Modulation of Motor Cortex Excitability by Glucose Administration
Phase: NA
Conditions: Glucose Metabolism Disorders
Sponsor: University of North Carolina, Chapel Hill

Study Code: Glucose 
IRB #: 19-1451 
 
CONFIDENTIAL 
 
0 
 
 
 
Modulation of Motor Cortex Excitability by Glucose Administration 
 
 
 
 
NCT number: NCT04031404 
Document Date: March 3rd, 2020 
 

Study Code: Glucose 
 
Version 1.6 
IRB #: 19-1451  
 
3 March 2020 
CONFIDENTIAL 
 
1 
 
MODULATION OF MOTOR CORTEX 
EXCITABILITY BY GLUCOSE ADMINISTRATION 
 
A pilot and single-site study for investigating neuronal excitability of blood glucose dynamics. 
 
Study Code: Glucose 
 
Funding Mechanism: 
NORC Pilot Grant 
Principal Investigator: 
Flavio Frohlich, PhD 
Co-Investigator: 
John Buse, MD PhD; Kai Xia, PhD 
Protocol Number: 
19-1451 
Version Number: 
1.6 
Date: 
3 March 2020 
 
 

Study Code: Glucose 
 
Version 1.6 
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3 March 2020 
CONFIDENTIAL 
 
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Initial version: 
10 April 2019. Ver. 1.0 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .....................................................................................................................5 
STUDY SUMMARY ..............................................................................................................................6 
1 KEY ROLES ....................................................................................................................................7 
1.1 INDIVIDUALS .................................................................................................................................7 
1.2 INSTITUTIONS ...............................................................................................................................8 
1.3 OPTIONAL ....................................................................................................................................8 
1.4 FUNDING SOURCES ........................................................................................................................8 
2 INTRODUCTION ............................................................................................................................8 
2.1 BACKGROUND ...............................................................................................................................8 
2.2 DOSE RATIONALE...........................................................................................................................9 
2.3 STUDY AIMS/HYPOTHESES ...............................................................................................................9 
2.3.1 SPECIFIC AIMS ....................................................................................................................................... 9 
2.3.2 
RESEARCH HYPOTHESES .......................................................................................................................... 9 
3 SUBJECT SELECTION AND WITHDRAWAL ..................................................................................... 10 
3.1 INCLUSION CRITERIA ..................................................................................................................... 10 
3.2 EXCLUSION CRITERIA .................................................................................................................... 10 
3.3 STRATEGIES FOR RECRUITMENT AND RETENTION ................................................................................. 11 
3.3.1 RECRUITMENT..................................................................................................................................... 11 
3.3.2 RETENTION ......................................................................................................................................... 11 
4 BASIC STUDY DESIGN .................................................................................................................. 12 
4.1 TREATMENT ASSIGNMENT PROCEDURES ............................................................................................ 12 
5 STUDY SCHEDULE ....................................................................................................................... 13 
5.1 SCREENING ................................................................................................................................. 13 
5.2 STUDY SESSIONS .......................................................................................................................... 15 
6 STUDY PROCEDURES/EVALUATIONS ........................................................................................... 16 
6.1 SELF-REPORT MEASURES ................................................................................................................ 16 
6.2 SPECIAL ASSAYS OR PROCEDURES ..................................................................................................... 16 
6.3.1 GLUCOSE TOLERANCE TEST .................................................................................................................... 16 
6.3.2 MOTOR-EVOKED POTENTIALS AND TMS-EVOKED POTENTIALS .................................................................... 16 

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7 STUDY INVESTIGATIONAL PRODUCT ........................................................................................... 17 
7.1 SAFETY FEATURES ........................................................................................................................ 19 
7.2 PREPARATION AND ADMINISTRATION OF STUDY INVESTIGATIONAL PRODUCT ............................................ 19 
7.3 ASSESSMENT OF PARTICIPANT COMPLIANCE WITH STUDY INVESTIGATIONAL PRODUCT ................................. 19 
8 POTENTIAL RISKS AND BENEFITS ................................................................................................. 20 
8.1 BENEFITS TO SUBJECTS AND SOCIETY ................................................................................................ 20 
8.2 POTENTIAL RISKS ......................................................................................................................... 20 
8.2.1 PSYCHOLOGICAL .................................................................................................................................. 20 
8.2.1 PHYSICAL ........................................................................................................................................... 20 
8.3 REFERRALS FOR MEDICAL FOLLOW-UP OR PSYCHOLOGICAL COUNSELING .................................................. 21 
9 DATA AND SAFETY MONITORING ................................................................................................ 22 
9.1 FROHLICH LAB MONITORING PLAN .................................................................................................. 22 
9.2 SAFETY OVERSIGHT BY THE DSMB ................................................................................................... 22 
9.3 EARLY WITHDRAWAL OF PARTICIPANTS ............................................................................................ 22 
9.3.1 REASONS FOR WITHDRAWAL ................................................................................................................. 22 
9.3.2 DATA COLLECTION FOR WITHDRAWN PARTICIPANTS ................................................................................. 23 
9.4 TERMINATION OF STUDY ............................................................................................................... 23 
10 SAFETY & REPORTING ............................................................................................................... 24 
10.1 SAFETY PARAMETERS .................................................................................................................. 24 
10.2 METHODS AND TIMING FOR ASSESSING, RECORDING, AND ANALYZING SAFETY PARAMETERS ...................... 24 
10.2.1 UNANTICIPATED PROBLEMS ................................................................................................................ 24 
11 STATISTICAL PLAN .................................................................................................................... 25 
11.1 STATISTICAL ANALYSIS STRATEGIES................................................................................................. 25 
11.2 CHOICE OF SAMPLE SIZE ............................................................................................................... 25 
11.3 DATA MANAGEMENT ................................................................................................................. 26 
12 DATA HANDLING AND RECORD KEEPING ................................................................................... 27 
12.1 PHI AND HIPAA ....................................................................................................................... 27 
12.2 CONFIDENTIALITY ....................................................................................................................... 27 
12.2.1 ACCESS TO SOURCE DOCUMENTS ......................................................................................................... 27 
12.2.3 OTHER ............................................................................................................................................. 27 
12.3 SOURCE DOCUMENTS ................................................................................................................. 27 
12.4 DATA MANAGEMENT RESPONSIBILITIES ........................................................................................... 28 
12.5 DATA CAPTURE METHODS (REDCAP) ............................................................................................. 28 
12.6 PROTOCOL DEVIATIONS ............................................................................................................... 28 
12.7 RECORD RETENTION ................................................................................................................... 29 

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13 ETHICAL CONSIDERATIONS ....................................................................................................... 30 
13.1 ETHICAL STANDARD .................................................................................................................... 30 
13.2 INSTITUTIONAL REVIEW BOARD (IRB) ............................................................................................. 30 
13.3 INFORMED CONSENT PROCESS ...................................................................................................... 30 
13.4 EXCLUSION OF WOMEN, MINORITIES, AND CHILDREN (SPECIAL POPULATIONS) ........................................ 31 
13.5 PARTICIPANT CONFIDENTIALITY ..................................................................................................... 31 
13.6 STUDY DISCONTINUATION ............................................................................................................ 31 
14 PUBLICATION POLICY ................................................................................................................ 31 
15 LITERATURE REFERENCES .......................................................................................................... 32 
APPENDIX A: SCHEDULE OF EVENTS .................................................................................................. 34 
APPENDIX B: IRB AMENDMENT TRACKING LOG ................................................................................ 35 
APPENDIX C: INFORMED CONSENT QUIZ .......................................................................................... 36 
APPENDIX D: NOTE TO FILE .............................................................................................................. 37 
APPENDIX E: TELEPHONE SCRIPT ...................................................................................................... 38 
APPENDIX F: QUESIONNAIRES .......................................................................................................... 39 
APPENDIX G: FASTING INSTRUCTIONS FOR GLUCOSE TOLERANCE TEST ............................................. 47 
 
 
 
 
 
 

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LIST OF ABBREVIATIONS 
ANOVA 
Analysis of Variance 
BIS/BAS 
Behavioral Inhibition System / Behavioral Approach System 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
Co-I 
Co-Investigator 
CRF 
Case Report Form 
DHHS 
Department of Health and Human Services 
DMV 
Department of Motor Vehicles 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders (Version 5) 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
EEG 
Electroencephalogram 
EMG 
Electromyography 
EOG 
Electrooculography 
FDA 
Food and Drug Administration 
FDI 
First Dorsal Interosseous 
GCP 
Good Clinical Practice 
GTT 
Glucose Tolerance Test 
Hz 
Hertz 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IDE 
Investigational Device Exemption 
IRI 
Interpersonal Reactivity Index 
NAMI 
National Alliance on Mental Illness 
NIH 
National Institutes of Health 
NIMH 
National Institute of Mental Health 
NORC 
Nutrition Obesity Research Center 
OHRE 
Office of Human Research Ethics 
OHRP 
Office for Human Research Protections 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PMA 
Premarket Approval 
SMC 
Safety Monitoring Committee 
SPI 
Serial Peripheral Interface 
SOP 
Standard Operating Procedure 
TEP 
TMS-evoked potential 
TMS 
Transcranial Magnetic Stimulation 
UE 
Unexpected Event 
UNC 
University of North Carolina 
UNC-CH 
University of North Carolina at Chapel Hill 
US 
United States 
 
 
 
 
 
 

Study Code: Glucose 
 
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STUDY SUMMARY 
Title 
Modulation of motor cortex excitability by glucose administration 
Short Title 
Glucose 
Protocol Number 
19-1451 
Phase 
Pilot 
Methodology 
Single-site 
Study Duration 
This study is expected to last 1 year. 
Study Center(s) 
This is a single-site study performed at The University of North Carolina at Chapel 
Hill. 
Objectives (Purpose) 
Purpose of this pilot study is to investigate how changes in blood glucose level 
modulates neuronal excitability and brain network dynamics. 
Number of Subjects 
20 
Diagnosis and Main 
Inclusion Criteria 
Eligible participants will be healthy individual without any severe illness and mental 
disorder. 
Description of 
Intervention 
(Procedures/methods) 
Each participant will be seated in a reclining chair and receive transcranial magnetic 
stimulation (TMS) to determine resting motor threshold (RMT). At baseline, 
participants will receive 10 TMS pulses (120% intensity relative to RMT) while 
wearing an electroencephalography (EEG) net to record brain activity on the scalp. 
TMS-induced motor-evoked potentials (MEPs) and EEG data will be recorded. In 
addition, blood glucose level testing will be performed by finger prick to measure 
baseline glucose level. In an intervention step, glucose drink (75g of sugar) or 
drinking water (control condition) will be administered. Both blood glucose level 
testing and TMS-induced MEPs and EEG data collection will be performed at 0, 30, 
60, 120, and 180 minutes after drink administration. 
Related IRB Applications 
17-0149 
 
 
 

Study Code: Glucose 
 
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1 
KEY ROLES 
1.1 
INDIVIDUALS 
Principal Investigator 
Flavio Frohlich, PhD 
Co-Investigator 
John Buse, MD. PhD; Kai Xia, PhD 
Medical Monitor 
 
 
Flavio Frohlich, PhD – Principal Investigator 
UNC – Chapel Hill Department of Psychiatry 
Email: flavio_frohlich@med.unc.edu 
Office: Mary Ellen Jones #6018 
Phone: (919) 966-4584 
 
John Buse, MD. PhD – Co-Investigator 
UNC – Chapel Hill Division of Endocrinology 
Email: john_buse@med.unc.edu 
Office: UNC Hospital Diabetes and Endocrinology Clinic Suite 202 
Phone: (984) 974-2950 
 
Kai Xia, PhD – Co-Investigator 
UNC – Chapel Hill Department of Psychiatry 
Email: kai_xia@med.unc.edu 
Office: Medical School Wing B 336 
Phone: (919) 843-5508 
 
Christopher Walker –  Project Manager 
UNC – Chapel Hill Department of Psychiatry  
Email:  christopher_walker@med.unc.edu 
Office: Mary Ellen Jones #6102 
Phone: (919) 966-3630 
 
Amber McFerren – Study Coordinator 
UNC – Chapel Hill Department of Psychiatry 
Email: ambermcf@live.unc.edu 
Office: Mary Ellen Jones #6102 
Phone: (919) 763-2005 
 
 
 
 

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1.2 
INSTITUTIONS 
The University of North Carolina at Chapel Hill 
1.3 
OPTIONAL 
IRB 
The University of North Carolina – Chapel Hill 
Medical School Building 52 
Mason Farm Road 
CB #7097 
Chapel Hill, NC 27599-7097 
(919) 966-3113 
1.4 
FUNDING SOURCES 
Please list below the funding sources for this project:  
Sponsor Name 
UNC Ramses 
Number 
Sponsor Type 
Prime Sponsor 
Name 
Prime Sponsor 
Type 
Sponsor/Grant 
Number 
UNC NORC 
 
 
NIH/NIDDK 
Federal 
P30 DK056350 
External Funding: This project is externally funded and UNC-CH is the direct recipient of federal funds. 
UNC-CH Funding: This project is funded through UNC-CH Nutrition Obesity Research Center. 
Classified: This project is not classified. 
2 
INTRODUCTION 
This document is a protocol for a human research study. This study is to be conducted according to U.S. 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. 
2.1 
BACKGROUND 
 
More than a third of the adult US population has impaired glucose tolerance, which is tightly linked to obesity and a 
risk factor for the development of diabetes and disorders of the central nervous system. In particular, diabetes 
exhibits a bidirectional causal association with depression. A growing literature delineates the pathophysiology 
underlying mood disorders at the level of large-scale activity patterns in brain circuits (Davidson, 1985; Nusslock et 
al., 2015; Smart et al., 2015; Sutton and Davidson, 1997), which has enabled the development of novel brain 
stimulation treatments such as transcranial magnetic stimulation (TMS) (George et al., 1995). TMS is one of the non-
invasive brain stimulation tools used to deliver electrical stimuli through the scalp in humans. In general, single-pulse 
TMS (including paired-pulse TMS) is used to explore brain functioning. TMS on the motor cortex leads to a twitch in 
the target muscle evoking motor-evoked potentials (MEPs) on electromyography (EMG) electrodes. The MEP is 
usually used to assess corticospinal tract excitability (Tofts, 1990). In addition, combining TMS with 
electroencephalography (EEG) can capture cortical excitability beyond corticospinal excitability since EEG mainly 
captures neural activity of cortical neurons (Farzan et al., 2016). The concurrent combination of TMS with EEG can 
be a powerful technology for characterizing and modulating brain networks.  

Study Code: Glucose 
 
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2.2 
DOSE RATIONALE 
 
In this study, our primary purpose is to investigate how changes in blood glucose level affect neuronal excitability. 
We will administer a 75g load of glucose (oral glucose tolerance test, OGTT) that complies with the standard 
guidelines for diagnosing diabetes  
 
2.3 
STUDY AIMS/HYPOTHESES 
2.3.1 
SPECIFIC AIMS 
Aim 1. Examine how glucose levels gate neuronal excitability measured by the response to TMS. 
Aim 2. Delineate how brain network dynamics are modulated by experimentally induced elevated blood 
glucose levels. 
2.3.2 
RESEARCH HYPOTHESES 
We hypothesize that glucose administration modulates neuronal excitability measured by TMS-induced 
MEPs and TEPs. We also hypothesize that frontal theta (4-8Hz) and left frontal alpha (8-12Hz) oscillations, 
which represent an engaged (theta) and disengaged (alpha) cortical state, are modulated in response to 
glucose administration compared to water drink. The modulation of neuronal excitability and brain 
network dynamics is depending on blood glucose level 
 
 

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3 
SUBJECT SELECTION AND WITHDRAWAL 
A total of 20 healthy participants will be recruited for this study and all data will be collected at UNC-CH. No 
specific plans have been made to enroll participants from vulnerable populations.  
3.1 
INCLUSION CRITERIA 
In order to be eligible to participate in this study, a participant must meet all of the following criteria: 
• 
Between the ages of 35 and 65 
• 
Right-handed 
• 
Body mass index (BMI) < 30 
• 
Fasting blood glucose test level < 95 mg/dL 
• 
Capacity to understand all relevant risks and potential benefits of the study (informed consent) 
• 
Willing to comply with all study procedures and be available for the duration of the study 
• 
Speak and understand English 
3.2 
EXCLUSION CRITERIA 
A potential participant who meets any of the following criteria will be excluded from participation in the study: 
• 
Diagnosis of diabetes or pre-diabetes 
• 
Neurological disorders and conditions, including, but not limited to: 
o 
History of epilepsy 
o 
Seizures (except childhood febrile seizures and ECT-induced seizures) 
o 
Dementia 
o 
History of stroke 
o 
Parkinson’s disease 
o 
Multiple sclerosis 
o 
Cerebral aneurysm 
o 
Brain tumors 
• 
Medical or neurological illness or treatment for a medical disorder that could interfere with study 
participation (e.g., unstable cardiac disease, HIV/AIDS, malignancy, liver or renal impairment) 
• 
Prior concussion 
• 
Prior brain surgery 
• 
Any brain devices/implants, including cochlear implants and aneurysm clips 
• 
Traumatic brain injury  
• 
Anything that, in the opinion of the investigator, would place the participant at increased risk or preclude 
the participant’s full compliance with or completion of the study 
Justifications for any exclusions based on race, gender, or ethnicity: Non-English speaking individuals are 
excluded because the ability to accurately and completely communicate study information, answer questions 
about the study, and obtain consent are necessary. 
 
 

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Justification for excluding women or women who become pregnant 
Pregnant participants will be excluded despite the fact that theoretical risk to mother or fetus is exceedingly small, 
since no safety data for pregnancy is known to exist for TMS studies. Furthermore, the TMS device description 
indicates that the device should not be applied to the head, neck, or abdomen of pregnant women. We will verify 
pregnancy status via a urine pregnancy test for all female participants prior to receiving treatment on the first 
session of the study. Women will be asked prior to each test sessions about the likelihood they could be pregnant. 
Any woman who indicates there may be a possibility or is unsure will be reminded the testing is contraindicated in 
pregnant women and will be offered the opportunity to have pregnancy testing repeated prior to TMS. 
 
3.3 
STRATEGIES FOR RECRUITMENT AND RETENTION 
3.3.1 
RECRUITMENT 
We intend to recruit 20 healthy participants at the University of North Carolina at Chapel Hill. Study 
coordinator will be informed of the inclusion and exclusion criteria and will be asked to discuss the study 
with their subjects. Study coordinator will identify subjects they believe to be appropriate for this study 
based on the information we will provide them about the study. Study coordinator will ask subjects 
whether they are willing to be contacted by the research team regarding participation. 
3.3.2 
RETENTION 
Our retention strategy includes monetary compensation for the time and effort required to participate in 
the study. The participant will receive payment at the stimulation session. The research staff will also give 
each participant a reminder call or email for the stimulation session. Each research staff member will be 
easily available for the participants to contact via email or phone. 
The inclusion criteria state that each participant must be able to understand all risks and benefits 
associated with this study. We will be asking each participant to answer questions about the consent form 
to determine that the study process and the duration of participation are completely understood by all 
participants. We will aim to have a specific research team member assigned to complete all sessions with 
the same participant to establish rapport and encourage the participant to continue attending sessions.  

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4 
BASIC STUDY DESIGN 
Participants who pass an initial screening by phone are asked to attend a screening visit where consent is provided, 
eligibility for study participation is confirmed and demographic information is collected. Participants who are 
eligible to participate will then be asked to return for two study sessions after an MRI scan. Sessions will start at 
8.00 am and study participants will be asked to fast for the preceding 12 hours and to consume approximately 
150g of carbohydrates each day for the 3 days prior to the session. The study procedures are identical for both 
study visits. The order of the two sessions is equally randomized across participants.  
In one visit, an oral 3-hour GTT with a 75g load of glucose will be administered. In the other visit, pure drinking 
water will be used. Both study visits have the following time-line: 
1. Determined the target (hand area of the left precentral gyrus, left primary motor cortex) based on MR 
images using a TMS neuro-navigation system.  
2. Fitting of an EEG electrode net. 
3. Baseline EEG and MEP measurements elicited by TMS 
4. Measurement of fasting blood glucose level by finger prick 
5. Administration of drink (glucose drink or water, 296mL of H2O for both drinks) 
6. Capillary blood draw (finger prick) for glucose level testing and TMS-induced EEG and MEP measurements 
at 0, 30, 60, 120, 180 minutes after drink administration 
7. Digitization of EEG electrodes on the scalp using a camera-type scanner 
 
 
4.1 
TREATMENT ASSIGNMENT PROCEDURES 
Each participant will experience two experimental conditions (glucose drink and water). There are 2 ways to order 
the two conditions (glucose drink and then water, water and then glucose drink). By randomization, each 
participant will be assigned to one of the sequences. Ten participants will be assigned to each of these 2 sequence 
groups. Each session has at least a 3-day gap to minimize the presence of outlasting effects of either the GTT or the 
TMS. The randomization schedule will be computed prior to recruitment of subjects and the random assignments 
will be concealed from the personnel who screen potential participants until the moment that the participant is 
enrolled and ready for baseline evaluations. To accomplish this, the randomization schedule will be used to create 
a set of sequentially-numbered opaque sealed envelopes.  
Glucose drink → Drinking water (10 participants) 
Drinking water → Glucose drink (10 participants) 
 

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5 
STUDY SCHEDULE 
In order to increase data quality, the assessments for an individual participant will be administered by the same 
researcher. It is important to note that consent, scales, and experiments will all take place in a private room. Any 
phone calls will take place in a private lab environment as well.  
5.1 
SCREENING 
• 
Phone screening 
The phone screening allows researchers to screen out participants based on self-report responses and for potential 
participants to become familiar with the study schedule, including procedures. During the telephone screening, 
researchers will provide a brief background about GTT, TMS, and EEG. The timeline will be explained to the 
participants and the participant will be informed of compensation, both amount and payment schedule. The 
participant will be asked if they have any questions. Once all questions have been answered, the participant will be 
asked if he/she is still interested in participating in the study. If yes, the researcher will ask if the participant will 
provide verbal consent to begin the initial phone screening which will determine eligibility for the stimulation 
session. A telephone script, which includes the screening questions, is provided in Appendix E.  
• 
Screening visit (Visit 1) 
Participants who pass an initial screening by a telephone call are asked to attend a screening visit where consent is 
provided, eligibility for study participation is confirmed and demographic information is collected. To ensure that 
all aspects of the research are understood, participants may be asked a series of questions about the research they 
are about to take part in (Appendix C). After then, participants are asked to provide weight and height for 
calculating body mass index (cut-off level < 30). Fasting blood sugar test level will be collected (cut-off level < 95 
mg/dL). If participants meet the inclusion/exclusion criteria, they will be asked to visit 2 study sessions after an MRI 
scan. Also, participants will perform a cognitive control task to measure baseline cognitive function. At the 
screening session, the participants will complete the STAI form Y-2 and the IDAS to determine their trait levels of 
anxiety and depression. This data will be used to explore how a participant’s trait levels of anxiety and depression 
affect their corticospinal activity. The BIS/BAS and STAI form Y-1 questionnaires will be administered twice at each 
experimental session, once before the drink administration and once three hours after. The PANAS questionnaire 
will be administered before the drink administration, as well as 0, 30, 60, 120, and 180 minutes after the drink 
administration. The scores on these questionnaires will be compared before and after the drink administration to 
determine how the drink affected the participants’ psychological state over time. For each participant, scores on 
these questionnaires will be compared between the session during which they consumed glucose and the session 
during which they consumed water. 
• 
Questionnaires (Appendix F) 
Participants will be asked to complete the following questionnaires. 
1. State-Trait Anxiety Inventory (STAI): a 40-item self-report questionnaire for assessing state and trait anxiety). 
This questionnaire will be used to determine each participant’s level of both state and trait anxiety 
2. The Positive and Negative Affect Schedule (PANAS): a self-report questionnaire that consists of two 10-item 

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scales to measure both positive and negative affect. This questionnaire will be used to measure participants’ 
positive and negative effect. 
3. The Edinburgh Handedness Inventory: a well-known questionnaire for determining objectively whether one is 
left or right handed. This will be used to confirm that all participants are right-handed. 
4. Behavioral avoidance/inhibition (BIS/BAS) scales: a questionnaire that consists of 24-item for assessing 
behavioral inhibition, behavioral activation, and affective responses to impending reward and punishment. This 
questionnaire measures each participant’s motivation to avoid adverse events and approach goal-directed activity. 
Since a loss of motivation is a key element of depression and other psychological illnesses, this questionnaire can 
indicate psychological well-being. 
5. Inventory of Depression and Anxiety Symptoms (IDAS): a questionnaire that consists of 64 items to assess 
specific symptom dimensions of major depression and related anxiety disorders. The IDAS consists of ten symptom 
scales including suicidality, lassitude, insomnia, appetite loss, appetite gain, ill temper, well-being, panic, social 
anxiety, and traumatic intrusions. 
 
 

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5.2 
STUDY SESSIONS 
• 
MRI scan (Visit 2) 
We will ask participants to come in and complete an MRI scan. MRI scan imaging will take place at the Biomedical 
Research Imaging Center (BRIC), located on the first floor in Marsico Hall. Screening questions will be completed 
prior to the MRI scan (attached) and all preparations for the scan will take place in a facility area behind a locked 
door, where only research study personnel have access. When subjects are required to change their clothing, they 
will be allowed to do so alone, in a room with a door that locks. MRI scan will be performed by trained study 
personnel or designees of the PI that are approved to complete an MRI scan. 
• 
Study sessions (Visit 3-4) 
All participants will undergo two study sessions (glucose or water administration) with at least 3-day gap to 
minimize the effect of either GTT or TMS. In each visit, all participants will be asked to fill out the questionnaires at 
the beginning and end of the session. Participants undergo a two-minute eyes-open resting-state EEG recorded 
with high-density, 128 channels EEG system (Netamps 410, Electrical Geodesics Inc, EGI) using Geodesic Sensor 
Nets (sampled at 1000 Hz). EEG nets will be fitted at the beginning of the two study visits and remain in place until 
completion of the study visit. Also, participants will perform a cognitive control task to investigate if changes in 
glucose blood level could modulate cognition. 
Single-pulse TMS on the motor cortex leads to a twitch in the target muscle evoking a motor-evoked potential 
(MEP) measured by electromyography (EMG) electrodes. Participants will be seated in a comfortable armchair 
with their hands positioned on the armrest. Two disposable electrodes (15x21mm, Ambu Neuroline) will be placed 
in a tendon-belly arrangement over the first dorsal interosseous muscle and a ground electrode will be placed over 
the styloid process of the ulna. A figure-eight coil (C-B60, MagVenture) will be used for stimulation and EMG 
signals will be recorded by an amplifier (MagPro X100, MagVenture). The coil will be placed tangentially over the 
scalp with the handle pointing backwards and laterally at 45° from the mid-sagittal line. Biphasic TMS pulses will be 
applied over the motor cortex and the resting motor threshold (RMT) will be defined by the minimum TMS 
intensity required to evoke MEP of at least 50 uV in 50% of 10 consecutive trials. At baseline, 10 TMS pulses will be 
applied on the scalp and EEG and EMG data will be collected. At the same time, blood glucose level will be 
measured by 5uL of finger prick blood sampling as a baseline glucose level. In an intervention step, we will 
administer a 75g load of glucose drink or drinking water at each study visit. After then, glucose level testing and 
EMG/EEG data collection will be performed at 0, 30, 60, 120, and 180 minutes after the drink administration. Once 
participants complete the first study visit, a study coordinator will schedule their next visit with at least 3-day gap.  
 
 

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6 
STUDY PROCEDURES/EVALUATIONS 
6.1 
SELF-REPORT MEASURES 
Study coordinators will consider using a standard safety questionnaire to screen TMS candidates. The following 
questions represent the basic information required. Additional information may change according to particular 
demands. Consensus has been reached for this questionnaire (Rossi et al., 2009). 
1. Did you ever have a concussion? 
2. Do you have or have you ever had diabetes? 
3. Do you have or have you ever had anorexia? 
4. Do you have or have you ever had OCD? 
5. Do you have or have you ever had ADHD? 
6. Have you ever had a fainting spell or syncope? If yes, please describe in which occasion(s) 
7. Have you ever had severe (i.e., followed by loss of consciousness) head trauma? 
8. Do you have any hearing problems or ringing in your ears? 
9. Are you pregnant or is there any chance that you might be? 
10. Do you have metal in the brain/skull (except titanium)? (e.g.,splinters, fragments, clips, etc.) 
11. Do you have cochlear implants? 
12. Do you have an implanted neurostimulator? (e.g., DBS, epidural/subdural, VNS) 
13. Do you have a cardiac pacemaker or intracardiac lines or metal in your body? 
14. Do you have a medication infusion device? 
15. Are you taking any medications? (Please list) 
16. Did you ever have a surgical procedures to your spinal cord? 
17. Do you have any disorder related to spinal cord or ventricle? 
18. Did you ever undergo TMS in the past? 
 
We will ask these questions in order to follow the standard safety guidelines for TMS studies. Answers from the 
questions will help us to exclude study participants regarding the safety of TMS  
6.2 
SPECIAL ASSAYS OR PROCEDURES 
6.3.1 
GLUCOSE TOLERANCE TEST 
All participants will be asked to fast 12 hours prior to the test. In addition, we will ask participants to 
consume approximately 150 g of carbohydrates per day on the 3 days prior to the test to stabilize the 
participant’s glucose response (See Appendix G for instruction sheet). We will perform a capillary blood 
draw by finger prick to obtain approximately 5uL of blood using a microcuvette. The blood sample will be 
immediately analyzed by an FDA-cleared glucose analyzer or stored in a refrigerator (below 46°F). We will 
be using HemoCue Glucose 201 system (HemoCue, Angelholm, Sweden).  
6.3.2 
MOTOR-EVOKED POTENTIALS AND TMS-EVOKED POTENTIALS 
We will collect TMS-induced motor-evoked potentials (MEPs) and EEG potentials using EMG electrodes 
and a high-density EEG. Resting motor threshold (RMT) is determined while the target test muscle is at 
rest. EEG will be collected using Geodesic 400 system (EGI Inc., Eugene, OR, USA). 

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7 STUDY INVESTIGATIONAL PRODUCT 
• 
Glucose solution 
We will use a FDA-cleared glucose drink (Azer Scientific Inc., Morgantown, PA) contains the following ingredients: 
dextrose (source: corn), citric acid, artificial flavoring, sodium benzoate (0.1%), and purified water. The glucose 
solution is manufactured according to WHO and ADA standards, and it is produced in a FDA certified, 
pharmaceutical facility. The glucose drink is 10 fluid ounces (296mL), so the participants will receive 10 fluid 
ounces of water during the other session. 
• 
Glucose tolerance test (GTT) 
We will use the Glucose 201 system (HemoCue, Angelholm, Sweden) for measuring blood 
glucose level. The HemoCue Glucose 201 System is based on a glucose dehydrogenase method 
and consists of a small dedicated analyzer and a unique disposable microcuvette. The system 
combines the precision and accuracy of a central laboratory with the speed and convenience of 
obtaining results at the point-of-care. With just a fraction of a drop of whole blood and three 
simple steps, the HemoCue Glucose 201 System will produce immediate, accurate results for 
diagnosing or monitoring diabetes, as well as monitoring neonatal blood glucose levels.  
The system has several features: 
- 
Factory calibrated and traceable to ID GC-MS method, needs no further calibration and no coding 
- 
Approximately 5 μL whole blood sampling 
- 
Sample material: Capillary, venous or arterial whole blood including neonatal blood 
- 
Display range: Plasma equivalent values 0-444 mg/dL 
- 
Result calculation time: 40-240 seconds 
 
• 
Transcranial magnetic stimulation (TMS) 
We will use the MagPro X100 system (MagVenture Inc., Alpharetta, Georgia, USA) 
for magnetic stimulation. The MagPro X100 is an advanced, high performance 
magnetic stimulator designed primarily for research purposes. It is a high-quality 
tool for researchers with a large choice of stimulating parameters and has 
stimulation rates up to 100 pps at high intensities and the possibility to combine 
waveforms and pulse modes.  
The simulator has several features: 
- 
3 waveforms: Biphasic, Biphasic Burst and Monophasic. 
- 
Selectable current direction. 
- 
Stimulation rates up to 100 pulses per second. 
- 
Easily connects to external equipment via programmable input/output triggers. 
- 
System operation control via a built-in computer, eliminating the need for an external computer to set up 
and control the timing of stimulus sequences. 

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- 
Controllable from an external device. 
 
 

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7.1 
SAFETY FEATURES 
• 
GTT 
According to the Hazard Communication Standard 29 CFR 1910.1200 and the Guidance for Hazard determination, 
chemicals that falls under the category "articles" does not apply to this standard. 
"Article" means a manufactured item other than a fluid or particle: 
(i) which is formed to a specific shape or design during manufacture; 
(ii) which has end use function(s) dependent in whole or in part upon its shape or design during end use; and 
(iii) which under normal conditions of use does not release more than very small quantities, e.g., minute or trace 
amounts of a hazardous chemical and does not pose a physical hazard or health risk to employees. All HemoCue 
Microcuvettes are articles, therefore this standard is not applicable. 
• 
TMS 
In the USA federal law regulates the sale of Medical Devices through the US Food and Drug Administration (FDA). 
This is done to ensure safety and effectiveness. Devices which are permitted to be marketed for their intended use 
must either have a 510(k) or PMA clearance. The use of devices for other than their FDA cleared intended use is 
considered as investigational. Such use is only permitted if the Investigational Device Exemption (IDE) guidelines 
have been followed. All investigational devices must be labeled in accordance with the labeling provisions of the 
IDE regulation (§ 812.5) and must bear a label with this statement:  
7.2 
PREPARATION AND ADMINISTRATION OF STUDY INVESTIGATIONAL PRODUCT 
After participants have completed the questionnaire, they will be comfortably seated. The study coordinator 
and/or the research assistant will be thoroughly trained and have trainings documented on the glucose blood 
sampling and TMS device and will be present during all sessions. To monitor side effects of blood sampling and 
stimulation, a questionnaire will be administered after each session.  
7.3 
ASSESSMENT OF PARTICIPANT COMPLIANCE WITH STUDY INVESTIGATIONAL PRODUCT 
Compliance for this study includes making 2 study sessions. Participants have the ability to schedule their second 
visit 3 days after the first visit. Follow-up emails will be sent out 1 day before the scheduled second visit. 

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8 
POTENTIAL RISKS AND BENEFITS 
8.1 
BENEFITS TO SUBJECTS AND SOCIETY 
There is no direct benefit to participants but the research outcome will help to design new study for understanding 
the underlying mechanism of brain network excitability and diabetes. 
8.2 
POTENTIAL RISKS 
8.2.1 
PSYCHOLOGICAL 
Risk of Embarrassment: Self-report questionnaire contains questions regarding personal information. This 
risk is necessary in order to assess symptomology and associated psychopathology. Participants will be 
assured upon intake that only study personnel will see any answers. 
Risk of Confidentiality Breach. To avoid breaches in confidentiality, study documents that contain 
personal information, including the informed consent, and the document that links study ID numbers to 
personal identifying information are kept in locked filing cabinets in locked rooms, separate from any 
source documents containing participating dummy identifiers. All data is stored in locked cabinets inside 
locked offices; electronic data will be stored only on password-protected computers, and data encryption 
methods will be used during communication between investigators. Only study personnel will have access 
to these data. All study staff participate in annual human participating training that includes education 
about responsibilities to minimize the risk of confidentiality breach. In the unlikely event of a breach of 
confidentiality, people might discover that an individual was involved in this research study and some 
people might not agree with the principle of participating in research or of changing natural brain activity.  
8.2.1 
PHYSICAL 
Risk of Injury and Discomfort: Non-invasive brain stimulation has been used without any reports of 
serious side-effects for more than a decade and TMS has been cleared for use in the USA by the FDA. The 
stimulation made nothing to do with electroconvulsive therapy that applies many orders of magnitude 
higher stimulation current. Some participants report a scalp pain, tingling, burning, or itching on the 
stimulation site but no other side effects have been noted. In order to monitor these side-effects, we will 
be administering side effects stimulation questionnaire after each stimulation session to determine 
whether these effects were experienced. Research personnel present during these sessions will also check 
in with the participant periodically during the stimulation to see whether they are comfortable. If any 
side-effect occurs (rated by the participant as stronger than “moderate”) or the participant is experiencing 
severe discomfort, the stimulation will be immediately stopped.  
Risk of Bleeding: The glucose tolerance test is a medical test in which glucose is given and blood samples 
taken afterward to determine how quickly it is cleared from the blood. The test is usually used to test for 
diabetes, insulin resistance, impaired beta cell function, and sometimes reactive hypoglycemia and 
acromegaly, or rarer disorders of carbohydrate metabolism. We strictly follow the medical guidelines 
using an FDA-cleared device and sampler and blood sampling will be immediately stopped if any 
unexpected bleeding occurs.  
 
Risk of Glucose Ingestion: The risks associated with glucose ingestion in healthy participants are minimal. 

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The potential side effects include nausea, sweating, light-headedness, vomiting, bloating, headache, 
diarrhea, and constipation. Serious side effects from the test are very uncommon. 
 
 
8.3 
REFERRALS FOR MEDICAL FOLLOW-UP OR PSYCHOLOGICAL COUNSELING 
There is a purely theoretical likelihood that stimulation of neuronal circuits can lead to epileptic discharge. To 
minimize this occurrence, we screen and exclude subjects with personal history of neurological conditions from 
the study. If abnormalities or a seizure is witnessed during the course of the study, a referral will be made to the 
UNC Department of Neurology for follow-up. In the theoretical event that a seizure is witnessed that involves the 
loss of consciousness, the subjects will be told not to operate a motor vehicle until cleared by the DMV. 
There is an additional albeit small likelihood that a participants blood glucose levels at 2 hours may be indicative of 
impaired glucose tolerance and a possible undiagnosed status of diabetes or prediabetes. Since the GTT is not 
administered in a medical context or under the supervision of an MD, this is not taken as a conclusive result. 
Therefore in the event that this occurs, the participant will be contacted by our study diabetes doctor (Dr. John 
Buse, MD, PhD) or the participant may be referred to follow up with his or her own primary care doctor.  
To ensure participant comfort, a study coordinator or research assistant will periodically check in with the 
participant about any side-effects he/she may be experiencing during each stimulation.  
 
 

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9 
DATA AND SAFETY MONITORING 
9.1 
FROHLICH LAB MONITORING PLAN 
The purpose of this monitoring plan is to present the Frohlich Lab’s approach to monitoring clinical trials. The plan 
facilitates compliance with good clinical practice (GCP): 
a. 
The rights and well-being of human subjects are protected. 
b. 
The reported trial data are accurate, complete, and verifiable from source documents 
c. 
The conduct of the trial is in compliance with the currently approved protocol/amendment(s) with GCP, 
and with applicable regulatory requirement(s) 
This section identifies key monitoring activities and specifies the data to be reviewed over the course of a clinical 
trial. This is a single site, investigator-initiated, clinical trial, so there will be no site monitoring plan in place. 
The latest version of the approved IRB application for this clinical trial will be followed at all times. This 
responsibility falls into the hands of the study coordinator and research assistants. If at any time there is a 
deviation from protocol, the deviation from protocol log will be filled out. All team members will be trained on 
how and when to use this log. The most up-to-date IRB application will be on file in the Clinical Trials office in 
Room 233 of the Medical School Wing C. Deviations will be sent to the IRB every 4-6 weeks (if necessary). 
Periodically, study staff should review 3 randomly selected informed consent forms to ensure that (1) these forms 
have been filled out appropriately, and (2) the consent form process was followed and properly documented. 
Should any consent form be in violation, the research team will perform and document a complete review of all 
consent forms.  
AE and SAE are clearly defined in this document. Documents of AE and SAE can be found in the study binder on file 
in the Clinical Trials office in Room 233 of the Medical School Wing C. It is the responsibility of the study 
coordinator to report all events to the PI in a timely manner (see 9.3 Reporting Procedures). All AEs and SAEs will 
be discussed with the PI. For our practices, we have adapted the decision tree provided by the UNC-CH IRB to 
assist with reporting of such events. 
Periodically, the study coordinator should also choose one CRF/eCRF and Source Document to assess for 
completion and maintenance. In addition, the PI will assess completeness of data on REDCap. The PI has read-only 
access. This allows the PI to view reports that provide information on any missing data on an individual participant 
basis, but does not allow the PI to add, change, or input any data. A data safety monitor will review blinded AEs 
every month. 
9.2 
SAFETY OVERSIGHT BY THE DSMB 
A data safety monitoring board will not be used for this study. 
9.3 
EARLY WITHDRAWAL OF PARTICIPANTS 
9.3.1 
REASONS FOR WITHDRAWAL 
A study participant will be discontinued from further participation if: 

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• 
The participant meets any exclusion criteria (either newly developed or not previously 
recognized). 
• 
Anything that, in the opinion of the investigator, would place the participant at increased risk or 
preclude the participant’s full compliance with or completion of the study. 
Participants are free to withdraw from participation in the study at any time upon request. 
9.3.2 
DATA COLLECTION FOR WITHDRAWN PARTICIPANTS 
We will collect safety data on any participant discontinued because of side effect. In any case, every effort 
will be made to undertake protocol-specific follow-up procedures. If voluntary withdrawal occurs, the 
participant will be asked to continue scheduled evaluations and complete an end-of-study evaluation. In 
the case of an early withdrawal, the researcher will make a note to file indicating this. 
9.4 
TERMINATION OF STUDY 
Participants will be informed of their right to discontinue the study at any time with no penalty. If a participant 
decides to drop out of the study, either because they cannot tolerate the 75 grams of glucose or they are 
uncomfortable with the stimulation, the experiment will be immediately stopped. The participant will still be 
compensated for the entire session. The data from that participant will not be used in analysis. If the participant 
has already completed either a blood draw or TMS stimulation when they decide to drop out of the study, they will 
be asked to complete the blood sampling and stimulation questionnaire. 
If a seizure occurs at the time of a study visit, a temporary hold will be placed over the study and further 
investigation will ensue. This could lead to stopping the study prematurely or continuing on with further safety 
measures in place. If two seizures are witnessed during the study visit, the entire study will be stopped 
prematurely. These individuals would be referred for further medical attention. It is very unlikely that a seizure will 
occur. 
The study will also be stopped (at least temporarily) if studies provide evidence that transcranial current/magnetic 
stimulation caused brain damage or other harmful effects on subjects, either short-term or long-term 
The IRB will also be informed promptly and provided the reason(s) for the termination of suspension of by the 
investigator, as specified by the applicable regulatory requirement(s). 
 
 

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10 
SAFETY & REPORTING 
It is important to assess safety over the course of this study. This section describes in detail how safety is assessed, 
reporting of side effects and unanticipated problems. This section is a reference for internal use. 
10.1 
SAFETY PARAMETERS 
STIMULATION SIDE EFFECTS. The side effects listed are headache, neck pain, scalp pain, tingling, itching, 
ringing/buzzing noise, burning sensation, local redness, sleepiness, trouble concentrating, improved mood, 
worsening of mood, dizziness, flickering lights, and other (specify). Participants are also asked to rate on a 5 point 
likert scale how related they believe the side effects to be to stimulation (1 = no relation, 2 = remote, 3 = possible, 
4 = probable, 5 = definite). 
10.2 
METHODS AND TIMING FOR ASSESSING, RECORDING, AND ANALYZING SAFETY 
PARAMETERS 
10.2.1 UNANTICIPATED PROBLEMS 
Unexpected Events (UE) will be recorded) and will include information such as the date of the event, 
when the study team was informed of this event, details of the event, when the IRB was notified.  The IRB 
will be notified of each UE that may occur during the study. 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
subjects or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
• 
unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that 
are described in the protocol-related documents, such as the IRB-approved research protocol 
and informed consent document; and (b) the characteristics of the subject population being 
studied; 
• 
related or possibly related to participation in the research (in the guidance document, 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); and 
• 
suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
If an UE occurs the IRB will be notified and the study will be adjusted as needed to protect the health and 
safety of the participants.  Depending on the nature of the UE, the research protocol, inclusion/exclusion 
criteria, and informed consent will be changed to reflect the possibility of this event reoccurring. During 
this time, no new participants will be recruited and the research procedures for currently enrolled 
participants will be stopped.  Each UE will be recorded and reported throughout the study.      
 
 
 

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11 
STATISTICAL PLAN 
The statistician for this study is Dr. Kai Xia.  
 
11.1 
STATISTICAL ANALYSIS STRATEGIES 
Outcome variables include: 
Aim 1 
1) motor-evoked potentials to measure corticospinal excitability (unit: uV) 
2) TMS-evoked potentials to measure cortical excitability (unit: uV) 
Aim 2 
1) EEG spectral power in the theta-band (4-8Hz) averaged over frontal EEG channels to measure engaged brain 
network dynamics (unit: dB). 
2) EEG spectral power in the alpha-band (8-12Hz) averaged over left frontal EEG channels to measure disengaged 
brain network dynamics (unit: dB). 
For all analyses, outcome measures are analyzed as the difference from baseline metrics before the GTT. The 
repeated measures of primary outcome will be fitted into general linear mixed effect model where baseline 
measures (continuous), time of measures (categorical), treatment method (binary) and time by treatment as fixed 
effects, while the within-subject effect among different time point (0, 30, 60, 120, 180 minutes) is modeled as 
random intercept assuming autoregression model (AR(1)) as covariance structure. The two sided Wald-test of 
treatment method (fixed effect) between the verum GTT versus control GTT condition is our primary result of 
interest. We hypothesize a significant main effect for factor GTT but no effect for factor time nor the interaction of 
GTT by time. We hypothesize that verum-GTT will modulate corticospinal and cortical excitability. In case we do 
find a significant interaction of GTT by time, we will use post-hoc contrast test to compare the overall differences 
between verum-GTT versus control-GTT at each time point and correct for multiple comparisons using false 
discovery rate (FDR) method. All hypothesis tests that are observed to be not statistically significant will be 
reported as being inconclusive. Based on the nature of our study design, we assume missing data to be minimal, 
where linear mixed effect model is robust to handle such missing value situations without creating any obvious 
bias. For all the result tables of statistical analysis, statistical estimates of population parameters will be tabulated 
along with corresponding confidence intervals (CIs). Given the lack of any comparable study in the literature, we 
performed a power analysis guided by the number of participants we are able to enroll based on the size of the 
grant. Briefly, with a sample of N=20 participants, we will be able to detect an effect size of dz = 0.66 with alpha = 
0.05 and beta = 0.2. Power analysis was performed with G*Power. 
 
Questionnaire data 
The level of trait anxiety, as indicated by the STAI form Y-2, will be compared to the participant’s corticospinal 
excitability to investigate whether a correlation between the two factors exists. Lower motivation, as measured by 
the BIS/BAS, is hypothesized after glucose consumption as compared to after water consumption. Greater state 
anxiety, as measured by the STAI form Y-1, is hypothesized after glucose consumption as compared to after water 
consumption. Greater negative affect and lesser positive affect, as measured by the PANAS, is hypothesized after 
glucose consumption as compared to after water consumption. 
11.2 
CHOICE OF SAMPLE SIZE 

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The choice of sample size was based on expert opinion and funding limit; we conjecture that 20 participants may 
be sufficient to provide adequate precision for the estimators of variance components and other parameters for 
which information is needed to plan a future study. As a rough and indirect assessment of the precision afforded 
by studying a sample of 20 subjects, we considered that an estimate of the proportion of subjects in the target 
population that would experience a greater decrease in MEP and TEP amplitude with verum-GTT (Glucose), 
relative to control-GTT(water) for an observed estimate of 50%, the 95% confidence interval would span [50% ± 
20%]. Or, if 80% was the observed estimate, then the 95% CI would span [80% ± 16%].  
11.3 
DATA MANAGEMENT 
The glucose solution will be acquired from Azer Scientific and stored in a secure air-conditioned facility. The 
solution will be packaged and shipped in shatter-proof 10 fluid ounce plastic bottles with clear labels 
Data will be stored in a password-protected cloud-based data system that does not contain any participant 
information. Individual records are referred to by dummy identifiers that cannot be traced back to the study 
participants except with the master code list that is stored separately in a secured location. 
 
 

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12 
DATA HANDLING AND RECORD KEEPING 
The study coordinator and research assistants are responsible for the accuracy, completeness, legibility, and 
timeliness of the data reported. 
12.1 
PHI AND HIPAA 
Information about study participants 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 the participants in this study 
• 
Who will have access to that information and why 
• 
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 participant revokes authorization to collect or use PHI, the investigator, by regulation, retains 
the ability to use all information collected prior to the revocation of participant authorization. For participants 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. 
12.2 
CONFIDENTIALITY 
12.2.1 ACCESS TO SOURCE DOCUMENTS 
The research coordinator, research assistants, and PI will have access to all of the source documents 
collected over the course of the study. The Co-I and medical monitor will have access to files upon 
request, as they will need access to the locked rooms and filing cabinets in which these documents are 
located.  
Data will stay on a password-protected computer. Subsequently, a copy will be processed on a separate, 
password-protected desktop computer in the Frohlich Lab (Neuroscience Research Building 4129). 
12.2.3 OTHER 
Please note that there is no significant risk of deductive disclosure in this study. In addition, none of the 
groupings or subgroupings used in analysis will be small enough to allow individuals to be identified. 
12.3 
SOURCE DOCUMENTS 
Source data is all information, original records of clinical findings, observations, or other activities in a study 
necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents. 
Source data include: 
PARTNERS HUMAN RESEARCH COMMITTEE (IRB). 
• 
All IRB correspondences are documented 
• 
The study staff is IRB approved prior to performing any study procedures 
• 
All versions of the IRB protocols and informed consent forms are on file 

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INFORMED CONSENT. 
• 
Ensure that participant identification is not recorded on the ICF (i.e., no participant ID) 
• 
There is documentation that the participant is given a copy of the consent form 
• 
The participant and study representative signed and dated the consent form for him/herself 
• 
The participant initialed and dated all appropriate pages on the informed consent form 
• 
Note to file (Appendix D) made for any informed consent deviations 
• 
Ensure a valid (current version date) copy of the consent form was used 
PROTOCOL DEVIATIONS. 
• 
Any and all protocol deviations (exceptions and violations) are documented in the participant folder and 
reported to the IRB as required 
OTHER SOURCE DOCUMENTS. 
• 
Each participant folder will contain a checklist to ensure that all source documents are administered and 
collected properly. The checklist will be dated by the researcher for each time an assessment is 
administered 
• 
Review participant folders to ensure the accuracy, completeness, and legibility of the data. 
• 
Any correction made to the source documents is dated, initialed, and explained. The original entry should 
not be obscured. 
• 
The protocol-specific source documents are on file. 
• 
Source documents are completed in ink. 
• 
Note to files (Appendix D) are made for missing or incomplete data and to explain any discrepancies or 
additional comments. 
12.4 
DATA MANAGEMENT RESPONSIBILITIES 
The responsibilities designated to each member of the research team are documented on the Delegation of 
Authority Form. The study coordinator and research assistants will be responsible for the informed consent 
process, review for eligibility, questionnaire administration, data entry, device administration, EEG administration, 
and CRF entries. The study coordinator will be responsible for documentation and reporting, while the PI will be 
responsible for review of the documentation forms, and overview of the research staff.  
12.5 
DATA CAPTURE METHODS (REDCAP) 
All data will be entered into a data capture system provided by REDCap. The data system includes password 
protection and internal quality checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete, or inaccurate. Clinical data will be entered directly from the source documents. 
All assessments completed by the participant at home will be completed via REDCap as well, ensuring participant 
security and confidentiality.  
12.6 
PROTOCOL DEVIATIONS 
All deviations from the protocol will be addressed in study participant source documents. The researcher will 
complete a Protocol Deviation Log using the participant code as the identifier. This form will collect information 
such as the date the deviation occurred, details of what the deviation consisted of, any corrective and preventative 
actions that were taken as a result of the deviation, and the date that the PI and IRB were notified. The PI will 

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review the information and initial once approved. A completed copy of the Protocol Deviation Form will be 
maintained in the regulatory file, as well as in the participant’s source document. Protocol deviations will be sent 
to the IRB per their guidelines. The site PI/study staff will be responsible for knowing and adhering to their IRB 
requirements. 
12.7 
RECORD RETENTION 
According to the University of North Carolina at Chapel Hill’s Archives and Record Management Services schedule 
for General Records Retention and Disposition Schedule 6.10, records will be kept for 5 years after the completion 
of the study or grant end date, whichever is later. 
 
 

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13 
ETHICAL CONSIDERATIONS 
13.1 
ETHICAL STANDARD 
The investigator will ensure that this study is conducted in full conformity with the principles set forth in the 
Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research, as drafted by 
the US National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (April 
18, 1979) and codified in 45 CFR Part 46 and/or the ICH E6; 62 Federal Regulations 25691 (1997). 
13.2 
INSTITUTIONAL REVIEW BOARD (IRB) 
The Office of Human Research Ethics is responsible for ethical and regulatory oversight of research at UNC-Chapel 
Hill that involves human participants. The OHRE administers, supports, and guides the work of the Institutional 
Review Boards and all related activities. Any research involving human participants proposed by faculty, staff, or 
students must be reviewed and approved by an IRB before research may begin, and before related grants may be 
funded. OHRE and the IRBs are critical components of the coordinated Human Research Protection Program, which 
serves to protect the rights and welfare of human participants. All components of this program must work 
together to ensure institutional compliance with ethical principles and regulatory requirements. The following is a 
mission statement for the coordinated Human Research Protection Program: 
The University of North Carolina at Chapel Hill is committed to expanding and disseminating knowledge for the 
benefit of the people of North Carolina and the world. An important part of that commitment to knowledge is 
research of the highest quality on all aspects of the health and behavior of people, and such research is only 
possible through the participation of humans as research participants. Human participants are partners in research 
and a precious resource to the university. At UNC-Chapel Hill, human participant research is a privilege, but not a 
right. Consistent with that philosophy, it is the mission of the UNC-Chapel Hill Human Research Protection Program 
to ensure that: 
a. The rights and welfare of human participants are paramount in the research process; 
b. The highest standards of ethical conduct are employed in all research involving human participants; 
c. 
Research investigators are properly trained in the ethical and regulatory aspects of research with human 
participants; 
d. Research investigators deal honestly and fairly with human participants, informing them fully of 
procedures to be followed, and the risks and benefits of participating in research; and 
e. Research using human participants at UNC-CH conforms to applicable local, state, and federal laws and 
regulations and the policies of the university. 
13.3 
INFORMED CONSENT PROCESS 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study and 
continues throughout the individual’s study participation. Extensive discussion of risks of TMS and GTT will be 
provided to the participants. Consent forms describing, in detail, the study intervention, device, procedures, and 
risks are given to the participant and written documentation of informed consent is required prior to the 
administration of any assessments used in this study. All consent forms will be IRB-approved and updated with any 
new information as modifications are made throughout the study. 
Together, the researcher and potential participants will review the study in its entirety by reviewing the consent 
form together in a private location. At several intervals during the consent review, the researcher will ask the 

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participant questions that will assess the comprehension of the information in the consent. If the participant is 
unsure or does not know, the researcher will return to that section and more carefully explain the information. 
Participants must sign the informed consent document prior to any procedures taking place.  If needed, the 
participants will have the opportunity to discuss the study with their surrogates or think about it prior to agreeing 
to participate.  Participants may withdraw consent at any time throughout the course of the trial.  A copy of the 
informed consent document will be given to the participants for their records.   
13.4 
EXCLUSION OF WOMEN, MINORITIES, AND CHILDREN (SPECIAL POPULATIONS) 
Non-English speaking individuals are excluded because the ability to accurately and complete communicate study 
information, answer questions about the study, and obtain consent is necessary.  
13.5 
PARTICIPANT CONFIDENTIALITY 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the research 
team.  This confidentiality is extended to cover testing of biological samples and genetic tests in addition to the 
clinical information relating to participants. 
All data will only be referenced by dummy identifier code. Data will be stored on a password protected computer. 
A key connecting names and code numbers will be kept in a locked cabinet, accessible only by research personnel. 
All data will be stored and analyzed on password protected computers, also only accessible by research personnel. 
Participants will not be identified in any report or publication about this study. See 10 Data Handling and Record 
Keeping for more information on source documentation storage and security. 
13.6 
STUDY DISCONTINUATION 
In the event that the study is discontinued, participants who have completed or who are still enrolled in the study 
will be notified.  Any new information gained during the course of the study that might affect participant’s 
willingness to continue will be communicated within 2 days of the PI learning this information. 
 
14 
PUBLICATION POLICY 
There are no restrictions on publications since this is an investigator-initiated study funded by a grant agency that 
has no influence on the publications resulting from this study.  
 
 

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15 
LITERATURE REFERENCES 
Bäckström, T., 1976. EPILEPTIC SEIZURES IN WOMEN RELATED to PLASMA ESTROGEN and PROGESTERONE DURING 
the MENSTRUAL CYCLE. Acta Neurol. Scand. 54, 321–347. doi:10.1111/j.1600-0404.1976.tb04363.x 
Becker, D., Creutzfeldt, O.D., Schwibbe, M., Wuttke, W., 1982. Changes in physiological, eeg and psychological 
parameters in women during the spontaneous menstrual cycle and following oral contraceptives. 
Psychoneuroendocrinology 7, 75–90. doi:10.1016/0306-4530(82)90057-9 
Brötzner, C.P., Klimesch, W., Doppelmayr, M., Zauner, A., Kerschbaum, H.H., 2014. Resting state alpha frequency is 
associated with menstrual cycle phase, estradiol and use of oral contraceptives. Brain Res. 1577, 36–44. 
doi:10.1016/j.brainres.2014.06.034 
Creutzfeldt, O.., Arnold, P.-M., Becker, D., Langenstein, S., Tirsch, W., Wilhelm, H., Wuttke, W., 1976. EEG changes 
during spontaneous and controlled menstrual cycles and their correlation with psychological performance. 
Electroencephalogr. Clin. Neurophysiol. 40, 113–131. doi:10.1016/0013-4694(76)90157-7 
Davidson, R.J., 1985. Affect, cognition, and hemispheric specialization., in: Emotions, Cognition, and Behavior. 
Cambridge University Press, New York,  NY,  US, pp. 320–365. 
Farzan, F., Vernet, M., Shafi, M.M.D., Rotenberg, A., Daskalakis, Z.J., Pascual-Leone, A., 2016. Characterizing and 
Modulating Brain Circuitry through Transcranial Magnetic Stimulation Combined with 
Electroencephalography. Front. Neural Circuits 10, 73. doi:10.3389/fncir.2016.00073 
George, M.S., Wassermann, E.M., Williams, W.A., Callahan, A., Ketter, T.A., Basser, P., Hallett, M., Post, R.M., 1995. 
Daily repetitive transcranial magnetic stimulation (rTMS) improves mood in depression. Neuroreport An Int. 
J. Rapid Commun. Res. Neurosci. doi:10.1097/00001756-199510020-00008 
Hattemer, K., Knake, S., Reis, J., Rochon, J., Oertel, W.H., Rosenow, F., Hamer, H.M., 2007. Excitability of the motor 
cortex during ovulatory and anovulatory cycles: a transcranial magnetic stimulation study. Clin. Endocrinol. 
(Oxf). 66, 387–393. doi:10.1111/j.1365-2265.2007.02744.x 
Nusslock, R., Walden, K., Harmon-Jones, E., 2015. Asymmetrical frontal cortical activity associated with differential 
risk for mood and anxiety disorder symptoms: An RDoC perspective. Int. J. Psychophysiol. 98, 249–261. 
doi:10.1016/J.IJPSYCHO.2015.06.004 
Rossi, S., Hallett, M., Rossini, P.M., Pascual-Leone, A., 2009. Safety, ethical considerations, and application 
guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin. 
Neurophysiol. 120, 2008–2039. doi:10.1016/J.CLINPH.2009.08.016 
Smart, O.L., Tiruvadi, V.R., Mayberg, H.S., 2015. Multimodal Approaches to Define Network Oscillations in 
Depression. Biol. Psychiatry 77, 1061–1070. doi:10.1016/J.BIOPSYCH.2015.01.002 
Smith, M.J., Adams, L.F., Schmidt, P.J., Rubinow, D.R., Wassermann, E.M., 2003. Abnormal luteal phase excitability 
of the motor cortex in women with premenstrual syndrome. Biol. Psychiatry 54, 757–762. 
doi:10.1016/S0006-3223(02)01924-8 
Smith, M.J., Keel, J.C., Greenberg, B.D., Adams, L.F., Schmidt, P.J., Rubinow, D.A., Wassermann, E.M., 1999. 
Menstrual cycle effects on cortical excitability. Neurology 53, 2069–72. doi:10.1212/WNL.53.9.2069 
Solis-ortiz, S., Ramos, J., Arce, C., Guevara, M.A., Corsi-cabrera, M., 1994. Eeg Oscillations During Menstrual Cycle. 
Int. J. Neurosci. 76, 279–292. doi:10.3109/00207459408986010 
Sutton, S.K., Davidson, R.J., 1997. Prefrontal Brain Asymmetry: A Biological Substrate of the Behavioral Approach 
and Inhibition Systems. Psychol. Sci. 8, 204–210. doi:10.1111/j.1467-9280.1997.tb00413.x 

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Tofts, P.S., 1990. The distribution of induced currents in magnetic stimulation of the nervous system. Phys. Med. 
Biol. 35, 1119. doi:10.1088/0031-9155/35/8/008 
 
 
 

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APPENDIX A: SCHEDULE OF EVENTS 
A detailed schematic describing phone screening and study visits. 
 
 
 
 
Procedures 
Phone 
Screening 
On-Site 
Screening 
Study Sessions 
Provide Verbal Consent 
x 
 
 
Signed Consent Form 
 
x 
 
Assessment of Eligibility Criteria 
x 
x 
 
Review of Medical History 
x 
x 
 
Review of Concomitant Medications 
x 
x 
 
Behavioral and Mood 
Questionnaires 
 
x 
x 
Glucose Drink Administration 
 
 
x 
Capillary blood sampling  
(finger prick) 
 
 
x 
Non-Invasive Brain Stimulation 
 
 
x 
Side-Effects Questionnaires 
 
 
x 
 
 

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APPENDIX B: IRB AMENDMENT TRACKING LOG 
 
Change 
Initiated 
By: 
Description 
of IRB: 
Type and 
Brief 
Summary 
Date 
Submitted 
to IRB 
Date of IRB 
Response 
Requires 
Stipulation
s? (Y/N) 
Requires 
Updated 
Consent 
Form? 
(Y/N) 
Stipulation 
Submission 
Date 
IRB 
Approval 
Date 
Initials 
Reference 
ID 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX C: INFORMED CONSENT QUIZ 
Name of Research Study:  
You have been asked to be in a research study. This sheet will help you think of 
questions to ask but you may have other questions.  This is not a test.  We want to be 
sure you understand what it means to be in this research study.  You should understand 
the research before you decide whether or not to participate. 
1. What is the purpose of the research? 
2. What are the possible risks of the research? 
3. Does in the research cost me anything extra? 
4. Can you stop being in the research once you’ve started? 
5. Who will view your medical records? 
6. Who do you call if I have questions about being a research subject? 
7. Any questions?   
 
 

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APPENDIX D: NOTE TO FILE 
 
IRB#: 
19-XXXX 
 
 
 
 
 
      
         PI: Flavio Frohlich 
Study Title: [Insert Short Name] 
Researcher: ________________ 
 
 
 
       Date of Occurrence: ____________ 
Participant ID: _________________ 
 
Reason for Note: 
_____________________________________________________________________________________
_____________________________________________________________________________________ 
 
Note: 
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________ 
 
Corrective action (if applicable): 
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________ 
 
 
Signature: ______________________________      Date: _______________ 
 

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APPENDIX E: TELEPHONE SCRIPT 
Hello, my name is __________ and I am a __________ from the University of North Carolina at Chapel Hill 
conducting a research study about investigation of blood glucose level and neuronal excitability. Based on your 
history, you may be eligible to participate in our study. 
Do you have time now to hear about the study, answer a few screening questions?  
(If ‘No’, ask for a good time to call back) 
 
(If ‘Yes’, proceed) 
Great!  This study is investigating how changes in blood glucose level modulate neuronal excitability. Findings from 
this study will help the development of new study. In this study, a very weak electric current will be applied to your 
scalp. Some people report a tingling, itching because of this stimulation, but no other side effects have been found.  
It is not a shock and should not cause pain. Also, we will collect your 5uL blood on your finger by pricking to 
measure your blood glucose level. This procedure is widely used for diagnosing diabetes in hospitals thus there is 
no other side effects for blood sampling. 
Participation in this study includes 1 on-site screening visit and 2 study sessions. You will be compensated for your 
time spent participating in the study. The maximum compensation for this study is $200 for completing all 
sessions. Are you still interested in participating? 
(If ‘No’, thank them for their time; if ‘Yes’, proceed) 
Great! In order to make sure you’re eligible for the study, I need to ask you a few questions. Please answer yes or 
no. You do not need to provide any further details.  
(If the answer given is not the same as the answer shown, thank the individual for his or her interest and say, 
unfortunately, they do not qualify for the current study) 
• 
Are you between 35 to 65 years old and right-handed?  (Yes) 
• 
Have you ever, or are you currently being diagnosed with diabetes and pre-diabetes? 
• 
Have you ever, or are you currently being treated for a neurological condition (e.g., epilepsy, migraines)? (No) 
• 
Are you currently taking medication for any other psychiatric illness? (No) 
• 
Have you ever had brain surgery? (No) 
• 
Do you have any brain devices or implants, including a cochlear implant or aneurysm clip? (No) 
• 
Have you ever been diagnosed with a traumatic brain injury? (No) 
 
 
Phone Screening: 
 Pass 
 Fail 
Reason for failing: _______________________________________________ 
You are eligible for participation in the stimulation session of the study. 
Scheduled Session 
 
Date: _______________ 
 
Time: _______________ 
I will send you an email confirming this time, and providing directions on how to find the specific location of your 
session. We will also send you an email to confirm your appointment 24 hours beforehand. Please respond to this 
email so we know you are still coming. If you have any questions before then, please don’t hesitate to contact us at 
this phone number or at christopher_walker@med.unc.edu. Thank you for your time. 
 

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APPENDIX F: QUESIONNAIRES 
1. STAI 
 

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2. PANAS 
 
 
 
 
 

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3. Edinburgh Handedness Inventory 
 
 
 

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4. BIS/BAS 
 

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5. IDAS 
 

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APPENDIX G: FASTING INSTRUCTIONS FOR GLUCOSE TOLERANCE TEST 
 
 
Preparing for the oral glucose challenge test:  
For three days before the test, you should eat a diet that contains at least 150 grams of carbohydrates a 
day and particularly eat at least 50 grams of carbohydrates in the meal the evening before the test.  
Foods that contain 15 grams of carbs include: 
A small piece of fruit 
1 slice of bread 
1/2 cup cooked oatmeal 
1/3 cup cooked pasta or rice 
4 to 6 crackers 
1/2 cup black beans or other starchy vegetable 
1/4 large baked potato 
2/3 cup nonfat yogurt 
2 small cookies 
1/2 cup ice cream or sherbet 
6 chicken nuggets 
1/2 cup of casserole 
1/4 serving of medium french fries 
You should have at least 3-4 servings of these 
at each meal for 3 days before the test. You 
can have more if you like.  The meal before the 
test is the most important meal to eat plenty 
of carbohydrates
These are food groups and other examples of carbohydrate containing foods: 
Dairy: Milk, yogurt, and ice cream 
Fruit:  Whole fruit and fruit juice 
Grains:  Bread, rice, crackers, and cereal 
Legumes: Beans and other plant-based proteins 
Starchy Vegetables: Potatoes and corn 
Sugary Sweets: Soda, candy, cookies, cakes
 
You should have nothing by mouth after 10PM the night before the test except for water, which you 
should drink freely to ensure that you stay well hydrated.  You should not smoke after 9PM. No 
coffee, juice or other beverages in the morning except for water.