Double-Blind, Sham-Controlled Crossover Pilot Study of Low Field Magnetic Stimulation (LFMS) on Subjective and Objective Measures of Sleep
Phase: NA
Conditions: Insomnia, Primary
Sponsor: Medical University of South Carolina

LFMSProtocol_Insomnia.v.1.4_10.15.2016
Protocol Title:  Double-Blind, Sham-Controlled Crossover Pilot Study of Low Field Magnetic Stimulation 
(LFMS) on Subjective and Objective Measures of Sleep
PI Name:  Thomas Uhde, MD 
1.0
 
  OJECTIVES/SPECIFIC AIMS
Insomnia is a risk factor for the later development of mood and anxiety disorders, alcohol and substance use 
relapse, peripartum depression, suicide, motor vehicular accidents, poorer outcome in the treatment of a large 
array of medical diseases, increased economic burden, and lost work and social productivity (Dorheim, Bjorvatn, 
& Eberhard-Gran, 2014; Morin & Jarrin, 2012; Taylor & Bramoweth, 2010; Woznica, Carney, Kuo, & Moss, 2015). 
Several classes of medications are used to manage insomnia; however, currently available medications have 
limitations in terms of durability and side-effects, including the risk of abuse and dependence with hypnotic and 
benzodiazepine compounds.  And, even though non-pharmacological treatments of insomnia, such as sleep 
restriction, are effective, patients often refuse and/or are unwilling to participate in the requirements of this 
intervention due to poor tolerance and/or potential cognitive impairments. Thus, poor tolerance and/or 
acceptability of sleep restriction are limiting factors in the utility of current non-pharmacological treatments of 
insomnia.  
The medical field needs new modalities, which do not involve benzodiazepine or hypnotic medications, for treating
insomnia. We propose to study the effects of Low Field Magnetic Stimulation (LFMS) on sleep in patients suffering
from insomnia disorder.  LFMS has several similarities to repetitive transcranial magnetic stimulation (rTMS), 
which already has been approved by the FDA as a treatment for depression.  However, in contrast to rTMS, LFMS
produces a much smaller magnitude of electric field in the brain (approximately 1 V/m) compared to rTMS devices
(approximately 100 V/m).  Also, LFMS has magnetic field indices (20 Gauss peak field strength, 1 KHz frequency, 
trapezoidal magnetic field waveforms) that fall within the range of those used in spectroscopic and standard fMRI 
studies. Thus the FDA has conferred a non-significant risk determination of LFMS for humans.  LFMS is unlikely 
to directly cause neuronal firing or neuronal depolarization and no seizures have been reported with LFMS in any 
investigational trials to date.  Taken together, these observations indicate that LFMS has a very safe adverse-risk 
profile.  Of note, Dr. George and his team at MUSC also have been investigating the effects of low frequency 
magnetic stimulation (LFMS) on pain threshold in healthy normal controls.  Preliminary data in 43 healthy 
volunteers as well as over 300 depression patients studied to date have found LFMS to be well-tolerated and 
devoid of any serious adverse effects.  The most common self-reports in the MUSC trial have been a mild tingling 
sensation on the scalp, which typically lasts for a few seconds; note, however, that subjects and investigators are 
still blind to condition, and thus the tingling may be occurring in sham control sessions as well as active treatment.
Thus, neurostimulation with the current LFMS device, provided by Tal Medical and approved by the MUSC IRB 
(Pro00048321), has been extremely well-tolerated and without any adverse events.  
Low field magnetic stimulation (LFMS) is a novel and safe form of brain neurostimulation that has shown rapid 
antidepressant effects in both humans and animal models of depression (Carlezon et al., 2005; M. L. Rohan et al.,
2014; M. Rohan et al., 2004). It is unknown whether LFMS has positive hypnotic effects in humans. 
Aim 1: To test whether a 20 minute session of LFMS, compared to sham LFMS, has sleep-promoting effects.  
Hypothesis: 20 minutes of active LFMS compared sham LFMS will decrease subjective and objective 
polysomnographic measures of sleep latency (SL), number of awakenings after sleep onset (#awake), and wake 
time after sleep onset (WASO) and increase total sleep time (TST).
Aim 2: To determine whether active LFMS compared to sham LFMS improves the overall quality of sleep.  
Hypothesis:  20 minutes of active LFMS compared to sham LFMS will be associated with a significantly 
greater improvement in overall quality of sleep (i.e. restorative sleep) as indicated by a change on the MUSC 
Sleep Quality Scale.  
Medical University of South Carolina Protocol

LFMSProtocol_Insomnia.v.1.4_10.15.2016
Aim 3: To examine the relationship between measures of state anxiety and change in insomnia severity from pre- 
to post-treatment in active LFMS compared to sham LFMS.
Hypothesis:  Higher baseline levels of state anxiety and greater decreases in state anxiety before and 
immediately after treatment with active but not sham LFMS will be significantly correlated with improvements on 
subjective and objective measures of sleep (SL, #awake, WASO, and TST).  
Aim 4: To examine the relationship between measures of depression and change in insomnia severity from pre- to
post-treatment in active LFMS compared to sham LFMS.***
Hypothesis:  Measures of depression or changes in ratings of depression will not be associated with any 
subjective or objective indices of sleep after either active or sham LFMS. 
***Note:  Patients with clinical depression will be excluded from this investigation.  
2.0 BACKGROUND AND SIGNIFICANCE
 It is well-known that depressed patients, particularly those with comorbid anxiety, often suffer from co-existing 
insomnia, which may take the form of one or more of the following characteristics:  difficulty falling asleep, multiple
awakenings from sleep, early morning awakening, or simply non-restorative sleep.   Within a single depressive 
episode, insomnia (when present) may precede the symptoms of sadness, co-emerge at the same time, or 
develop after the depressive episode has become fully established.  Insomnia also appears to be more prevalent 
in moderate-to-severe major depression and increasing evidence suggests that depression and insomnia share 
overlapping biological diatheses.  
Many depression rating scales used in clinical trials include individual items on sleep.  However, individual items 
or subscale factors related to disturbed sleep are not typically analyzed separately.  Clinical trial evidence 
generally suggest that changes in depressed mood, anxiety, and insomnia often change in parallel (i.e., when 
mood improves, sleep improves and vice versa), although the temporal time-course and severity of each 
symptom cluster may be out of phase.  Moreover, there may be different degrees of improvement and/or 
worsening of mood and sleep over the longitudinal course of illness in people suffering from co-existing 
depression and insomnia.  Taken together, these data and clinical observations suggest that some effective 
treatments of depression may also be effective in the treatment of insomnia disorder.  
The purpose of this study is to determine whether active LFMS improves, in the presence of high baseline anxiety
scores but the absence of clinical depression, the sleep of patients with insomnia disorder.  While the effects of 
LFMS on insomnia disorder are unknown, several studies have been conducted in patients with major depression 
where, based upon historical data, one might reasonably conjecture many, if not most, of the participants suffered 
from some degree of co-existing insomnia.  
  
Low field magnetic stimulation, as a potential treatment of depression, arose from clinical observations in 
depressed patients who were being studied with functional magnetic resonance imaging at the McLean Hospital 
in 2001. Bipolar depression patients undergoing an fMRI scan for research purposes unexpectedly reported mood
improvement following completion of a single, 20 minute diagnostic scan (M. Rohan et al., 2004).  Then, a single-
blind pilot study showed that a greater number of depressed patients improved with active LFMS exposure than 
with sham treatment. Another double-blind, LFMS versus sham cross-over study in patients with unipolar and 
bipolar depression demonstrated a rapid and large improvement in depression in the active treatment (M. L. 
Rohan et al., 2014). Notably, HAMD-17 scores describing anxiety levels showed substantial improvement in the 
depressed population. In our proposed study, we will use the similar type of device used in these aforementioned 
investigations, which were well-tolerated, and the same device being used here at MUSC.
The MUSC Brain Stimulation Laboratory has been a clinical and research center of excellence with respect to 
Brain Stimulation techniques for over 20 years now. We have three lab rooms (each 300 square feet) with an 
extensive array of devices.   The Sleep Research Laboratory is on the same floor within 100 feet of the LFMS 
device.  Forty-three healthy control subjects have been studied at MUSC (Pro00048321) using the same device 
and parameters of administration that are proposed for this study of participants with insomnia disorder. 
3.0 INTERVENTION TO BE STUDIED
The LFMS investigational device v1.1 is a table-top device intended for use in a clinic or hospital setting under the
supervision of a trained operator. The device has three major components:

LFMSProtocol_Insomnia.v.1.4_10.15.2016
1) Coil and Coil Housing. Mounted inside a patient friendly assembly, the magnetic coil delivers a low strength 
electromagnetic field to the head of the subject. The coil is designed to be used in conjunction with a standard 
hospital bed, exam table or gurney. The coil housing fits over the head down to the eyebrows leaving the field of 
vision about 50% unobstructed to avoid claustrophobic feelings.
2) PC with LFMS control software. The device is controlled by a personal computer with a custom software 
program that produces the desired waveform. The software enables randomization by blinding administration of 
sham or active treatment based on a unique patient ID and session ID number entered into the device. The 
software also tracks device function by monitoring in real time the electrical current to the coil and comparing it to 
the reference waveform.
3) Power system and control electronics. A pair of off-the-shelf amplifiers (AE Techron 7224) are set up in a 
parallel configuration and run under current control. The control electronics (USB data card – Measurement 
Computing USB-1608G) take the signal from the computer and convert it to the specified voltage waveform to the 
amplifiers corresponding to the electrical current waveform.
 
Figure B2: Pictures of LFMS Investigational Device v1.1 showing the device and how a patient is positioned
in the device during treatment.
Overall, LFMS at the intensity, frequency and number of stimuli proposed in the current protocol is considered a 
“non-significant risk” by the FDA; it does not meet the definition of a significant risk (SR) device under § 812.3(m) 
of the investigational device exemptions (IDE) regulation (21 CFR 812). Of the 43 subjects who have participated 
in the aforementioned trial at MUSC, 7 reported mild, transient tingling on the scalp, though it is unknown if these 
subjects were receiving active or sham treatment.  Otherwise, the treatments are well-tolerated and there have 
been no drop-outs.  
4.0 STUDY ENDPOINTS
The main subjective outcome measures will be sleep latency (sSL), wake after sleep onset (sWASO), total sleep
time (sTST), Ease of Falling Asleep (EFS), and Sleep Quality.
Secondary (exploratory)  subjective outcome measures will be number of nocturnal awakenings (sNA), ESS,
Concentration, and Fatigue.
The main  objective outcome measures of efficacy will be sleep latency to persistent sleep (i.e., latency to 10
minutes of persistent sleep), sleep efficiency (time in bed/total sleep time), and wake after sleep onset (WASO).
The following traditional polysomnographic indices will be obtained during both active and sham conditions: 
% Stage 1, % Stage 2, % Delta Sleep (Stages 3 & 4), and % Rapid Eye Movement (REM) Sleep.
5.0 INCLUSION AND EXCLUSION CRITERIA / STUDY POPULATION
Participants

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Participants will be adults, aged 18-65, who meet DSM-5 criteria for insomnia disorder.  Participants who 
meet both DSM-5 insomnia disorder and generalized anxiety disorder will be candidates for participating if the 
insomnia is their predominant complaint and the primary reason for seeking treatment.
Inclusion Criteria (all measures listed are described in detail in section 10.0) 
DSM-5 insomnia disorder (per the SCISD)
Difficulty falling asleep, maintaining sleep, waking up too early, or non-restorative sleep
Frequency: > 3 times per week
Duration: > 3 months
Daytime impairment (subjective) in at least one of the following areas:
Excessive Daytime Sleepiness
Fatigue
Problems attending or concentrating on tasks
Transient memory problems
Performing tasks in a timely manner (compared to the person’s usual level of 
performance)
Pittsburgh Sleep Quality Index (PSQI) > 6 and one of the following:
-
Sleep Efficiency < 85% (per Consensus Sleep Diary)
-
Insomnia Severity Index (ISI) score > 15
Sleep latency (subjective) and/or time awake after sleep onset (subjective) >30 minutes. 
Not currently depressed (previous major depressive episodes and current antidepressant medication 
permitted as long as remission and current medication dosage has been stable for ≥ 1 month).
Willing to refrain from alcohol for twenty-four hours before presenting to sleep lab for sleep studies
BMI > 18 and < 50 kg/m2
Exclusion criteria:  
Current major depressive episode 
Current substance-induced depressive disorder 
Self-reported use of benzodiazepines or hypnotic drugs in last two weeks
Self-reported use of marijuana in previous 72 hours
Alcohol Use Disorders Identification Test (AUDIT) score > 10
Fagerstrom Test for Nicotine Dependence (FTND) score > 4
Insomnia limited to early morning awakening (without difficulty initiating or maintaining sleep), 
Narcolepsy 
Seizure Disorder (not including childhood febrile seizures)
Recent treatment with anticonvulsant medications
Obstructive or central sleep apnea 
Circadian rhythm sleep-wake disorders 
Recurrent isolated sleep paralysis 
Current substance-induced insomnia 
Chronic pain disorder
Daily Caffeine Consumption > 500 mg/d (Uhde, 1989)   
Restless legs syndrome
Periodic Leg Movement Disorder
Benzodiazepines or antipsychotic medications during past 30 days 
Presence of drugs of abuse (excluding marijuana, urinalysis)
Pregnancy or plans to become pregnant
History of severe allergic reactions to adhesive tape
History of neurological disorder
Conductive, ferromagnetic or other magnetic-sensitive metals in the head, neck, chest, upper arms, or 
any area that will be within 18 inches of the treatment coil.
6.0 NUMBER OF SUBJECTS
We will enroll 20 male and female adults (with approximately equal gender distribution).
7.0 SETTING
Participants will be screened through the sleep and anxiety disorders clinic in the IOP on 5 South or in the sleep 
laboratory in the IOP on 5 North. Those that pass screening will be scheduled an appointment in the IOP on 5 

LFMSProtocol_Insomnia.v.1.4_10.15.2016
North to the brain stimulation laboratory and sleep laboratory where consenting and the remaining study 
procedures will be completed.
The MUSC Brain Stimulation Laboratories where the LFMS device will be located on the 5th floor of the IOP, and 
the Sleep Laboratory is also located on the 5th floor of the IOP within a few feet of the Brain Stimulation 
Laboratory.  The Sleep Research Laboratory employs certified PSG technicians. We currently use a 
Compumedics E-series Polysomnography system in our sleep research laboratory.  The data export program is 
capable of exporting data in several formats, including European Data Format (EDF).
After the 20 minute treatment (active versus sham) the participants will walk (or use a wheel-chair) to the sleep 
bedroom.  The participant will have an opportunity to use the bathroom.  Afterward, a registered sleep technician 
or trained research assistant will apply the leads for all-night sleep recording.  Immediately after the leads have 
been attached, rating scales will be administered as outlined in the Research Design section.  
8.0 RECRUITMENT METHODS
At any particular time we have approximately 75-100 patients who are being followed in our longitudinal course of 
sleep and anxiety disorders clinic.  This program is focused on gathering prospective, longitudinal data in 
individuals with sleep problems who are being treated as usual by the clinical members of our sleep-anxiety clinic.
Participants in this clinic are routinely invited to participate in separate sleep studies (e.g. Sleep Research Data 
Repository, Clinical Care Registry etc.) if they meet entry criteria. The majority of patients in this long-term, 
longitudinal treatment program suffer from insomnia disorder and represents one source of potential patients for 
the proposed LFMS study.  
In addition, 4-10 new patients with insomnia complaints are evaluated each week in our intake-evaluation unit.  
These initial evaluations are performed, under attending supervision, by psychology interns or senior level 
residents/fellows in the sleep-anxiety clinic. 
Potential participants for the proposed LFMS study will be recruited from these two sources.  Given the already 
well-established nature of these programs, we do not anticipate the need for separate advertisement for the LFMS
study.  Our sleep-anxiety clinic has a reputation in the region as a research-oriented treatment program.  Thus, 
most of the people referred to our sleep-anxiety program (or, on their own seek an evaluation) typically come with 
a pre-existing expectation and willingness to participate in research studies.
People being evaluated in the intake-evaluation unit with insomnia (over 90% of our referrals) are routinely offered
(after education) the choice of either CBT-I treatment or medications.  We will add the option of participating in the
LFMS study.  Thus, most of the candidates for this study will already be well-known to the investigators. If 
additional subjects are necessary to meet enrollment numbers, we would simply advertise in the local news media
and on campus for potential participants suffering from insomnia to contact our intake number at 843.792.9162. 
9.0 CONSENT PROCESS
The consent process will take place in the sleep laboratory in the IOP on 5 North. Participants will be given an 
overview of the study and informed of the requirement to be healthy [neither underweight nor overweight (BMI > 
18 and < 50 kg/m2)] without any current problems with substance, including alcohol abuse or dependence.  
Potential subjects will not be eligible for participation if they are nicotine dependent or report greater than 500 
mg/d caffeine consumption.  Participants will be instructed to avoid drinking any alcoholic beverages within 24-
hours of participating in any component of the study.  They will be informed during the initial screening interview 
that in order to participate in the study they cannot be taking any of the following substances, even if prescribed 
by a physician:   benzodiazepines, hypnotic medications (Z drugs), barbiturates, cocaine, amphetamines, opiates,
MDMA or PCP.  Candidates will be told that immediately after giving informed consent, a urine sample will be 
tested for the presence of these compounds.  If they are found to be positive, they would not be eligible for 
participation in the study and would not receive any compensation.  
10.0 STUDY DESIGN / METHODS
Design (Sham-controlled, within-subject cross-over study; see Table 1 for a timeline of measures)
Step 1:  
Recruitment, Screening & Consent 
Step 2:  
Adaptation Night (Rating Scales--Sham LFMS—Rating Scales--PSG--Rating Scales)
Steps 3-4:
Two Consecutive Treatment Nights (Rating Scales--Active or Sham LFMS—Rating Scales--PSG--Rating Scales)
Steps 5-6
Two Consecutive Treatment Nights (Rating Scales--Sham or Active LFMS--Rating Scales--PSG--Rating Scales)

LFMSProtocol_Insomnia.v.1.4_10.15.2016
Each of the two treatment conditions (active versus sham) will be conducted on two consecutive nights.  There 
will be no more than 7 days between the adaptation night and the first treatment condition; there will be no less 
than 6 and no more than 14 nights between each of the two-night treatment conditions.  Thus, each participant 
who completes the full study will spend a total of 5 nights in the sleep laboratory and the time interval from the first
adaptation night to completion of the study may range from 11-26 days for any particular individual.
Step 1:  Recruitment, Screening, Consent, and Sleep Diaries
Recruitment, screening, and consent details described in detail above
 
After giving informed consent, subjects will participate in a brief interview, complete the following rating scales, 
receive a brief physical examination, and have a urine drug test. Additionally, participants will be asked to maintain
a Consensus Sleep Diary (CSD) throughout the study.  The CSD is a well-validated daily sleep log that gathers 
information about bedtime, arise time, time in bed, total sleep time, wake time after sleep onset, total number of 
awakenings, and self-rated sleep quality. Participants may also be asked to wear an actiwatch for the duration of 
the study (described in detail below)
Brief Structured Clinical Interview
Structured Clinical Interview for Sleep Disorders (SCISD) is an interview based on the DSM-5 criteria for 
sleep-wake disorders. Reliability and validity for each disorder has been analyzed based on 189 
participants and is in the process of being submitted for publication. For the present study, the module
for insomnia will be administered (5 questions, approximately two to five minutes to administer, 
minimal training required).
Self-Report Screening Measures 
Beck Depression Inventory (BDI) is a well-researched, brief, self-report depression screening instrument. 
It consists of 21-items that assess different aspects of depression (e.g., anhedonia, excessive guilt, 
suicidal ideation, vegetative symptoms, and tearfulness).
Pittsburgh Sleep Quality Inventory) (PSQI; Buysse, Reynolds, Monk, Berman, & Kupfer, 1989) is a 19-
item questionnaire that assesses subjective sleep quality, sleep latency, sleep duration, habitual sleep
efficiency, sleep disturbances, use sleep medication, and daytime dysfunction.
Insomnia Severity Index (ISI; Morin, 1993) is a self-rated instrument that determines the severity of 
insomnia along the following categories:  no clinically relevant insomnia, subthreshold insomnia, 
clinical insomnia (moderate severity), and clinical insomnia (severe).
Epworth Sleepiness Scale (ESS; Johns, 1991) is an 8-item questionnaire that measures self-reported 
average sleep propensity in daily life.
Spielberger Trait Anxiety Scale (STAI; Spielberger, 1968) is a validated 20-item rating scale that 
measures the person’s tendency to experience anxiety, a measure of trait anxiety.
Sleep Diaries. Sleep diaries will be used for seven days to measure subjective sleep patterns.  
Participants will be asked to make daily diary entries with an estimate of their sleep the night before 
(e.g., bedtime, sleep onset).
Alcohol Use Disorders Identification Test (AUDIT; Babor, Higgins-Biddle, Saunders, & Monteiro, 2002) is a
well-validated, 10-item screening questionnaire with 3 questions on the amount and frequency of 
drinking, 3 questions on alcohol dependence, and 4 on problems caused by alcohol.
Fagerstrom Test for Nicotine Dependence (FTND; Diaz et al., 2005) is a well-validated, six-item 
questionnaire to assess current nicotine dependence.
Positive and Negative Affect Scale (PANAS, Watson et al, 1988) is a well-validated 20 item questionnaire 
to assess components of affect (distress, alertness, nervousness, hostility, enthusiasm). 
Physical Examination
A brief physical and neurological examination will be provided, which will include vital signs, weight, head 
and neck circumference, head breadth and length, and cardiopulmonary examination.  
Urine Testing
Urine will be tested using a CLIA Waived kit, which included adulterant testing.
Step 2:  Adaptation Night
 
 
Rating Scales:  

LFMSProtocol_Insomnia.v.1.4_10.15.2016
Baseline Only:  Spielberger State Anxiety Scale, Beck Depression Scale, ESS, PANAS
Before & After Sham LFMS:  Uhde Sleepiness Scale (USS), Anxiety (100 mm), Depression (100 mm), PANAS
After PSG: ESS, Sleep Latency, WASO, Number Awakenings, MUSC Sleep Quality Scale, Sleep Diary, PANAS 
     Ease in Falling Asleep (100 mm), Concentration (100 mm), Fatigue (100 mm)
Physiological Measures
Polysomnogram (PSG)
Participants who complete the full study will have five nights of sleep recordings (i.e. polysomnography, 
PSG).  Our standard PSG procedure requires surface electrodes to be placed on the face and scalp. 
An EEG (electroencephalogram) will be used to measure and record brain wave activity. An EMG 
(electromyogram) records muscle activity such as face twitches, teeth grinding, and leg movements. 
Together, these recording provide data to determine the presence of REM versus non-REM stage 
sleep. An EOG (electro-oculogram) will be used to record eye movements. These movements are 
important in determining the different sleep stages, particularly REM stage sleep. Elastic belts will be 
placed around the chest and abdomen to measure patterns of breathing. A bandage-like oximeter 
probe will be placed on a finger to measure the amount of oxygen in the subject's blood. An EKG 
(electrocardiogram) will record heart rate and rhythm. A nasal airflow sensor may also be used to 
record airflow. A snore microphone will be used to record snoring activity, and video recording capture
movements, movement artifacts and sleep related movement disorders. Subjects will be video and 
audio recorded during all PSG testing. All data will be recorded digitally and saved for a future 
analysis.
The  sleep  recordings  will  be  amplified  using  standard  clinical  polygraphs  (E-series  Compumedics
Amplifier System) in accordance with American Academy of Sleep Medicine requirements. The sleep
records  subsequently  will  be  scored  independently  of  knowledge  of  the  diagnoses  as  well  as
treatment condition (active and sham), according to standardized criteria. After each PSG night,
subjects will complete a post-sleep questionnaire upon awakening in the morning and will estimate
time to fall asleep, number of nightly awakenings, total sleep time, soundness and quality of sleep,
and morning sleepiness. These dependent variables will be assessed with both parametric and
nonparametric statistical tests. For example, regression analyses may be used to predict developing
and/or the progression of psychopathology and/or medical illnesses. 
Actigraphy
An actigraph is a small watch-like devise that records body movements and light intensity that may
correlate with the quality of sleep and circadian rhythms. Subjects will be asked to wear the actigraph
during the study from the time of consent until completion of the last treatment night.  Actigraphy data
will be combined with PSG and subjective symptoms to provide a multifactorial assessment of sleep.  
Steps 3-6:  Cross-Over Treatments
Rating scales and polysomnography will be the same as adaptation night.     

LFMSProtocol_Insomnia.v.1.4_10.15.2016
Table 1. Timeline of Measures
Condition
screening
visit
PM
Adaptation
AM
Post
ptation
Interval
PM - Session
1
AM – post
on 1
PM - Session
1
AM – post
on 1
Interval
PM - Session
2
AM – post
on 2
PM - Session
2
AM – post
on 2
Visit
day
1
2
3
(0-7
days
)
4
5
5
6
(6-14
days
)
7
8
8
9
Active LFMS
X
X
Sham LFMS
X
X
X
SCISD
X
AUDIT
X
FTND
X
ISI
X
PSQI
X
Physical
X
Urine test
X
STAI
X
X
X
X
X
X
BDI
X
X
X
X
X
X
ESS
X
X
X
X
X
X
X
X
X
X
X
USS
2X
2X
2X
2X
2X
Anxiety
2X
2X
2X
2X
2X
Depression
2X
2X
2X
2X
2X
PSG
X
X
X
X
X
MSQS
X
X
X
X
X
X
Ease of sleep
X
X
X
X
X
Concentratio
n
X
X
X
X
X
Fatigue
X
X
X
X
X
PANAS
X
2X
X
2X
X
2X
X
2X
X
2X
X
Sleep Diary
X
X
X
X
X
X
X
X
X
X
X
X
11.0 SPECIMEN COLLECTION AND BANKING (if applicable)
Participants will provide a urinalysis at baseline. This will be discarded immediately after testing.
12.0 DATA MANAGEMENT
The value of this new non-pharmacological treatment will be determined in part by its relative efficacy to hypnotics
and other psychotropic medications used to treatment insomnia disorder. Sleep promoting agents with significant 
clinical efficacy as measured by selective behavioral measures (e.g., subjective sleep latency) have been 
demonstrated in placebo-controlled studies with 20 subjects. We will therefore enroll 20 participants. Given the 
exploratory nature of this cross-over study, twenty patients with insomnia disorder contains sufficient power to 
determine whether active LFMS has evidence of a sleep-promoting “signal”  compared to the sham treatment 
condition. Due to this uncertainty, a preliminary analyses will be run once at least first 5 participants have 
completed the study, so as to estimate the effect size. Recruitment and randomizations will continue while the 
data is being analyzed and interpreted. Primary subjective and objective endpoints will be analyzed for the interim
analysis. If a signal is found in the interim analyses and subsequent final analyses, a larger and more highly 
powered investigation will be conducted in the future. 
The interim analysis will be based on unblinded data. To preserve the integrity of the study blind, a Data 
Review Group (DRG) will review the data to estimate the effect size and if 20 subjects will afford sufficient power. 
The DRG will consist of a statistician not directly affiliated with the study, and with individuals who are not involved
in recruiting, randomizing, or treating study participants. The results of the interim analysis will be known only to 
the DRG. 
In the formal analysis, order and gender will be balanced across the two treatment conditions (i.e., sham and 
active LFMS).  Efficacy analyses will be performed using the mean values of dependent measures obtained on 

LFMSProtocol_Insomnia.v.1.4_10.15.2016
the two consecutive treatment nights for each treatment condition.  Given that this is an exploratory examination, 
all primary and secondary dependent measures will be compared using 1-tailed, paired t-tests for normally 
distributed data and the Mann-Whitney U or Wilcoxon’s tests for non-normally distributed data.   Correlations will 
be assessed using Pearson’s correlation coefficient.
As per standard sleep research methodology, data from the adaptation night will not be incorporated into the 
formal analyses.  However, adaptation data may be used in an exploratory analysis to examine the possible role 
of adaptation as a predictor of response.  
All files will be kept confidential according to HIPAA rules and regulations. In relation to the collected data, the
names and all other unique identifiers of the subjects will be coded to ensure confidentiality. A number will be
assigned  to  each  subject  and  this  number  will  be  used  for  registration,  data  analyses,  and  exchange  of
information within the research community. 
The list that matches the names with the code numbers will be kept in a locked file in the sleep laboratory (located
in the IOP on 5 North). Only investigators associated with this protocol and essential technical staff will have
access to this locked file. All unique identifiers will be removed from the data prior to publication/presentation in
the research community.
13. PROVISIONS TO MONITOR THE DATA TO ENSURE THE SAFETY OF SUBJECTS (if applicable)
This is a small pilot study of a device already determined by the FDA to be NSR.  Polysomnography (PSG) is a 
standard and validated diagnostic test, which is used to evaluate patients with a wide-range of different medical 
and sleep disorders.  PSG are obtained in thousands of people throughout the world each year without significant 
complications or untoward effects.  
The data acquired during the PSG testing could uncover a previously unknown problem or medical condition. In
this case, participants will be informed of the findings and, if necessary, given a referral the appropriate medical
professionals at MUSC. Additionally, one question on one measure (BDI-II) inquires about feelings of self-
harm/suicide. This question will be examined individually every time the measure is completed. One of the
clinicians on our team (Uhde, Milanak) will be present or on call at all times to assist with further assesment and
referral if appropriate. If pt requires immediate referral he or she will be excused from the remainder of the study.
We do not anticipate any major safety issues and will thus keep the data blinded for the entirety of the study. If 
there are major SAE’s and/or unanticipated problems, we will work closely with the IRB to consider pausing or 
stopping the study. 
14.0 WITHDRAWAL OF SUBJECTS
Patients can withdraw from the study at any time. However, they will not receive payment for time points they do 
not complete. 
15.0 RISKS TO SUBJECTS
Potential risks r
 
 elated to:
 
  
Low Frequency Magnetic Stimulation (LFMS):  Overall, LFMS at the intensity, frequency and number 
of stimuli proposed in the current protocol is considered a “non-significant risk” by the FDA; it does not 
meet the definition of a significant risk (SR) device under § 812.3(m) of the investigational device exemptions 
(IDE) regulation (21 CFR 812).  Nonetheless, we list the conceivable “potential” risks associated with LFMS 
below:
 
Mood Worsening- Although possible, there is no evidence to date in over 300 patients that 
LFMS causes depression or worsens mood.   Patients with current major depression disorder are excluded from 
participation in this study.  If a worsening of mood were to develop, Dr. Uhde would provide medical care or refer 
to a member of the department’s mental health team.
Pain-Most evidence suggests that rTMS provides temporary relief from pain, a temporary 
decrease in sensitivity to pain, or no effect at all.   No data are not available for LFMS.  Taken together, other than 
mild tingling of the scalp, there is little evidence that LFMS would induce pain.

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  Brain Tissue Damage- LFMS is thought to be safe.It is derived from MRI, the treatment which 
is routinely used to assess brain damage..
Safety in case of pregnancy-This protocol will exclude pregnant women. The risks of using 
LFMS with pregnant women are currently unknown.  Known pregnancy, detection of HCG in urine, or active plans 
on becoming pregnant is an exclusion criterion for participation in this study. 
Unknown Risks-LFMS is an experimental procedure that has not been approved by the FDA as 
a treatment for insomnia disorder and it may have unknown side effects. 
Polysomnography:
Tape Irritation-There is minimal risk associated with the discomfort of having standard clinical
EEG paste electrodes applied to the scalp. Rarely, an individual will have a mild irritation to the tape applied over
electrodes. People who report past severe allergic reactions or pain to adhesive tape will be excluded from the
study.
Anxiety-Some people may find sleeping in an unfamiliar setting uncomfortable. Participation in
the adaptation night PSG usually alleviates such anxiety.  Participants will be thoroughly educated in advance
about the sleep laboratory environment and arrangements.  Participants will be invited to visit the laboratory prior
to the adaptation PSG if they would find this helpful.  
Excessive Daytime Drowsiness-Participants who appear unable to safely operate equipment
due to excessive drowsiness after the sleep night electroencephalography will be asked to refrain from driving.
They may stay in the lounge area of the sleep laboratory or further rest in the sleep bed until they have recovered
from the procedure.  They may also be sent home by taxi or picked up by a friend.  
Unknown  Medical  Problems-Although  sleep  studies  are  being  performed  for  research
purposes, an unknown medical problem or condition might be identified or suggested from PSG findings.  This
would usually be found on the adaptation night.  It is also possible, however, that an existing medical condition or
sleep disorder unrelated to insomnia disorder might not be revealed through this research. Another potential risk
is that some medical conditions may not be possible to diagnose with a certainty, even when the problem is a
sleep disorder.  For example, we would be unable to calculate with certainty the severity index of an individual
found to have probable obstructive sleep apnea on the PSG. If the participant is found to have (or is suspected to
have) sleep apnea, another sleep disorder or medical condition, the subject will be given information regarding
appropriate clinical testing and evaluation.
 
Actigraphy: In rare instances, the Actiwatch worn by participants causes minor skin irritation. All 
participants will be informed of this risk and reminded they should remove the watch and clean and dry the area 
each day.
Psychological Testing: 
Breach  of  Confidentiality-The  Department  of  Psychiatry  and  Behavioral  Neurosciences  is
extremely concerned about all issues related to confidentiality and is experienced in procedures of maintaining it
effectively. In relation to this specific study, all data will be identified only by a code number rather than a name.
Whenever data are reported, no individual subject will be identified. 
Anxiety-A small number of participants may be uncomfortable or anxious when completing rating
forms, questionnaires, or answering personal questions about their mental health. All subjects will be informed
that they may choose not to answer any questions in which they are uncomfortable answering. 
Laboratory testing: 
Social Anxiety-Very rarely, participants are uncomfortable providing urine samples for testing.
In the event that a person is too shy and/or suspected of having a substance misuse problem, they will be
informed that they may choose not to participate in the study, as urinalysis is required.  
16.0 POTENTIAL BENEFITS TO SUBJECTS OR OTHERS
Potential Benefits of the Proposed Research to the Subjects and Others 
It is important to determine if this new form of brain stimulation, which in preliminary investigations has rapid 
antidepressant effects (within 20 minutes), will also have positive sleep-promoting effects in people with insomnia 
disorder.  A non-invasive, non-addicting, and non-benzodiazepine treatment for insomnia would potentially have 

LFMSProtocol_Insomnia.v.1.4_10.15.2016
widespread health promoting value insofar as insomnia and insomnia disorder are risk factors for developing or 
worsening a wide range of sleep, psychiatric and medical disorders.  
Importance of the Knowledge to be Gained
See above.
Data obtained in this study will provide useful information regarding the indications for investigating LFMS in a 
larger cohort of patients suffering from insomnia disorder or co-existing insomnia in medical diseases in which 
benzodiazepine or hypnotic drugs are contraindicated.
Payment
Participants will be paid by gift cards: $10.00 for the screening visit, $35.00 for the first adaptation night, $35.00 
for the first night of a-sLFMS-PSG, $40.00 for each of the next two nights of a-sLFMS-PSG and $75.00 for the final a-
sLFMS night and next morning follow-up interview.  The total compensation for participating in this study is 
$235.00. This will be paid with gift cards in two payments. The first payment will be provided following completion 
of the screening appointment and first three nights in the sleep laboratory. The second payment will be provided 
at the end of the last visit.
18. DRUGS OR DEVICES
The LFMS machine used in this study is a large piece of equipment that is permanently housed securely in the 
MUSC Brain Stimulation Laboratories on the 5th floor of the IOP. Only key study personnel and their guests (i.e., 
participants) have access to it.

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