date 
it. 
4. Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 2 years after the last 
approval of a marketing application in their country and until there are no pending or contemplated 
marketing applications in their country or at least 2 years have elapsed since the formal discontinuation 
of clinical development of the investigational product.  These documents should be retained for a longer 
period if required by an agreement with the sponsor.  In such an instance, it is the responsibility of the 

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sponsor to inform the investigator/institution as to when these documents no longer need to be 
retained.  
 
8. Study Monitoring, Auditing, and Inspecting 
1. Study Monitoring Plan 
Because of the potential risk of adverse side effects, patients will be monitored closely during the study 
period through detailed medication history, physical examinations, and close follow-up, as described in 
the protocol. Study participants will be able to contact one of the study members at any time with 
questions or concerns, as indicated in the consent form. All adverse events will be recorded, scored for 
severity and for relationship to the study, as described. All serious and unexpected adverse events will 
be reported to the IRB and the DMC within 72 hours. All regulatory authorities will be able to inspect the 
collected data. Should a safety concern arise, the study will be voluntarily paused until further review. 
Specific events that may prompt a study pause are: seizure, syncope, exacerbation of underlying 
neurologic symptoms. 
2. Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, the 
sponsor, government regulatory bodies, and University compliance and quality assurance groups of all 
study related documents (e.g. source documents, regulatory documents, data collection instruments, 
study data etc.).  The investigator will ensure the capability for inspections of applicable study-related 
facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
 
9. Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical Practice (FDA 
Title 21 part 312 and International Conference on Harmonization guidelines), applicable government 
regulations and Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent Ethics 
Committee (EC) or Institutional Review Board (IRB), in agreement with local legal prescriptions, for 
formal approval of the study conduct.  The decision of the EC/IRB concerning the conduct of the study 
will be made in writing to the investigator and a copy of this decision will be provided to the sponsor 
before commencement of this study.  The investigator should provide a list of EC/IRB members and their 
affiliate to the sponsor. 
 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study.  Dr. Liu, Dr. 
Friedman, and Dr. Kuzniecky will be allowed to consent patients.  All have significant experience with 
patient oriented clinical research, and are specialists in epilepsy and clinical neurophysiology. Only 
subjects, their family members, and study team members will be present during the consent process to 
protect patient privacy. Informed consent will be documented by obtaining a signed and witnessed copy 
of the informed consent. 
 
 

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10. Study Finances 
1. Funding Source 
Finding a Cure for Epilepsy and Seizures (FACES) will support all research related costs. 
 
10.1.1 Subject compensation. Patients will be compensated $15 per hour of participation in this study 
plus an additional $25 for completing all visits.  The study requires approximately 27.5 participation 
hours over 15 visits for a total of approximately $437.50.  Subjects will be paid at the end of study 
participation, for whichever portion of the study they completed (even if subjects decided to withdraw 
during the study), via a mailed check.  
 
10.1.2 Study related costs.  The costs of all study visits will be billed to the research team.  There will be 
no cost of participation to the patient. The cost of subject compensation, fMRI studies, and EEG will be 
supported by research funds.   
 
2. Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial 
gain greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by a 
properly constituted Conflict of Interest Committee with a Committee-sanctioned conflict management 
plan that has been reviewed and approved by the study sponsor prior to participation in this study.  All 
NYU investigators will follow the applicable University conflict of interest policy(ies). 
 
11. Publication Plan 
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of 
the information provided by the sponsor for the purposes of performing the study, will be published or 
passed on to any third party without the consent of the study sponsor.  Any investigator involved with 
this study is obligated to provide the sponsor with complete test results and all data derived from the 
study. 
 
 
 
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