Targeting Inter-Hemispheric Alpha Coherence With tACS To Treat PMDD
Phase: NA
Conditions: Premenstrual Dysphoric Disorder
Sponsor: University of North Carolina, Chapel Hill

1 
 
 
Complete Title: Targeting Inter-Hemispheric Alpha Coherence with tACS to Treat PMDD  
 
 
Short Title: UNC tACS Study 
Device Name: XCSITE100 tACS Stimulator 
Sponsor: Foundation of Hope for Research and Treatment of Mental Illness 
Protocol Date: 8/14/2020 
NCT:  NCT02362191 
 
 
 
 
Sponsor 
Foundation of Hope for Research and Treatment of Mental Illness 
3108 Glen Royal Road 
Raleigh, NC 27617 
 
Study Principal Investigator  
Dr. David Rubinow, MD 
304 MacNider 
Chapel Hill, NC, 27599 
Phone 919-445-0220 
email: david_rubinow@med.unc.edu 
 
 
 
 
 
 
 

2 
 
TABLE OF CONTENTS 
Table of Contents ................................................................................................................. 3 
Abbreviations and Definitions of Terms ................................................................................ 4 
Protocol Synopsis ................................................................................................................. 5 
1 
BACKGROUND  AND RATIONALE .......................................................................................................................... 8 
2 
STUDY OBJECTIVES .............................................................................................................................................. 13 
3 
INVESTIGATIONAL PLAN ..................................................................................................................................... 13 
4 
STUDY PROCEDURES ........................................................................................................................................... 15 
5 
STUDY EVALUATIONS AND MEASUREMENTS ................................................................................................... 17 
6 
STATISTICAL CONSIDERATIONS .......................................................................................................................... 18 
7 
STUDY INTERVENTION (DEVICE OR OTHER INTERVENTION) ............................................................................ 20 
8 
STUDY INTERVENTION ADMINISTRATION ......................................................................................................... 21 
9 
SAFETY MANAGEMENT ....................................................................................................................................... 21 
10  DATA COLLECTION AND MANAGEMENT ............................................................................................................ 22 
11 RECRUITMENT STRATEGY ................................................................................................................................... 23 
12 CONSENT PROCESS ............................................................................................................................................. 23 
13 PUBLICATION ....................................................................................................................................................... 23 
14 REFERENCES ........................................................................................................................................................ 24 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

3 
 
 
 
 
 
 
ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
 
 
 
Abbreviation 
Definition 
MRMD 
Menstrually Related Mood Disorder 
PMDD 
Premenstrual Dysphoric Disorder 
tACS 
Transcranial Alternating Current Electrical Stimulation 
tDCS 
Transcranial Direct Current Electrical Stimulation 
EEG 
Electroencephalography 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

4 
 
PROTOCOL SYNOPSIS 
Study Title 
Targeting Inter-Hemispheric Alpha Coherence with tACS to Treat PMDD 
Funder 
Foundation of Hope for Research and Treatment of Mental Illness 
Clinical Phase 
Not Applicable 
Study Rationale 
Impaired balance in activation between left and right prefrontal cortex has 
been described in patients with PMDD, consistent with its view as a 
network disorder. In particular, similar to major depressive disorder, the 
balance between alpha oscillation power in the left and the right 
hemisphere is shifted towards the left in patients with PMDD, more so 
during the luteal phase. We hypothesize that normalization of alpha 
oscillations in women with PMDD may be accomplished with brain 
stimulation by application of weak electric currents through transcranial 
alternating current stimulation (tACS), thereby altering the temporal 
activity structure of electric signaling in the brain. In this study, we will 
obtain electroencephalograms (EEGs) to assess whether a single session of 
tACS will enhance bilateral alpha synchronization (8-12 Hz) (by reducing 
left prefrontal alpha power) and whether this varies by menstrual cycle 
phase. An exploratory objective will be to examine the severity of the 
PMDD symptoms collected daily during the stimulation cycle compared 
with the baseline cycle.   
 
Study Objective(s) 
Primary  
• 
To determine whether a single session of tACS will reduce left 
prefrontal alpha power and thereby restore alpha symmetry 
Secondary 
• 
To determine whether the impact of tACS on alpha power and 
distribution differs across menstrual cycle phases  
 
Test Article(s) 
(If Applicable) 
XCSITE 100 Stimulator 
The device consists of the following main components/subsystems: 1. 
Tablet with user interface application (App) 2. Microprocessor 3. Function 
generator chip 4. Voltage controlled current source 5. Safety circuitry 
First, the stimulation parameters are specified by the user through the 
app. The parameters are: 1. tDCS/tACS 2. Number of channels 3. 
Amplitude 4. Test duration 5. Frequency (for tACS) 6. Password. Next, the 
parameters are sent via Bluetooth to the microprocessor. The 
microprocessor interprets these parameters, and programs the function 
generator chip accordingly through a SPI. The function generator then 
creates the programmed waveform, which is ultimately a voltage signal. 
The voltage signal is applied to a voltage controlled current source, which 
generates the specified amount of current through an arbitrary load 
resistance. 
Study Design 
 
Repeated measure, open-label trial 
Subject Population 
Inclusion Criteria: 
· 
Age 18-52 

5 
 
key criteria for Inclusion 
and Exclusion: 
· 
Have a prospectively confirmed diagnosis of PMDD 
· 
Regularly menstruating without hormonal contraceptives 
· 
Medication free or regularly taking medication that has no effect 
on the nervous system 
· 
Not currently pregnant or planning to become pregnant 
Exclusion Criteria: 
· 
Brain surgery or brain implants, including cochlear implants or 
aneurysm clips 
· 
Neurologic disease (e.g. epilepsy or brain tumor) 
· 
Traumatic brain injury 
· 
Pregnant or nursing 
· 
An unstable medical illness (e.g. congestive heart failure or end-
stage kidney disease) 
· 
History of severe or recurrent substance abuse within 2 years of 
study enrollment 
· 
History of suicidal behavior within 5 years of study enrollment 
· 
UNC Department of Psychiatry faculty, employee, or trainee 
Number Of Subjects  
 
20 
Study Duration 
Each subject’s participation is expected to last approximately one month. 
Two tACS with EEG recording sessions will occur, one during the follicular 
phase (5-9 days after menstruation) and one in the luteal, premenstrual 
phase (9-13 days after ovulation). Subjects will test their urine at home 
each morning for approximately one week to determine ovulation. Each 
tACS/EEG session will last up to 90 minutes. 
The entire study is expected to last four and a half years 
Study Phases 
Screening 
Study Treatment 
 
(1) Screening: Subjects with a diagnosis of PMDD confirmed by 
participation in a PMDD diagnostic study will be screened for eligibility in 
the tACS Study and review the informed consent forms. (2) Intervention: 
After consent is obtained, subjects will be asked to notify study personnel 
when they begin menstruating. If the subject is randomized to receive 
tACS in the follicular phase first, they will schedule a tACS session within 9 
days of the onset of menses. If they are randomized to receive tACS in the 
luteal phase first, the subjects will then perform a home urine ovulation 
test every morning until they receive a positive result, at which point they 
will schedule their tACS session 9-13 days after the positive test result. 
Each stimulation session will last 40 minutes, plus the time it takes to 
place electrodes. EEG will be recorded before and after stimulation. At the 
end of the first session, subjects will be instructed to complete daily 
symptom rating scales for one completed menstrual cycle, or about 28-32 
days. The second tACS session will be identical to the first, except it will 
occur in the opposite menstrual cycle phase as the first session. 
Efficacy Evaluations 
Primary efficacy measurement will be changes in left prefrontal alpha 
power or distribution (asymmetry) following tACS 
Pharmacokinetic 
Evaluations 
Not Applicable 
Safety Evaluations 
Primary measurements that will be used to assess safety: 

6 
 
• 
Subject semi-structured interview 
• 
Physical symptom items on the Daily Record of Severity of 
Problems (DRSP) 
Statistical And Analytic 
Plan 
We will use a t-test of pre-post changes to examine effects of tACS on left 
prefrontal alpha oscillations (primary outcome) and differences in effects 
as function of menstrual cycle phase (secondary outcome). There will be 
two levels of each of the two repeated within-subjects measures (pre vs 
post stimulation and follicular vs luteal phase). Order of administration will 
be assessed by considering order as a between- subjects variable.  
DATA AND SAFETY 
MONITORING PLAN 
Previous studies employing tACS, a non-invasive, non-pharmacologic 
procedure, have shown tACS to be safe and devoid of serious adverse 
effects. However, tACS does have some mild side effects, such as transient 
mild tingling, burning, or itching under the electrode sites. In our 
experience to date, subjects have reported either absent or mild side 
effects, and there was no difference between the groups with the 
exception of “flickering lights” (or phosphenes, p = 0.014) (Alexander et 
al., in preparation). Nonetheless, we will employ the following safety 
measures: subjects will be told that they can stop the stimulation at any 
time during the procedure and research personnel present during these 
sessions will also check in with the subject periodically during the 
stimulation to see whether they are comfortable.. Each subject will 
receive a semi-structured interview at the conclusion of the stimulation, 
and any side effects of greater than mild severity will be reported to the 
study PI. Possible side effects will be more formally evaluated with the 
daily rating forms, which will ask the subject to rate physical symptoms 
such as fatigue, headache, pain as well as any symptoms (which the 
subject can provide in text in the DRSP). The study coordinator will review 
the subjects’ daily rating forms daily. The PI will review adverse events and 
side effects in an aggregate format across all subjects enrolled on a 
quarterly basis. Substantial clinical worsening (compared with the baseline 
cycles) may result in a subject’s discontinuation from the study, at the 
discretion of the PI. Development of suicidal ideation more than just 
passive ideation (i.e., sometimes I feel like life is not worth living – not 
uncommon in women with PMDD in their symptomatic phase) for any 
reason or any unanticipated serious side effect will result in the subject’s 
discontinuation. Failure of the subject to experience symptom attenuation 
following the cessation of menses will result in the subject’s evaluation, 
discontinuation from the study, and recommendation of therapeutic 
intervention if required. The PI is responsible for the assessment and, 
where appropriate, the reporting of any adverse effects, and the PI can be 
reached 24/7. Finally, there is a theoretical likelihood that stimulation of 
neuronal circuits can lead to seizure. However, no studies have reported 
seizure as a 
side effect in recent trials of transcranial stimulation for depression or 
schizophrenia. To further minimize this very small, theoretical likelihood of 
a seizure, we screen and exclude patients with personal and family history 
of neurological conditions from the study. 
 
 

7 
 
1 
BACKGROUND AND RATIONALE 
 
Introduction 
Premenstrual Dysphoric Disorder (PMDD) describes the cyclic appearance of affective symptoms 
and resultant impairment during the luteal phase of the menstrual cycle. The objective of the 
experiment is to determine if transcranial alternating current electrical stimulation (tACS) 
will alter prefrontal alpha oscillatory frequencies in women with PMDD, disruption of which has 
been implicated in other mood disorders. A secondary objective is to determine if menstrual cycle 
phase will influence the effects of tACS on alpha oscillations. Demonstration of ‘target engagement’ 
(alterations in left prefrontal alpha oscillatory frequencies with tACS) is a necessary first step before 
moving forward with subsequent research that would test whether tACS is a potential treatment for 
this disorder - promising research in other mood disorders suggests that it may be. 
 
The cause of PMDD is unknown, the morbidity substantial, and the identified treatments limited in 
their effectiveness, since 40% of PMDD women are non-responders to SSRIs (Yonkers et al. 1997) 
and many additional women are intolerant of antidepressant induced side effects. PMDD is 
prevalent (6-8% of women of reproductive age), attended by substantial morbidity, and hence a 
significant public health problem. Indeed, by World Health Calculations, PMDD is associated with 
4.5 million Disability Adjusted Life Years in the US alone (Halbreich et al. 2003). The rationale for 
testing whether tACS differentially alters target engagement in the follicular 
versus luteal phases of the menstrual cycle is described below. 
 
Differential Effects on Cortical Activity: The rationale for testing whether tACS differentially alters 
target engagement in the follicular versus luteal phases of the menstrual cycle is as follows: 1) Role of 
Hormones: While there is little evidence for ovarian dysfunction in PMDD (Rubinow et al. 1988) a role 
for the reproductive hormones is clearly implicated, since our own work and that of others has shown 
that suppression of ovarian function results in a complete remission of symptoms in a majority of 
women with PMDD, while adding back gonadal hormones results in the return of symptoms in women 
with PMDD, with no symptoms seen in controls (Schmidt et al. 1998). Both estradiol and progesterone 
appear capable of precipitating mood destabilization in this paradigm. Recently completed studies 
from our group further demonstrate that continuous administration of hormones for longer than one-
month results in a sustained symptom remission subsequent to the initial precipitated episode. Thus, 
dysphoric mood states in PMDD appear to be induced by normal 
changes in gonadal hormones rather than by exposure to elevated hormone levels (i.e., women with 
PMDD are differentially sensitive to the mood dysregulatory effects of reproductive steroids). 
 
Although there is substantial literature demonstrating the effects of reproductive steroids and, by 
extension, the menstrual cycle on cortical activity, the usually described effects are disturbed in 
women with PMDD. Examples include the following: 1) in normal women, activation of the medial 
orbitofrontal cortex is diminished during the luteal phase and the affective valence of the stimulus to 
which it responds is reversed (i.e., it responds only to negative stimuli rather than to positive stimuli, as 
occurs during the follicular phase). These changes are absent in women with PMDD. (Protopopescu et 
al. 2008) 2) in normal women during the luteal phase, there is an increase in cortical inhibition - a 

8 
 
presumed effect of the GABA receptor activating effects of the progesterone metabolite 
allopregnanolone. This effect is absent in women with PMDD (Smith et al. 2003). Both animal and 
human data further suggest the role of a disturbed cortical response to progesterone-derived 
neurosteroids in PMDD (Epperson et al. 2002; Shen et al. 2007). Thus, sudden changes in the levels of 
allopregnanolone (as occurs at the start of the luteal phase with increasing levels of progesterone) 
result in subcortical excitability and irritability in rodents (Shen et al. 2007), while elimination of 
changes in progesterone-derived neurosteroids (with neurosteroid synthesis inhibition) successfully 
prevents the emergence of the dysphoric state in PMDD. 
 
Differential Network Activation: Psychiatric disorders characterized by dysregulation of affective 
state –depression and PMDD - are increasingly recognized as are “network disorders” in which 
aberrant electric signaling in large-scale neuronal networks mediates the clinical symptoms. Recent 
studies have documented impaired balance in activation between left and right prefrontal cortex in 
patients with PMDD (Baehr, Rosenfeld et al. 2004; Accortt, Stewart et al. 2011; Lin, Tsai et al. 
2013). In particular, similar to major depressive disorder (Henriques and Davidson 1990), the 
balance between alpha oscillation power in the left and the right hemisphere is shifted towards the 
left in patients with PMDD. The presence of alpha oscillations corresponds to a relative decrease in 
neuronal activity (inverse relationship). Therefore, such a left-shifted alpha asymmetry is indicative 
of hypoactivation of the left hemisphere – a common finding in imaging studies of patients with 
MDD (Grimm, Beck et al. 2008).  Since this asymmetry is exacerbated during the luteal but not the 
follicular phase (corresponding to the time course of symptom presentation in PMDD, (Baehr, 
Rosenfeld et al. 2004; Lin, Tsai et al. 2013), we hypothesize that successful normalization of alpha 
oscillations in women with PMDD would be a plausible approach to symptom remediation. This 
network level intervention can be accomplished with brain stimulation by application of weak electric 
currents, a non-invasive approach to modulating intrinsic cortical network dynamics. The advantage 
of this approach is twofold: it is non-pharmacologic and thus avoids the otherwise attendant side 
effects; and it will provide systems level insights into the pathophysiology underlying mood state 
dysregulation. 
 
Brain stimulation by constant electric currents applied to the scalp (tDCs) modulates neuronal 
excitability in humans (Wagner, Valero-Cabre et al. 2007; Zaghi, Acar et al. 2010; Stagg and 
Nitsche 2011). Transcranial current stimulation with sine-wave stimulation waveforms (transcranial 
alternating current stimulation, tACS) likely enhances cortical oscillations in a frequency specific 
manner. The mechanisms of weak electric fields generated by tDCS and tACS previously have been 
demonstrated to interact with cortical network activity by altering the temporal activity structure of 
electric signaling in cortex (Frohlich and McCormick 2010; Ali, Sellers et al. 2013). In this study, 
we will assess whether tACS will decrease left frontal alpha power (8-12 Hz) and whether 
the extent of the decrease varies by menstrual cycle phase. An exploratory objective will be to examine 
the severity of the PMDD symptoms collected daily during the stimulation cycle and compare that 
severity with baseline symptoms ratings collected during the PMDD diagnostic study from which these 
participants will be recruited. The rationale for this stimulation is the known deficits in the overall 
structure of cortical activity in this frequency band in patients with mood disorders (Henriques and 
Davidson 1990; Baehr, Rosenfeld et al. 2004; Bruder, Sedoruk et al. 2008; Accortt, Stewart et al. 

9 
 
2011; Lin, Tsai et al. 2013) and the previously demonstrate clinical benefits of tDCS in the treatment 
of mood disorders (Berlim, Van den Eynde et al. 2013; Brunoni, Valiengo et al. 2013). In this study, 
we will use more targeted stimulation waveforms by employing bilateral tACS instead of tDCS. We 
hypothesize that this choice of a more sophisticated waveform that directly enhances 
synchronization between the two hemispheres may be more effective in engaging the target. tDCS 
modulates overall activity levels of the targeted cortical area in a non-specific manner. Here, 
however, we propose to evaluate a more specific stimulation modality, tACS, (10 Hz stimulation 
frequency) that has been shown to selectively enhance cortical alpha rhythms (Neuling et al. 2013). 
Since the selected patient population reportedly exhibits specific deficits in the alpha frequency band, 
our stimulation approach will provide a more targeted and therefore possibly a more effective 
manipulation. 
 
Protocol History: This protocol was originally designed to test the therapeutic efficacy of tACS in PMDD 
in a double blind, randomized, sham controlled, cross-over study of 5 tACS sessions. We were unable 
to recruit subjects, largely consequent to the many daily treatment sessions required. We 
subsequently changed the primary focus of the study to that of determining whether a single session 
of tACS engaged left prefrontal cortical alpha oscillations and, by reducing them, reduced alpha 
asymmetry. We further asked whether this effect was menstrual cycle phase-dependent. If target 
engagement was demonstrated, we then intended to perform a follow-up study to assess clinical 
efficacy, particularly but not exclusively if there were any evidence for reduction of mood symptoms on 
the exploratory analysis.  
 
Name and Description of Investigational Product or Intervention  
XCSITE100 Stimulator 
We will be using the XCSITE100 stimulator designed in the Frohlich Lab for investigational purposes. 
The device is not implanted and has not been designed for or being used to support or sustain human 
life. This device does not have a potential for serious risk to the health, safety, or welfare of the 
participant. There has never been an instance of serious side-effect reported due to the use of 
transcranial brain stimulation. Previous studies in the Frohlich lab that used comparable devices (i.e., 
the commercial, CE-certified Neuroconn Plus stimulator) have always been classified as “non-
significant risk” by the full UNC IRB. The Neuroconn Plus stimulator and the XCSITE100 stimulator are 
electrically equivalent and provide the same stimulation.  
The XSCITE100 is the first non-invasive brain stimulator designed for research purposes to provide an 
active sham for tACS and record the stimulation output for later validation. This stimulator may apply 
either tDCS or tACS for up to 40 minutes (2400 seconds) with appropriate current ramp-up at the 
beginning of stimulation and ramp-down at the end of stimulation. Both tDCS and tACS may be applied 
for currents between 100 μA and 2 mA (peak-to-peak for tACS). 
The stimulator has two main components: 
1. 
Android tablet with user interface application (i.e., App) 
2. 
Stimulator with: 
a. 
Microprocessor 

10 
 
b. 
Function generator chip 
c. 
Voltage controlled current source 
d. 
Safety circuitry 
To ensure appropriate blinding for each stimulation session, there are designated unblinded individuals 
to ensure the appropriate stimulation parameters are applied to each participant. These individuals 
will not interact with participants and will only be involved with the creation of a study file and 
validation of stimulation waveform. 
1.1 
Non-Clinical and Clinical Study Findings 
Potential Benefits: Research is designed to benefit society by gaining new knowledge. This study is not 
designed to benefit participants. Affective disorders are prevalent and representative an enormous 
public health burden. This study offers the general benefit of advancing our understanding of the brain 
circuitry that may be altered by the menstrual cycle in women with PMDD. In other ongoing studies, 
our results show enhanced alpha oscillations by tACS in patients with schizophrenia or depression, with 
associated decreased hallucinations in the former and depressive symptoms in the latter. 
 
Risk/Benefit Assessment: Transcranial current stimulation has been used in hundreds of studies 
without any reports of serious side-effects (Brunoni and Amadera 2011). In our experience to date in 
studies of patients with schizophrenia and with depression, no serious adverse events have been 
reported. Therefore, transcranial current stimulation represents an extremely safe and non-invasive 
therapeutic approach. 
 
Passing weak electric current through the scalp is also routinely done for measuring 
electrode resistance in all EEG recordings, a known safe procedure. Importantly, this stimulation mode 
has nothing to do with electroconvulsive therapy, which applies many orders of magnitude higher 
stimulation current. Rather, transcranial current stimulation is so weak that it does not produce super-
threshold activation of neurons (Frohlich and McCormick 2010). There is a rare/theoretical likelihood 
that stimulation of neuronal circuits can lead to seizure. However, no studies have reported seizure as 
a side effect in recent trials of tDCS for depression or schizophrenia (Brunelin et al., 2012; Berlim et 
al. 2013) (nor in any trials to date). To further minimize this very small, theoretical likelihood of a 
seizure, we screen and exclude patients with personal and family history of neurological conditions 
from the study. 
 
When comparing input of energy into the subject, both the amount of current and the area over which 
this current is dispersed are critically important. The value of interest is called the current density, 
which is the amount of current divided by the area. Our stimulation area is 25 cm2. Therefore, we will 
use this device at 2mA, resulting in a current density of 0.08mA/cm2. Our use of this transcranial 
current stimulation device poses 'minimal risk' to subjects because of the low current density being 
applied. Our application of current will result in an equivalent current density as performed in prior 
studies, in which subjects experienced no serious side-effects or harm. Prior studies using other brain 
stimulators have used a range of current densities: (Iyer, Mattu et al. 2005) used a maximum current 
density 0.08mA/cm2, conducted at NINDS with DC stimulators, and (Groppa, Bergmann et al. 2010) 
used a maximum current density of 0.125mA/cm2 with no reported side effects 
 
With use of this technology, some subjects report transient tingling underneath the electrode on the 
scalp, itching, headache, burning sensation, and discomfort. However, a recent meta-review has 

11 
 
failed to find any significant difference in occurrence rates between transcranial current stimulation 
and sham control itching (39.3% vs. 32.9%, p>0.05), tingling (22.2% vs. 18.3%, p>0.05), headache 
(14.8% vs. 16.2%, p>0.05), burning sensation (8.7% vs. 10%, p>0.05) and discomfort (10.4% vs. 13.4%, 
p>0.05)). (Brunoni, Amadera et al. 2011).  In our experience, increased sleepiness and flickering lights 
were more common than sham stimulation. During stimulation, the research assistant will ask the 
subject about her comfort level. If the subject reports any pain, stimulation will immediately be 
stopped.  
 
EEG: EEG is a commonly used measure and is not associated with adverse events. Individuals may find 
the electrode gel annoying, as hair will require shampooing after the conclusion of the EEG. 
Embarrassment: Self-report assessments contain questions regarding sensitive personal information. 
This risk is necessary to assess mood symptoms and psychopathology. Subjects 
will be assured upon intake that only study personnel will see associated DRSP responses. 
 
Confidentiality breach: A breach of confidentiality could indicate to others a participant's history of 
PMDD. Risk of breach of confidentiality is minimized by identifying research subjects by a study 
number on all research documents. Study documents that must contain personal information, 
including the informed consent document will be kept in filing cabinets in locked rooms. The 
document that links study ID number to personal identifying information will be kept electronically 
on a UNC password protected server. All data will be 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 subject training that includes 
education about responsibilities to the minimize risk of confidentiality breach. 
 
1.4 
Relevant Literature and Data 
There is a growing literature on the use of tACS to understand the role of brain oscillations in behavior, 
cognition, and memory (see references Negahbani). Brain stimulation by constant electric currents 
applied to the scalp (tDCs) modulates neuronal excitability in humans (Wagner, Valero-Cabre et al. 
2007; Zaghi, Acar et al. 2010; Stagg and Nitsche 2011). Transcranial current stimulation with sine-wave 
stimulation waveforms (transcranial alternating current stimulation, tACS) likely enhances cortical 
oscillations in a frequency specific manner. The mechanisms of weak electric fields generated by tDCS 
and tACS previously have been demonstrated to interact with cortical network activity by altering the 
temporal activity structure of electric signaling in cortex (Frohlich and McCormick 2010; Ali, Sellers et 
al. 2013).  
 
The rationale for this stimulation is the known deficits in the overall structure of cortical activity in this 
frequency band in patients with mood disorders (Henriques and Davidson 1990; Baehr, Rosenfeld et al. 
2004; Bruder, Sedoruk et al. 2008; Accortt, Stewart et al. 2011; Lin, Tsai et al. 2013) and the previously 
demonstrate clinical benefits of tDCS in the treatment of mood disorders (Berlim, Van den Eynde et al. 
2013; Brunoni, Valiengo et al. 2013). Patients with MDD exhibit elevated oscillatory activity in the 
alpha band (8-12Hz), which is often localized to left frontal regions, resulting what has been called 
“frontal alpha asymmetry.” (Leucher, Cook, et al. 2012; Henriques and Davidson 1990).   
 

12 
 
In this study, we will use more targeted stimulation waveforms by employing bilateral tACS instead of 
tDCS. We hypothesize that this choice of a more sophisticated waveform that directly enhances 
synchronization between the two hemispheres may be more effective in engaging the target. tDCS 
modulates overall activity levels of the targeted cortical area in a non-specific manner. Here, 
however, we propose to evaluate a more specific stimulation modality, tACS, (10 Hz stimulation 
frequency) that has been shown to selectively enhance cortical alpha rhythms (Neuling et al. 2013). 
Since the selected patient population reportedly exhibits specific deficits in the alpha frequency band, 
our stimulation approach will provide a more targeted and therefore possibly a more effective 
manipulation. 
 
Mood ratings in this study will be obtained with the DRSP (Endicott et al. 2006).   This rating scale is 
among the most widely used for assessment of symptoms of PMDD (and their requisite change in 
severity over the course of the menstrual cycle). 
 
2 
STUDY OBJECTIVES  
The purpose of this study is to determine in women with PMDD whether a single session of tACS will 
alter left prefrontal alpha oscillatory power (enhance bifrontal symmetry, which is described as 
abnormal in PMDD). The secondary objective will be to determine if this ‘target engagement’ will differ 
by menstrual cycle phase. Our exploratory objective will be to examine whether changes in cortical 
dynamics will be associated with symptom reduction relative to baseline, pre-stimulation levels 
(obtained in the diagnostic feeder protocol IRB# 05-3000).  
 
2.1 
Primary Objective  
2.1.1 To determine whether a single session of tACS in women with PMDD decreases left prefrontal alpha 
power, ascertained by comparing EEG prior and subsequent to tACS.  
2.1.2 To determine whether a single session of tACS will alter prefrontal alpha symmetry 
 
2.2 
Secondary Objective 
2.2.1 Determine whether the impact of tACS on left alpha power differs across menstrual cycle phases by 
comparing primary outcome measures obtained in the follicular vs the luteal phase of the menstrual 
cycle.  
 
3 
INVESTIGATIONAL PLAN 
 
3.1 
Study Design 
Repeated measure, open-label study design.  
Overview of study phases: 
- 
Screening/Baseline: subjects will be followed for three months in a related protocol to document 
that subjects meet criteria for PMDD, showing affective symptoms of requisite severity as present 
during the luteal phase and relatively absent during the follicular phase.  
- 
Intervention/Treatment: a single 40-minute session of tACS, administered once each in the 
follicular and luteal phases of the menstrual cycle 

13 
 
- 
Follow up: subjects will be followed with daily ratings until completion of the menstrual cycle 
following the second tACS. Any subject endorsing suicidal ideation, severe deterioration of mood, 
or distressing somatic symptoms on daily rating forms will be referred to Dr. Rubinow for acute 
evaluation and determination of appropriate subsequent clinical response.  
- 
Unscheduled Visits: not applicable 
3.2 
Allocation to Treatment Groups and Blinding (if applicable): Not applicable 
3.3 
Study Duration, Enrollment and Number of Subjects 
The study is anticipated to last five years. After being shown as eligible (in our screening protocol), 
subjects will sign an informed consent form and be deemed as enrolled when they have participated in 
the first tACS session. We will enroll 22 subjects to accommodate a 10% drop-out and achieve a sample 
size of 20. Each subject’s participation is expected to last approximately one month. Two tACS sessions 
with pre-post EEG recordings will occur, one during the follicular phase (5-9 days after menstruation) 
and one in the luteal, premenstrual phase (9-13 days after ovulation). Subjects will test their urine at 
home each morning for approximately one week to determine ovulation. Each tACS/EEG session will 
last up to 90 minutes. There will be approximately 20 people in this research study.  
3.4 
Study Population 
-Inclusion and Exclusion Criteria 
Subjects will be women with PMDD. All subjects will have had their diagnoses confirmed by 
participation in our diagnostic study. The diagnosis requires demonstration of at least a 30% increase in 
symptom ratings in the seven days preceding menses compared with the seven days following the 
cessation of menses in two of three menstrual cycles. 
 
In addition to PMDD diagnosis, all women enrolled must also meet the following criteria: 
Inclusion Criteria: 
· 
Age 18-52 
· 
Have participated in our PMDD diagnostic study 
· 
Regularly menstruating without hormonal contraceptives (e.g., birth control pills, injections, 
implants, progestin IUDs) 
· 
Medication free or regularly taking medication that has no effect on the nervous system 
· 
Not currently pregnant or planning to become pregnant 
· 
With sufficient resource to prevent pregnancy 
Exclusion Criteria: 
· 
Brain surgery or brain implants (e.g., cochlear implants or aneurysm clips) 
· 
Neurologic disease (e.g., epilepsy or a brain tumor) 
· 
Traumatic brain injury 
· 
Pregnant or nursing 
· 
Any unstable medical illness (e.g., congestive heart failure or end-stage kidney disease) 
· 
History of severe or recurrent substance use disorder, or any substance abuse within 2 years of 
study enrollment 
· 
History of suicidal behavior within 5 years of study enrollment 
· 
UNC Psychiatry faculty, employee, or trainee 
· 
 

14 
 
4 
STUDY PROCEDURES  
• tACS administered on two  
• High density EEG recording before and after each tACS administration 
• Daily Record of Severity of Problems (DRSP) ratings daily throughout the study administered 
electronically via Qualtrics survey platform. This 20-item self-report rating scale assesses 
physical and mood symptoms that accompany ovarian hormone changes and is often used as a 
dimensional measure of PMDD. 
4.1 
Screening/Baseline Visit procedures 
Effect of Menstrual Phase on Target Engagement 
Diagnostic/Baseline Phase: We will attempt to recruit subjects whose PMDD status has been 
confirmed in our screening protocol (diagnostic study).  Using the DRSP (Daily Record of Severity of 
Problems), subjects must show symptom severity of 4 or greater (scale range 1-6) for two days on a 
core emotional symptom in the luteal phase, absence of symptom severity during the follicular phase, 
and a 30% or greater increase in severity of symptoms in the 7 days preceding menses with 7 days 
following the end of menses. For those who meet criteria, we will describe the tACS study during their 
last visit in the diagnostic (screening) study. It will be during this in person visit that interested subjects 
would review the consent form and we would confirm eligibility for the tACS study. Consequently, no 
separate recruitment materials or phone screening materials are required for this study as all women 
will be recruited from the diagnostic study. After consent is provided, subjects will be asked to call and 
notify the study staff when they begin menstruating. If the subject is randomized to receive tACS in the 
follicular phase first, they will schedule a tACS session within 9 days of the onset of menses. If they are 
randomized to receive tACS in the luteal phase first, the subjects will then perform a home urine 
ovulation test every morning until they receive a positive result, at which point they can schedule their 
tACS session 9 - 13 days after the positive test result. 
 
Transcranial Current Stimulation: Subjects will report for bilateral stimulation with tACS 
(one session) per menstrual phase, over the course of one menstrual cycle (unless it is an 
anovulatory cycle, in which case the participant will be asked to conduct the ovulation testing 
for one additional cycle). Each participant will receive tACS once in the follicular cycle phase 
and once in the luteal cycle phase, in counterbalanced order. The tACS stimulation will 
deliver a maximum amplitude of 2mA for a total of 40 minutes of stimulation per session. 
Electrodes will be saline soaked, 5x5cm, and placed over F3 and F4 locations to target 
dorsolateral prefrontal cortex. The return electrode will be located over CZ. A transcranial 
current stimulator designed by the Frohlich lab (XCSITE 100 stimulator) will be used. After the first tACS 
session, participants will be instructed to begin daily mood ratings as recorded in the Daily 
Record of Severity of Problems. This 20-item self-report rating scale assesses physical and 
mood symptoms that accompany ovarian hormone changes and is often used as a dimensional 
measure of PMDD. 
 
Electroencephalography (EEG): Each EEG session will last 8 minutes, and participants will 
alternate between having eyes open and closed at 2-minute intervals. A total of four EEG 
recordings will be performed throughout participation; two recordings per menstrual phase to 
be collected before and after stimulation. EEG will be recorded with a standard Nicolet v32 

15 
 
clinical EEG machine that is approved for clinical use and that has been used in all previous 
studies by the Frohlich Lab. Briefly, 10mm gold cup electrodes are fitted to the individual 
participants for brief, non-invasive recordings of brain activity. 
 
4.2 
Intervention/Treatment procedures (by visits) 
Effect of Menstrual Phase on Target Engagement 
Transcranial Current Stimulation: Subjects will report for bilateral stimulation with tACS 
(one session) per menstrual phase, over the course of one menstrual cycle (unless it is an 
anovulatory cycle, in which case the participant will be asked to conduct the ovulation testing 
for one additional cycle). Each participant will receive tACS once in the follicular cycle phase 
and once in the luteal cycle phase, in counterbalanced order. The tACS stimulation will 
deliver a maximum amplitude of 2mA for a total of 40 minutes of stimulation per session. 
Electrodes will be saline soaked, 5x5cm, and placed over F3 and F4 locations to target 
dorsolateral prefrontal cortex. The return electrode will be located over CZ. A transcranial 
current stimulator designed by the Frohlich lab (XCSITE100 stimulator) will be used. After the first tACS 
session, participants will be instructed to begin daily mood ratings as recorded in the Daily 
Record of Severity of Problems via electronic Qualtrics survey. This 20-item self-report rating scale 
assesses physical and mood symptoms that accompany ovarian hormone changes and is often used as 
a dimensional measure of PMDD. 
Electroencephalography (EEG): Each EEG session will last 8 minutes, and participants will 
alternate between having eyes open and closed at 2-minute intervals. A total of four EEG 
recordings will be performed throughout participation; two recordings per menstrual phase to 
be collected before and after stimulation. EEG will be recorded with a standard Nicolet v32 
clinical EEG machine that is approved for clinical use and that has been used in all previous 
studies by the Frohlich Lab. Briefly, 10mm gold cup electrodes are fitted to the individual 
participants for brief, non-invasive recordings of brain activity. 
 
4.3 
Follow- up procedures (by visits): Will be scheduled only as necessary to assess acute suicidal ideation, 
severe mood deterioration, or severe somatic symptoms. 
4.4 
Unscheduled visits: not applicable 
4.5 
Concomitant Medication documentation: not applicable 
4.6 
Rescue medication administration (if applicable) 
4.7 
Subject Completion/ Withdrawal procedures:  While extremely unlikely, any subject who becomes 
pregnant or who experiences a seizure during this study will be withdrawn. Any subject who 
experiences an acute worsening of mood or appearance of suicidal ideation will be assessed by the PI 
and may be withdrawn from the study. Subjects will be compensated monetarily for time and effort. 
For mileage subjects will be reimbursed 34 cents/mile. Compensation structure is as follows: 
 
Participants will be paid $40 per each tACS stimulation study visit, and an 
additional $25 upon completion of the Daily Rating Forms. Total: $105 per subject 
 
Subjects will be paid at the end of their participation. If a subject is withdrawn by the investigators 
or withdraws herself, she will be compensated for participation up to the point of withdrawal. 

16 
 
4.8 
Screen failure procedures: As potential subjects will have been identified as appropriate through the 
related diagnostic screening protocol, we do not anticipate screening failures.  In the case that a 
subject enrolls to participate in the trial but does not meet criteria, the study coordinator completing 
the screening process will clearly explain why the subject does not meet criteria. However, in the case 
that a subject does not qualify based on acute suicide risk, Dr. Rubinow will evaluate the subject and 
determine the appropriate clinical intervention. 
 
5 
STUDY EVALUATIONS AND MEASUREMENTS 
- 
List variables that will be abstracted from medical charts – not applicable   
- 
Describe baseline evaluation –  
1) Prior to enrollment in the tACS study, subjects must meet diagnostic criteria for PMDD. The DRSP 
(Daily Record of Severity of Problems), a validated daily symptom chart widely used for the 
diagnosis of PMDD, includes 21 items grouped into 11 domains that address the criterion of 
symptoms in PMDD (depression, anxiety, lability, anger, interest in activities, concentration, 
lethargy, appetite, sleep, control, and physical symptom). Each item is rated on a scale of 1 (“note 
at all”) to 6 (“extreme”). Using the DRSP, subjects must show symptom severity of 4 or greater for 
two days on a core emotional symptom in the luteal phase, absence of symptom severity during 
the follicular phase, and a 30% or greater increase in severity of symptoms in the 7 days preceding 
menses with 7 days following the end of menses. 
2) left prefrontal alpha power prior to tACS, obtained with EEG 
Describe how measurements will be taken.  
1) symptom measures are self-reported on DRSP via Qualtrics survey tool; 2) EEG will be obtained 
for 8 minutes, with two-minute alternating intervals of eyes open and eyes closed. 
- 
Describe rating scales, tests, psychological tools, laboratory evaluations, etc.  
1) Resting state EEG (RSEEG) recordings will be completed at several times during the course of the 
study. Subjects will complete an alternating eyes open/eyes closed RSEEG immediately before and 
after the 40 minutes of stimulation. This measure is used to determine the immediate after-effects 
of tACS on brain activity, specifically on alpha oscillation power, as well as how consecutive 
stimulation sessions may affect these after-effects.  
2) DRSP - Daily Record of Severity of Problems (DRSP) ratings daily throughout the study 
administered electronically via Qualtrics survey platform. This 20-item self-report rating scale 
assesses physical and mood symptoms that accompany ovarian hormone changes and is often used 
as a dimensional measure of PMDD. 
 
5.1 
Efficacy Evaluation (if applicable): Comparison of left prefrontal alpha power in post-tACS EEG 
compared with that preceding the procedure; comparison of degree of change in prefrontal alpha in 
follicular vs luteal phase.  
5.2 
Pharmacokinetic Evaluation: Not applicable 
5.3 
Safety Evaluations -   Previous studies employing tACS, a non-invasive pharmacologic procedure, have 
shown tACS to be safe and without adverse effects. Nonetheless, the study coordinator will review the 
subject’s daily rating forms on a daily basis. Subjects experiencing a worsening of mood symptoms, the 
failure of mood symptoms to improve following menses,  or the appearance of active suicidal ideation 

17 
 
will be immediately referred to the PI, who will evaluate the subject and decide whether acute 
treatment is required.  The PI will also review adverse events and side effects in an aggregate format 
across all subjects enrolled on a quarterly basis.  
 
 
6 
STATISTICAL CONSIDERATION    
This is repeated, single intervention (tACS) administered during the follicular and luteal phase. Change 
in left prefrontal alpha power on EEG is the primary outcomes. Effect of menstrual cycle phase is the 
secondary outcome. We plan to analyze our data using a repeated measure analysis of variance 
(ANOVA-R), with two within subject variables, each with two levels: time (pre vs post tACS), and 
menstrual cycle phase (follicular vs luteal).  We will assess any effects of order of administration 
(follicular first vs luteal first) by including order as a between-subjects variable.  
 
Clinical symptoms will be quantified as the mean of daily nighttime ratings (individual symptoms 
rated from 1 to 6) collected in the follicular (days 4 – 9) and luteal phases (the 6 days preceding 
menses) as recorded in the DRSP. 
 
Decrease in left prefrontal power (reflection of reduction in alpha asymmetry) will be calculated by 
comparing results from the following time points: 1) immediately before the stimulation and 2) 
immediately following the stimulation in each of the follicular and luteal phases. 
 
The main intent of this study is to conduct a pilot study, the results of which could be used in a larger 
trial that is appropriately powered for efficacy. Nonetheless, we intend to determine whether tACS 
influences alpha coherence on EEG. Due to the novelty of the application and the treatment strategy, 
we do not have all the required parameters to estimate the power for the repeated measure design on 
alpha coherence on EEG. However, the primary purpose is to demonstrate tACS associated changes 
in alpha coherence and whether that differs by cycle phase. The aim to 
demonstrate ‘target engagement’ does not necessarily lend itself to traditional power calculations 
and we will rely on Dr. Frohlich’s extensive experience with analyzing these data. In his experience, 
he is confident that if, in fact, if there are menstrual cycle differences in alpha coherence, 20 
participants will be sufficient to demonstrate that effect. 
 
6.1 
  Primary Endpoint 
Change in Alpha Frequency Electrical Activity in Left Frontal Cortex from Stimulation [Time Frame: 8-
minute recording before vs after intervention] 
6.2 
Secondary Endpoint 
Difference in magnitude of effect of tACS on left prefrontal alpha in follicular vs luteal phase.  
6.3 
Statistical Methods 
Baseline Data: alpha oscillations in left frontal cortex before stimulation; severity of luteal phase 
symptoms in screening DRSP. 

18 
 
Efficacy Analysis: This is repeated, single intervention (tACS) administered during the follicular and 
luteal phase. Change in left prefrontal alpha power on EEG is the primary outcome. Effect of menstrual 
cycle phase is the secondary outcome. We will use a t-test of pre-post changes to examine effects of 
tACS on left prefrontal alpha oscillations (primary outcome) and differences in effects as function of 
menstrual cycle phase (secondary outcome). There will be two levels of each of the two repeated 
within-subjects measures (pre vs post stimulation and follicular vs luteal phase). Order of administration 
will be assessed by considering order as a between- subjects variable. 
 
Exploratory analysis: Assessment of possible changes in mood will be assessed with linear mixed model 
regression analysis comparing mean luteal phase core affective symptoms (depression, irritability) after 
stimulation with means during baseline.  
Pharmacokinetic Analysis (if applicable): not applicable 
Safety Analysis - The PI will review any adverse effects and will quarterly review aggregated data, 
which will be recorded descriptively. Safety/ Tolerability will be assessed in two ways: 1) with somatic 
symptoms contained within the DRSP, completed daily, and with symptoms reviewed daily by the 
research coordinator. Any symptoms of moderate or greater severity appearing proximate to the tACS 
session will be reported to the PI. 2) with a semi-structured interview at the end of each tACS session, 
inquiring about possible side effects during the procedure (e.g., tingling, flickering lights, itching, 
burning sensation, headache, neck pain, scalp pain). Side effects of moderate or greater severity will be 
reported to the PI, who will also review aggregate data at the end of the experiment. 
 
6.4 
Sample Size and Power - The main intent of this study is to conduct a pilot study, the results of which 
could be used in a larger trial that is appropriately powered for efficacy. Nonetheless, we intend to 
determine whether tACS influences alpha coherence on EEG. Due to the novelty of the application, we 
do not have all the required parameters to estimate the power for the repeated measure design on 
alpha coherence on EEG. However, the primary purpose is to demonstrate tACS associated changes in 
alpha coherence and whether that differs by cycle phase. The aim to demonstrate ‘target engagement’ 
does not necessarily lend itself to traditional power calculations and we will rely on Dr. Frohlich’s 
extensive experience with analyzing these data. In his experience, he is confident that if, in fact, if 
there are menstrual cycle differences in alpha coherence, 20 participants will be sufficient to 
demonstrate that effect. 
Due to the novelty of the application, we do not have all the required parameters to estimate the 
power for the repeated measure design on alpha coherence on EEG. Nonetheless, preliminary data 
from a study of five tACS sessions in a study of patients with major depression showed a significant 
alteration in left frontal alpha power following  10Hz stimulation in a sample of 10 subjects (p<.05, 
paired t-test with FDR correction). Notably, there was no significant difference between results after 
one and five sessions. As such, we are confident that a sample size of 20 should enable us to establish 
target engagement as well as determine whether there are meaningful menstrual cycle differences in 
alpha coherence. 
 
6.5 
Interim Analysis 
Other than the quarterly review of safety data, no formal interim analysis is planned. 

19 
 
7 
STUDY INTERVENTION  
Device Description: XCSITE100 Stimulator 
We will be using the XCSITE100 stimulator designed in the Frohlich Lab for investigational purposes. 
The device is not implanted and has not been designed for or being used to support or sustain human 
life. This device does not have a potential for serious risk to the health, safety, or welfare of the 
participant. There has never been an instance of serious side-effect reported due to the use of 
transcranial brain stimulation. Previous studies in the Frohlich lab that used comparable devices (i.e., 
the commercial, CE-certified Neuroconn Plus stimulator) have always been classified as “non-
significant risk” by the full UNC IRB. The Neuroconn Plus stimulator and the XCSITE100 stimulator are 
electrically equivalent and provide the same stimulation.  
The XSCITE100 is the first non-invasive brain stimulator designed for research purposes to provide an 
active sham for tACS and record the stimulation output for later validation. This stimulator may apply 
either tDCS or tACS for up to 40 minutes (2400 seconds) with appropriate current ramp-up at the 
beginning of stimulation and ramp-down at the end of stimulation. Both tDCS and tACS may be applied 
for currents between 100 μA and 2 mA (peak-to-peak for tACS). 
The stimulator has two main components: 
1. 
Android tablet with user interface application (i.e., App) 
2. 
Stimulator with: 
a. 
Microprocessor 
b. 
Function generator chip 
c. 
Voltage controlled current source 
d. 
Safety circuitry 
To ensure appropriate blinding for each stimulation session, there are designated unblinded individuals 
to ensure the appropriate stimulation parameters are applied to each participant. These individuals 
will not interact with participants and will only be involved with the creation of a study file and 
validation of stimulation waveform. 
SAFETY FEATURES 
Current Sensor Circuit. A 33.2 Ω sense resistor is placed in series with the stimulation electrodes on the 
high side. Since high-side current sensing is used, any short circuit of the electrode terminals to ground 
will be detected. The stimulation current flows through this resistor and creates a voltage. The voltage 
across this resistor is sensed and amplified by the AD628 difference amplifier. The gain of the 
difference amplifier is set to 9.9039. The current sensor voltage is then shifted before it is read by the 
microprocessor and the hardware current safety feature. 
Voltage Sensor Circuit. The differential voltage across the electrodes is measured so that the impedance 
can be calculated. The voltage is measured by buffering the positive electrode and negative electrode 
each with a unity gain op-amp circuit. The voltage output is then shifted before it is read by the 
microprocessor using the same level shifting circuit described in the current sensor section. 
The device is equipped with 4 different stages of safety precautions, all of which protect the participant 
from high currents. The stages are as follows: 

20 
 
1. 
AUTOMATIC SOFTWARE CURRENT CUTOFF. The output of the current sensor described above is 
read by a microprocessor, which compares the reading to a value of ±3 mA peak. If the current exceeds 
these limits, stimulation is stopped, a relay in series with the electrode is opened, and the power 
supply used for stimulation is turned off. The user is then given the option to investigate the issue , and 
cancel or resume the test. Since high-side current sensing is used (described above), any short circuit of 
the electrode terminals to ground will be detected. 
2. 
AUTOMATIC HARDWARE CURRENT CUTOFF. The output of the current sensor is fed into a pair 
of comparators which detect if the current exceeds ±4.5 mA. If so, the fault is latched such that the 
relay in series with the electrodes is opened. Additionally, the microprocessor is notified of this 
instance through an interrupt. Upon this interrupt, the microprocessor immediately stops stimulation 
and the power supply used for stimulation is turned off. 
3. 
PERMANENT HARDWARE CURRENT CUTOFF. A 5 mA fast-acting fuse is in series with the 
electrode connector. If the above two over-current detection methods fail, the fuse will below, and the 
stimulator will no longer be electronically connected to the device. 
4. 
POWER SUPPLY FUSE. Finally, if for no other reason the entire device draws too much current, 
the main power supply fuse is blown. This fuse is sized with a cutoff of 200% of steady-state operating 
current. 
 
8 
STUDY INTERVENTION ADMINISTRATION (if applicable)  
- 
Randomization procedures - A random number table will be used to assign the first tACS session to 
either the follicular or luteal phase.  
- 
Blinding procedures – not applicable 
- 
Unblinding procedures not applicable 
 
9 
SAFETY MANAGEMENT 
Previous studies employing tACS, a non-invasive, non-pharmacologic procedure, have shown tACS 
to be safe and devoid of adverse effects. Nonetheless, the study coordinator will review the 
subjects’ daily rating forms daily. The PI will review adverse events and side effects in an aggregate 
format across all subjects enrolled on a quarterly basis. Substantial clinical worsening (compared with 
the baseline cycles) may result in a subject’s discontinuation from the study, at the discretion of the PI. 
Development of suicidal ideation more than just passive ideation (i.e., sometimes I feel like life is not 
worth living – not uncommon in women with PMDD in their symptomatic phase) for any reason or any 
unanticipated serious side effect will result in the subject’s discontinuation. Failure of the subject to 
experience symptom attenuation following the cessation of menses will result in the subject’s 
evaluation, discontinuation from the study, and recommendation of therapeutic intervention if 
required. If there are unanticipated serious adverse events or side effects, the information will be 
provided to the UNC Biomedical IRB for recommendation regarding the continuation or termination of 
the study. No seizures have been reported with administration of tACS or tDCS. Nonetheless, Dr. 
Bradley Vaugh, Department of Neurology, has agreed to be available should any untoward event occur.  
 

21 
 
DATA AND SAFETY MONITORING PLAN 
 
The NIH policy on Data and Safety Monitoring stipulates that, in most studies, the PI would be 
expected to perform some monitoring functions as part of the general oversight and scientific 
leadership of the study. This is the strategy that we intend to employ in the proposed research 
according to the following data and safety monitoring plans: 
 
I. Grading of adverse events (AEs) 
We will employ the grading scale adopted by the UNC IRB to grade and report AEs. Adverse events will 
be classified according to severity as either mild, moderate, or severe. 
 
Mild AE: is defined as having no effect on activities of daily living, such as transient lightheadedness or 
sweating with venipuncture; headache; mild skin irritation; or something of equal significance that 
requires no medical intervention and is of marginal clinical relevance. 
 
Moderate AE: would be associated with temporary (minutes to a few days) disruption in activities of 
daily living, such as temporary loss of consciousness with venipuncture;  worsening of migraines or 
headache that require bed rest; an increase in depressive symptoms; dizziness that precludes 
ambulation; or something of equal significance. 
 
Severe AE: would include any event that acutely threatens the patient’s health, is life-threatening, or 
potentially permanently disabling, or an event of equal significance. 
 
 
 
II. Monitoring and reporting of adverse events (AEs) 
The study coordinator and tACS technician will monitor side effects during and following tACS 
administration. Side effects consistent with moderate or severe AEs will be immediately reported to 
Dr. Rubinow, who will be responsible for determining the next course of action, which might include 
discontinuation of the subject from the study. Dr. Rubinow will review aggregate reports of side 
effects/AEs quarterly. As the contact PI, Dr. Rubinow will be the one responsible to report all AEs 
reported as moderate or severe to the IRB and CTRC within one week. 
 
10 
DATA COLLECTION AND MANAGMENT  
Daily Record of Severity of Problems (DRSP) responses will be collected using study ID number as the 
identifier, stored by Qualtrics survey software and will be monitored to ensure consistency and 
completion of responses. Symptom ratings will be used for safety during the study..  
 
EEG recordings will be kept on a secure server within the Department of Psychiatry and will be 
analyzed by Dr. Frohlich. 
 
 
Participants will be identified by study ID number on all research documents and in electronic data 
 
files. All data will be stored in locked cabinets inside locked offices, and electronic data will be 
 
stored only on password-protected file servers only accessible from computers in the Psychiatry 
Department. Only study personnel will have access to these data. Qualtrics will be used to collect self-
report questionnaire data for all participants. Participants will not enter any personally identifying 
information into the Qualtrics system, and they will be identified by their unique study ID only. 

22 
 
 
The document that associates subject names and study ID numbers will be destroyed 5 years 
following the last publication to come from the study. Consent forms and any other documentation 
containing subject information other than study ID will be destroyed at this time as well. Paper 
documentation will be shredded, and computerized data will be permanently deleted from the lab 
server. Subject names and contact information will be maintained indefinitely for the purpose of future 
studies and stored in a secure, password-protected database that meets UNC standards for data 
security as determined by department IT security specialists. 
 
11 
RECRUITMENT STRATEGY 
 
Potential subjects will have already identified themselves by participating in our diagnostic study. 
 
Subjects who will enter the experiment will be those women who demonstrate the presence of 
 
PMDD, defined by the demonstration with daily mood ratings of a 30% or more increase in mean 
 
affective symptom ratings in the seven days prior to menses (luteal phase) compared with ratings 
 
during the seven days following the cessation of menses (follicular phase). 
 
Based on when potential subjects are first identified as meeting criteria, they will either be recruited 
(and screened) at the second visit of the diagnostic feeder study, or they will be contacted by phone 
and re-screened via telephone interview. Given that the exclusion criteria for both the feeder study and 
this study are similar, the re-screening process is simply used to confirm that nothing has changed since 
they participated in the feeder study. 
 
12 
CONSENT PROCESS 
The study coordinator or other study staff will obtain informed consent from individuals during their 
second visit in the diagnostic feeder protocol. During the consenting process, all the 
applicable consent forms will be reviewed with each individual, who will be given as much time 
as she would like to decide whether to participate and have any questions answered. Additionally, 
during the discussion of consent forms, potential subjects are asked at the end of each section of the 
consent whether they understand what was described and whether they have any questions. Potential 
subjects will also be offered the chance to ask questions directly to the investigators. 
 
13 
PLANS FOR PUBLICATION: Upon completion of study, data will be analyzed and submitted for 
publication in an appropriate journal.  
 
 
 
 
 
 
 

23 
 
 
14 
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