The Effect of Cranial Electrotherapy Stimulation on Emotional and Cellular Wellbeing
Phase: NA
Conditions: Anxiety, Depression
Sponsor: University of California, Los Angeles

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The Effect of Cranial Electrotherapy Stimulation 
on Emotional and Cellular Wellbeing in Veterans 
Final Report including Study Protocol with Revisions, Statistical 
Analysis Plan and Results 
NCT03369418 
 
 
Principal Investigator: Kirsten Tillisch, MD 
Co-Investigator: Judith Carroll, PhD, Jennifer Labus, PhD 
 
June 30, 2020 
 
 

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TABLE OF CONTENTS 
PAGE 
TABLE OF CONTENTS ................................................................................................................ 2 
LIST OF ABBREVIATIONS ........................................................................................................... 4 
PROTOCOL SUMMARY ............................................................................................................... 6 
1 
KEY ROLES AND CONTACT INFORMATION .................................................................... 7 
2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ......... 9 
2.1 
Background Information ............................................................................................ 9 
2.2 
Rationale ................................................................................................................... 9 
2.3 
Potential Risks and Benefits ................................................................................... 11 
2.3.1 
Potential Risks ............................................................................................ 11 
2.3.2 
Potential Benefits ........................................................................................ 11 
3 
OBJECTIVES ..................................................................................................................... 12 
3.1 
Study Objectives ..................................................................................................... 12 
3.2 
Study Outcome Measures ...................................................................................... 12 
3.2.1 
Behavioral Measures .................................................................................. 12 
3.2.2 
Biological Measures .................................................................................... 13 
4 
STUDY DESIGN ................................................................................................................. 14 
4.1 
Basic Design Characteristics .................................................................................. 14 
4.2 
Study Population ..................................................................................................... 14 
4.3 
Study Timeframe .................................................................................................... 14 
4.4 
Randomization and Blinding ................................................................................... 14 
5 
STUDY ENROLLMENT AND WITHDRAWAL .................................................................... 16 
5.1 
Subject Inclusion Criteria ........................................................................................ 16 
5.2 
Subject Exclusion Criteria ....................................................................................... 16 
5.3 
Strategies for Recruitment and Retention ............................................................... 17 
5.4 
Reporting Suicidal Ideation ..................................................................................... 18 
5.5 
Treatment Assignment Procedures ........................................................................ 18 
5.6 
Subject Withdrawal ................................................................................................. 19 
5.6.1 
Reasons for Withdrawal .............................................................................. 19 
5.6.2 
Handling of Subject Withdrawals or Subject Discontinuation of Study 
Intervention ................................................................................................. 19 
6 
STUDY INTERVENTION .................................................................................................... 20 
6.1 
Study Device Description ........................................................................................ 20 
6.1.1 
Acquisition ................................................................................................... 20 
6.1.2 
Packaging ................................................................................................... 20 
6.1.3 
Product Storage .......................................................................................... 20 
6.2 
Preparation and Usage of Study Device ................................................................. 20 
6.2.1 
Dosage ........................................................................................................ 21 
6.3 
Assessment of Subject Compliance with Study Device Usage .............................. 21 
6.4 
Concomitant Medications/Treatments .................................................................... 21 
7 
STUDY SCHEDULE ........................................................................................................... 23 

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7.1 
Prescreening ........................................................................................................... 23 
7.2 
Enrollment/Baseline Screening (Visit 1) ................................................................. 23 
7.3 
Intermediate Study Visit (Visit 2) ............................................................................. 24 
7.4 
Final Study Visit (Visit 3) ......................................................................................... 24 
8 
STUDY PROCEDURES/EVALUATIONS ........................................................................... 26 
8.1 
Study Procedures/Evaluations ................................................................................ 26 
8.2 
Laboratory Procedures/Evaluations ........................................................................ 26 
8.2.1 
Sample Draws ............................................................................................. 26 
8.2.2 
Pre-Visit Sample Processing ...................................................................... 27 
8.2.3 
Study Visit Sample Processing ................................................................... 27 
8.2.4 
Sample Processing Directions .................................................................... 28 
9 
ASSESSMENT OF SAFETY .............................................................................................. 29 
9.1 
Specification of Safety Parameters ......................................................................... 29 
9.1.1 
Adverse Events ........................................................................................... 29 
9.1.2 
Serious Adverse Events .............................................................................. 29 
9.2 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 29 
9.3 
Characteristics of an Adverse Event ....................................................................... 30 
9.3.1 
Relationship to Study Intervention .............................................................. 30 
9.3.2 
Expectedness of SAEs ............................................................................... 31 
9.3.3 
Severity of Event ......................................................................................... 31 
9.4 
Reporting Procedures ............................................................................................. 31 
10 
STATISTICAL ANALYSIS PLAN ........................................................................................ 32 
10.1 
Sample Size ............................................................................................................ 32 
10.2 
Assessment of Primary and Secondary Outcomes ................................................ 32 
10.2.1 Primary Outcomes ...................................................................................... 32 
10.2.2 Secondary Outcomes ................................................................................. 32 
11 
ETHICS/PROTECTION OF HUMAN SUBJECTS .............................................................. 33 
11.1 
Institutional Review Board ...................................................................................... 33 
11.2 
Informed Consent Process ..................................................................................... 33 
11.3 
Subject Confidentiality ............................................................................................ 33 
11.4 
Future Use of Stored Specimens and Other Identifiable Data ................................ 34 
12 
DATA HANDLING AND RECORD KEEPING .................................................................... 35 
12.1 
Data Management Responsibilities ........................................................................ 35 
12.2 
Data Collection ....................................................................................................... 35 
12.3 
Study Records Retention ........................................................................................ 35 
13 
RESULTS SECTION 
14 
Conclusions and interpretation 
13 
REFERENCES ................................................................................................................... 36 
SUPPLEMENTAL MATERIALS .................................................................................................. 42 
 

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LIST OF ABBREVIATIONS 
ACE 
Adverse Childhood Experiences 
AE 
Adverse Event 
AID 
Anxiety Insomnia Depression 
BD 
Becton, Dickinson and Company 
BOLD 
Blood Oxygen Level Dependent 
C 
Celsius 
CD-RISC 
Connor-Davidson Resilience Scale 
CES 
Cranial Electrotherapy Stimulation 
CHAPS 
3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate 
CHS 
Center for Health Sciences 
CPT 
Cell Preparation Tube 
CRP 
C-Reactive Protein 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CT 
Cycle Threshold 
DNA 
Deoxyribonucleic Acid 
DVD 
Digital Video Disc 
GLA  
Greater Los Angeles 
HADS 
Hospital Anxiety and Depression Scale 
HIPAA 
Health Insurance Portability and Accountability Act 
HPA  
Hypothalamic Pituitary Adrenal 
Hz 
Hertz 
IBC 
Inflammatory Biology Core 
ICF 
Informed Consent Form 
IRB 
Institutional Review Board 
MD 
Doctor of Medicine 
MHC-SF 
Mental Health Continuum Short Form 
MINI 
Mini International Neuropsychiatric Interview 
mL 
Milliliter 
ng 
Nanogram 
NP 
Nurse Practitioner 
OCNS 
Oppenheimer Family Center for Neurobiology of Stress 
OEF 
Operation Enduring Freedom 
OIF 
Operation Iraqi Freedom 

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OPRS 
Office of Protection of Research Subjects 
PANAS-SF 
Positive and Negative Affect Schedule Short Form 
PBMC 
Peripheral Blood Mononuclear Cells 
PBS 
Phosphate Buffered Saline 
PCL-M 
PTSD Check List - Military 
PCR  
Polymerase Chain Reaction 
PhD 
Doctor of Philosophy 
PHQ 
Patient Health Questionnaire 
PI 
Principal Investigator 
PROMIS 
Patient Reported Outcomes Measurement Information System 
PSS 
Perceived Stress Scale 
PTSD  
Post-Traumatic Stress Disorder 
qPCR 
Quantitative Polymerase Chain Reaction 
R01 
Research Project Grant 
RN 
Registered Nurse 
S 
Hemoglobin Single Copy Gene 
SAE 
Severe Adverse Event 
SSL 
Secure Sockets Layer 
T 
Telomere Gene 
TPG 
Telomerase Product Generated 
TRAP 
Telomere Repeat Amplification Protocol 
UCLA 
University of California, Los Angeles 
VA 
Veterans Affairs 
μA 
Microampere 

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PROTOCOL SUMMARY 
Title: 
The Effect of Cranial Electrotherapy Stimulation on 
Emotional and Cellular Wellbeing  
Objectives: 
 
We aim to use a CES (cranial electrotherapy stimulation) 
intervention to improve emotional well-being by reducing 
symptoms of anxiety and depression and to assess for 
changes in markers of cellular health - specifically, telomere 
length and telomerase activity 
Study Design: 
Randomized, double-blinded, sham controlled trial 
Study Population: 
18-40 year old males, with symptoms of mild to moderate 
anxiety and/or depression, in the absence of a psychotic 
disorder  
Phase: 
Pilot 
Study Site: 
UCLA Oppenheimer Family Center for Neurobiology of 
Stress and Resilience 
Description of  
Intervention: 
A commercially available cranial electrotherapy stimulation 
device that applies an electrical current to a subject’s head 
to treat anxiety, depression or insomnia. Electrical 
stimulation will be applied via ear clip electrodes at the 
lowest setting (0.5 Hz, 100 μA) for 1 hour daily for eight 
weeks. In the sham group, the electrodes attached to the 
device will be inactive.  
Study Duration: 
24 months 
Subject Participation 
Duration: 
8-10 weeks 
 
Estimated Time to 
Complete 
Enrollment: 
20 weeks  

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1 KEY ROLES AND CONTACT INFORMATION 
Principal 
Investigator:   
Kirsten Tillisch, MD 
Professor 
UCLA Oppenheimer Family Center for Neurobiology of Stress 
Division of Digestive Diseases 
David Geffen School of Medicine at UCLA 
CHS 42-244 
10833 LeConte Ave 
Los Angeles, CA 90025 
Phone: 310-206-0192 
Fax: 310-825-1919 
Email: ktillisch@mednet.ucla.edu 
Co-Investigators: 
Judith Carroll, PhD 
UCLA Semel Institute for Neuroscience & Human Behavior 
300 Medical Plaza 
Suite 3330 
Los Angeles, California 90095 
Phone: 310-794-9678 
Fax: 310-794-9247 
Email: jcarroll@mednet.ucla.edu 
Jennifer Labus, PhD 
Professor 
UCLA Oppenheimer Family Center for Neurobiology of Stress 
Division of Digestive Diseases 
David Geffen School of Medicine at UCLA 
CHS 42-244 
10833 LeConte Ave 
Los Angeles, CA 90025 
Phone: 310-206-0192 
Fax: 310-825-1919 
Email: jlabus@ucla.edu 
Study Site: 
UCLA Oppenheimer Family Center for Neurobiology of Stress 
CHS 42-128 
10833 LeConte Ave 
Los Angeles, CA 90025 
Mail Code: 737818 
 
 

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Research Team: 
Nurse Coordinator 
Jean Stains, RN 
Phone: 310-206-1758 
Nurse Practitioner 
Suzanne Smith, RN, FNP 
Phone: 310-206-0845 
Research Assistant 
Christine Canilao, BS 
Email: ccanilao@mednet.ucla.edu 
IBC Lab Contacts: 
Stephanie Esquivel 
Email: sesquivel@mednet.ucla.edu 
Nancy Herrera-Morales 
Email: nherrera@mednet.ucla.edu 
Liz Breen 
Email: ebreen@mednet.ucla.edu 
Lab Phone: 310-825-0302 

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2 INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE  
2.1 
Background Information 
Chronic emotional distress can lead to detrimental biological outcomes, 
presumably via alterations in the hypothalamic pituitary adrenal axis (HPA axis), 
a sympathetic bias of the autonomic nervous system, and inflammatory 
dysregulation.1  At the cellular level, impairment of the telomere/telomerase 
system may be a result of this dysregulation, given the descriptions of shorter 
telomeres (a marker of cellular aging), as well as increased markers of 
inflammation, in subjects with depression, anxiety and PTSD, compared to aged 
matched healthy populations.2-5 These negative cellular effects of emotional 
distress have not been well studied. In this study we aim to use an auricular CES 
intervention to improve emotional well-being by reducing symptoms of anxiety 
and depression and to assess for changes in markers of cellular health - 
specifically, telomere length and telomerase activity.   
This feasibility study was initially developed to study Veterans specifically, 
however, due to difficulty with recruitment in the Veteran population the study 
inclusion criteria were adjusted to include non-Veteran eligible male subjects and 
appropriate modifications were made in the regulatory documents. 
2.2 
Rationale 
Auricular CES, anxiety and depression 
Auricular CES benefits centrally mediated symptoms such as anxiety, 
depression, insomnia and pain; however, the mechanism by which the benefit 
occurs is not entirely clear. Similar to auricular electro-acupuncture, auricular 
CES is believed to act on subcortical brain structures, including the thalamus and 
limbic regions. This concept is supported by several small functional 
neuroimaging and EEG studies.6-8 Neuroimaging during application of auricular 
CES shows alterations in resting brain networks, as well as a tendency toward 
widespread decreases in cortical activation.9 In a study of an 8 week auricular 
CES intervention for pain, post treatment subjects had pain reductions as well as 
decreased blood oxygen dependent (BOLD) response in the basal ganglia and 
parahippocampal gyrus compared to subject treated with a sham device.10 
Several small studies have shown benefits of auricular CES on negative affect 
symptoms. Anxiety symptoms were reduced by at least 50% in 67% of patients 
with generalized anxiety disorder using auricular CES in an open label study for 6 
weeks.11 Other studies have shown anxiety reductions in pre-procedure dental 
patients12 and fibromyalgia patients.13 Reduction in depression symptoms has 
been described in multiple reviews, with most studies only in abstract or 
unpublished forms, or using depression as a secondary outcome.14-17 Pilot 
evaluations of electro-acupuncture and of external trigeminal nerve stimulation, 

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two interventions with similar targets, have also suggested that this approach 
may have a benefit for depression.18,19 In one study of auricular CES using the 
same protocol proposed here, 115 patients with anxiety or anxiety and comorbid 
depression were studied over 5 weeks in a randomized, sham controlled trial, 
showing significant improvements in both anxiety and depression symptoms with 
high effect sizes (d=.8 and d=.94).17 Due to the complexity of overlapping 
negative affect symptoms that lead to impaired emotional wellbeing in Veterans, 
we chose in this proposal to evaluate a composite measure of emotional distress 
(a combined anxiety and depression score) as the primary outcome. Beyond 
depression and anxiety, CES has been associated with reductions in insomnia 
and pain, both of which are also significant problems in Veterans, likely 
contributing to reduced emotional well-being.14, 20-22 Data collected during 
program evaluation at a GLA affiliated (Veterans Integrated Service Network 22) 
VA Medical Center, use of CES in Veterans with comorbid PTSD, anxiety and 
depressive symptoms showed improvements in the Beck Depression Inventory, 
Beck Anxiety Index, and Insomnia Severity Index after a 1 week open label trial 
of 40-60 minutes of auricular CES per day (personal communication, Meredith 
Avedon, PsyD). While the published literature is still immature, we anticipate that 
CES may be a particularly useful treatment in the Veteran and non-Veteran 
populations given that it may target multiple symptoms causing emotional 
distress. 
Cellular aging, anxiety, and depression 
Telomeres are repeating DNA-protein complexes that cap the ends of 
chromosomes, protecting the DNA from damage during replication. The terminal 
end of the telomere shortens with successive replication as the cell ages. This 
aging can be accelerated in settings of stress, including symptoms of emotional 
distress such as anxiety and depression.1 Reductions in telomere length have 
been associated with anxiety, depression, PTSD, and unhealthy lifestyles, all 
common conditions in OIF/OEF Veterans.2-5 Little is known about telomere length 
and telomerase activity in Veterans specifically, though PTSD in Veterans has 
been associated with telomere shortening.5 The mechanism through which 
affective symptoms and emotional stress lead to peripheral changes in the 
telomere/telomerase system has not been completely elucidated but is likely the 
result of a dysregulated hypothalamic pituitary adrenal axis, impaired anti-
inflammatory pathways, and a sympathetic shift of the autonomic nervous 
system, all leading to greater cellular stress. It is unclear whether reductions in 
telomere length create a permanent "biological scar" during periods of systemic 
stress or whether compensatory increases in telomerase can lengthen the 
telomeres, as there is contradictory evidence for both situations in human 
studies.1 Mind-body interventions, such as meditation, as well as 
pharmacological approaches, have been shown to improve telomerase levels 
and telomere length.1,23 

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In this study we hypothesize that the complex chronic stressors, which include 
anxiety, depression, PTSD, insomnia, and chronic pain will lead to biological 
stress at the cellular level. This stress will have resulted in greater than normal 
telomere shortening and suppressed telomerase, as has been described in 
PTSD.24 Improvement in key symptoms of emotional distress, anxiety and 
depression, is expected to lead to decreased biological stress, and increases in 
telomerase activity, possibly with improvements in telomere length, though the 
latter may require a longer follow up. 
2.3 
Potential Risks and Benefits 
The study devices used are commercially available and have an excellent risk 
profile based on previous human clinical studies and post marketing data. 
2.3.1 
Potential Risks 
The most common side effects of the device are dizziness, headache, and 
local skin irritation. Dizziness and headache most commonly occur at higher 
current levels but will be minimized by having the first electrical stimulation 
session performed at the research center to make sure the study protocol is 
tolerated. Subjects who cannot tolerate the study protocol will be dropped 
from the study. Phlebotomy has a low risk of bruising, swelling or pain at the 
site, and a very low risk of infection. 
The collection of data contains the inherent risk of loss of privacy. This risk 
will be minimized by adequate training of all study staff according to 
institutional guidelines, use of unique subject identifiers, and by keeping 
data in password protected computer databases and/or locked cabinets. An 
informed consent document was approved by the local Institutional Review 
Boards at UCLA and a recruitment waiver was obtained from the IRB at the 
Greater Los Angeles VA. All subjects will read and document understanding 
of the consent form prior to enrolling in the study. 
2.3.2 
Potential Benefits 
This study may improve emotional well-being for individual subjects with 
proper and consecutive use of the CES device but any beneficial effects are 
not certain to occur. It is hoped that the research will also benefit Veterans 
and individuals suffering with anxiety and/or depression by increasing 
awareness of these conditions and further research to identify improved 
diagnostic markers for anxiety and depression. Societal benefits of this 
study include the potential addition of a non-invasive, non-medication 
treatment options for patients with anxiety and/or depression. Cellular 
marker identification and an improved understanding of the physiological 
mechanisms behind CES therapies may enhance and improve therapies 
currently available.  

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3 OBJECTIVES 
3.1 
Study Objectives 
We anticipate significant improvements in emotional well-being associated with 
eight-weeks of daily CES treatment. Scores on the individual and combined 
anxiety and depression subscales of the HADS will decrease. Improvements in 
other aspects of mental health (measured with the MHC-SF) are expected as a 
secondary effect of the improved negative affect measured in the HADS.  An 
increase in telomerase is expected at 8 weeks. In addition we expect 
improvements in the PROMIS measures of fatigue, sleep disturbance, and pain 
interference. 
Biological samples will be retained for measurement of additional inflammatory 
gene regulation pathways in peripheral immune cells if additional funding can 
be obtained for processing and analysis of the samples. We anticipate that 
inflammatory gene profiles would be improved in subjects who have improved 
emotional wellbeing with CES treatment. 
3.2 
Study Outcome Measures 
3.2.1 
Behavioral Measures 
1. PRIMARY OUTCOME:  The Hospital Anxiety and Depression Scale 
(HADS) will be used to measure emotional distress/well-being. The 
score for each of the two components will be summed to yield a 
composite score. The severity of emotional distress will be defined as 
normal range (0-7), mild (8-10), moderate (11-14) or severe (15-20).25 
Pre minus post intervention score will be assessed. 
2. EXPLORATORY OUTCOME: The Mental Health Continuum Short 
Form (MHC-SF), which measures psychological and social well-being, 
will be used to assess improvements in two forms of human flourishing 
or happiness, hedonic (self-gratification) and Eudaimonic (having a 
noble purpose) well-being.27  
3. EXPLORATORY OUTCOME: PROMIS-SF measures will be collected 
to assess ancillary symptoms in the domains of: fatigue, sleep 
disturbance, sleep related impairment, and pain interference. 
4. EXPLORATORY OUTCOME: The PCL-M is a frequently used 
instrument to screen for PTSD in the military population, correlates well 
with a clinical interview and has been shown to be responsive to 
symptom change.24  

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3.2.2 
Biological Measures 
The primary biological outcome will be telomerase activity determine using 
the telomere repeat amplification protocol (TRAP), performed as previously 
described with minor modification.28,29 Isolated PBMC are suspended in 
Chaps lysis buffer and telomerase extract obtained. Extracts are incubated 
to build telomere repeats, resulting in the product generated due to 
telomerase activity. To visualize, the PCR reaction included a labeled 
primer to amplify signal. The PCR product is then run in an acrylamide gel 
and detected by fluorescent imaging. Calculation of telomerase product 
generated (TPG) per 10,000 PBMC is performed using ImageQuant 
software, which takes the fluorescence intensity within a specified 
parameter and yields a numerical value representing TPG per 10,000 cells. 
Telomere length will be determined using real time quantitative polymerase 
chain reaction (qPCR) methodology as described previously with minor 
modifications.30,31 Peripheral blood mononuclear cells (PBMC) are isolated 
and genomic DNA extracted. Using the standard curve method, cycle 
threshold (CT) values are plotted on a standard curve of human genomic 
DNA to estimate an ng/microliter concentration value. Telomere length 
values are expressed as the ratio of the estimated concentration generated 
by PCR of the telomere gene (T) divided by the hemoglobin single (S) copy 
gene = (T/S).  

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4 STUDY DESIGN 
4.1 
Basic Design Characteristics 
This is a pilot, randomized, double-blinded, sham controlled study on the effect 
of transcutaneous electrical nerve stimulation on emotional and cellular 
wellbeing. This is a single center study and all visits will occur at OCNS. 
Subjects will be asked to use the CES device daily for 8 weeks. They will be 
provided with a tracking diary to record the start and stop time of usage daily. 
Device must be used at approximately the same time of day. Failure to comply 
is a violation of study protocol and will result in subject withdrawal (see 5.6.1). 
4.2 
Study Population 
Approximately 55 male subjects will be screened in an effort to obtain 22 
subjects in each treatment group after randomization. Due to the difficulty with 
recruitment of eligible Veterans in this feasibility pilot, the study period was 
extended and non-Veterans meeting the other inclusion criteria were recruited. 
The study enrollment was limited to 24 completed subjects based on insufficient 
resources to complete the study beyond the extended recruitment period.  
4.3 
Study Timeframe 
The study timeframe consists of a screening period of 1-2 weeks (commencing 
between Week -2 to Week -1 and ending on Week 1; see 7.1 and 7.2) followed 
by an 8-week treatment period (Week 1-Week 8). A flowchart showing the study 
schedule is provided in Error! Reference source not found.. 
The expected duration of subject participation is about 8-10 weeks.. 
4.4 
Randomization and Blinding 
This is a randomized, double-blinded, sham controlled study. The active and 
sham devices are identical in appearance and will only differ by the labeling of a 
unique serial number. In the sham devices, the electrodes attached to the 
device will be inactive. The subjects will be instructed that the device is set to a 
low level so that the current is not detectable but still effective. The current will 
not be detectable in both active and sham devices in order for adequate 
blinding to occur. 
To ensure that the allocation of subjects to treatment is properly concealed, the 
PI and research personnel will not know which devices are active or sham. The 
sponsor will provide the code to determine which devices are active and which 
are sham. Code will be in a sealed envelope that will not be opened until the 
end of data collection.  
 

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5 STUDY ENROLLMENT AND WITHDRAWAL 
55 Veterans with symptoms of mild to moderate anxiety and depression, in the 
absence of a psychotic disorder, will be recruited in order to complete 22 subjects 
per treatment group based on an estimated 25% rate of subject attrition. 
5.1 
Subject Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of 
the following criteria: 
1. Male, Veteran or non-Veteran 
2. Within the age range of 18-40 years old 
3. On a stable regimen for anxiety, depression, psychiatric or mental health 
treatment (pharmacological or non-pharmacological) for the past 3 
months 
4. No active suicidal ideation or psychosis (including schizophrenia and 
bipolar disorder) 
5. No uncontrolled or progressive severe medical illness (e.g., cancer, 
uncontrolled diabetes mellitus, active cardiac disease) 
6. No use of a pacemaker or any other implanted electrical device 
7. No alcohol consumption greater than 2 units daily 
8. No daily use of illicit drugs or marijuana 
9. Ability to independently complete the in-person study questionnaires and 
sign ICF without assistance 
10. Willing to comply with all study procedures and be available for the 
duration of the study  
11. No participation in another clinical trial study 
5.2 
Subject Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from 
participation in this study: 
1. Not male  
2. Younger than 18 years old or older than 40 years old 
3. Not on a stable regimen for anxiety, depression, psychiatric or mental 
health treatment (pharmacological or non-pharmacological) for the past 3 
months 

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4. Active suicidal ideation or psychosis (including schizophrenia and bipolar 
disorder) 
5. History of inpatient treatment or suicidal ideation within the last year 
6. Use of a pacemaker or any other implanted electrical device 
7. Current alcohol and/or substance abuse of illicit drugs or marijuana 
8. Unable to independently complete the in-person study questionnaires 
and sign ICF due to impaired cognitive function 
9. Unwilling to comply with all study procedures 
10. Unavailable for the duration of the study  
11. Current participation in another clinical trial study 
12. Any other condition that the investigator believes would jeopardize the 
safety or rights of the subject or would render the subject unable to 
comply with the study protocol or make use of acquired data non-
analyzable 
5.3 
Strategies for Recruitment and Retention 
Study participants will be recruited with flyers on UCLA and VA campuses, 
Internet web advertisements posted on non-interactive Facebook pages and 
Craigs List, and through direct contact from GLA VA physicians. Most subjects 
are expected to be recruited from the VA Physical Medicine and Rehabilitation 
clinic and from other primary providers in ancillary clinics at the VA. Physicians 
in these clinics are aware of this research study and will give information about 
who to contact if a Veteran is interested. Physicians will refer the potential study 
participants to the study team. 
Subjects will be compensated for study participation as follows: 
$50.00 for completing screening visit 1, $50.00 for completing the mid-study 
visit 2 and questionnaire completion, and $100.00 for the final visit and 
completing the final set of questionnaires. 
Only subjects who complete a minimum of 5 of 7 days per week compliance will 
be eligible to complete the final visit and thus be eligible for that payment. 
Subjects enrolled in study will be contacted weekly to assure subject 
compliance. 
Parking will be provided at all visits. 
The stipend payment subjects will receive will be up to $200.00. If the subject 
withdraws from the study before finishing, that person will be paid for the study 
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5.4 
Reporting Suicidal Ideation 
To minimize risk, patients will be selected based on mild to moderate but not 
severe depression and/or anxiety, and who are on a stable therapeutic regimen 
(medication, psychotherapy, or stable without treatment) to reduce the risk of 
harm with a new intervention. Patients will be interviewed for both physical and 
psychiatric symptoms. Patients with a history of suicide attempt in the past year, 
who express having an intention of acting on suicidal thoughts as measured by 
a positive answer to the Columbia-Suicide Severity rating scale questions 4-6, 
or have other clinical risks on interview deemed by the investigator to be 
exclusionary will be excluded from the study and referred to a mental health 
professional, primary care provider, or emergency room after assessment of the 
patient. If the patient already has a mental health care or primary care provider, 
the provider will be contacted by the medical staff, with the patient’s permission, 
to update them on the subjects’s change in condition. All subjects will be asked 
at entry to the study to sign a HIPPA release and provide their clinicians contact 
information, so that this option is available in the event of a clinical emergency. 
The Veteran’s Crisis line number will be provided to all Veteran subjects (1-800-
273-8255). Subjects whose answers to the Columbia screener “since last visit” 
questionnaire show an increase in suicidal thoughts will be discharged from the 
study after determination of appropriate follow up as described above. No 
attempt to control psychiatric medication will be made in this study. Types and 
doses of medications taken by the subject will be carefully documented and 
examined in post hoc analyses. 
5.5 
Treatment Assignment Procedures 
Stratified random sampling will be performed using SAS Proc Plan to 
generating random sequences and dispensing one of the Alpha-Stim AID kits 
provided by the sponsor (50% of kits active, 50% sham) and coded with unique 
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5.6 
Subject Withdrawal 
Study participation is voluntary and subjects have the right withdraw from the 
study at any time. The investigator may terminate a subject’s participation if 
necessary.   
5.6.1 
Reasons for Withdrawal 
Subjects are free to withdraw from participation in the study at any time 
upon request. 
An investigator may terminate a study subject’s participation in the study if: 
• Any clinical AE or SAE, laboratory abnormality, or other medical 
condition or situation occurs such that continued participation in the 
study would not be in the best interest of the subject. 
• The subject meets an exclusion criterion (either newly developed or 
not previously recognized) that precludes further study participation. 
• Non-compliance with study protocol 
5.6.2 
Handling of Subject Withdrawals or Subject Discontinuation of Study 
Intervention 
An adverse events report will be collected from subjects who choose to 
withdraw from the study. Subjects will be required to return study device to 
research personnel. 
In the event of an (S)AE, every effort will be made to obtain follow-up data 
on any subject who discontinued device treatment due to an (S)AE. To the 
extent possible, any withdrawn subject will be followed until the (S)AE has 
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6 STUDY INTERVENTION 
6.1 
Study Device Description 
The study device is a commercially available cranial electrotherapy stimulation 
device that applies an electrical current to a subject’s head to treat anxiety, 
depression or insomnia. 
6.1.1 
Acquisition 
Study device will be supplied and shipped by sponsor after IRB approval. 
6.1.2 
Packaging 
Study device comes complete with the following accessories: 
• One set of Earclip Electrodes 
• 256 Earclip Electrode Pads 
• 15ml Alpha Conducting Solution 
• Two AAA batteries 
• Storage case 
• AID DVD 
• Neck lanyard 
• Illustrated Owner’s Manual (multi-lingual Owner’s Manual also 
available) 
Weight: 2.0 lbs 
Dimensions: 9 x 8 x 2 in 
6.1.3 
Product Storage 
Study device should be stored inside provided storage case. The device 
and additional provided accessories should be kept in a safe place for 
subject use only and away from water. 
6.2 
Preparation and Usage of Study Device 
Study product: Alpha-Stim AID 
• Place earclip electrode pads to earclip electrodes 
• Attach earclip electrodes to CES device 
• Wet each electrode with Alpha Conducting Solution 

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• Clip electrodes to ears 
• Set device frequency to 0.5 Hz and 100 μA 
• Set current to maximum of 600 microamperes, or to a comfortable level 
on the head 
• Set probe timer at 60 minutes 
• Remove earclip electrodes from ears after 60 minutes 
• Unplug earclip electrodes from device and dispose of electrode pads 
• Store device and additional accessories in storage case 
6.2.1 
Dosage 
The dose selection (device frequency of 0.5 Hz and 100 μA) is based on 
previous positive studies of the device for anxiety, depression, and 
insomnia. The dose selected is not detectable by the subject, so that 
adequate blinding can occur. 
6.3 
Assessment of Subject Compliance with Study Device Usage 
Subjects will be provided with a tracking diary to record the start and stop time 
of daily usage, duration of usage, and any side effects if applicable. The 
research assistant will call every day during the first week of device treatment to 
ensure subjects are using the device, following instructions, and recording 
device usage times. Any reported side effects, additions or changes to 
medications or health care regime (i.e. non-pharmacological treatment), and 
adverse events will be noted. Subjects who note worsening of their anxiety or 
depression will be called by the study PI and if needed, they will be referred to 
their primary care of mental health provider for evaluation as appropriate, or if 
necessary for emergency treatment. During weeks 2-8 of device treatment, the 
research assistant will call once a week instead of daily. 
6.4 
Concomitant Medications/Treatments 
Subjects who are treated for anxiety, depression, psychiatric or mental health 
must be on a stable regimen for the past 3 months. A concomitant medication 
report will be collected during each visit at OCNS. 
Patients who add or change their medications or health therapy will be identified 
via weekly telephone check-up. We will allow necessary additions or changes in 
medications, specifically psychiatric medications, from the subject’s personal 
provider except for the use of narcotics/opiates. Subjects who use 
narcotics/opiates after study enrollment will be withdrawn by PI upon PI 
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Any subjects who express suicidal ideation will be referred to and followed up 
with their own primary care provider or psychiatric MD if they are able to 
contract for safety or to a psychiatric emergency department if they indicate a 
great risk of harm to themselves. In the absence of these, they will be referred 
to and followed up at a clinic/country medical system, which can provide proper 
care. All subjects sign a HIPAA or Release of Medical records if we feel this is a 
concern, enabling us to request past medical/psychiatric records if necessary. 
No prohibitions will be made for changing health therapy but we will record and 
account for any changes in our analysis. We assume such changes in therapy 
will be uncommon but if they occur they will be equally balanced between the 
randomized groups. 
While participating in this research study, subjects are not allowed to take part 
in any other research project. Simultaneous medications or treatments may 
invalidate the results of this research, as well as that of the other studies. 
Changes in concomitant medication and any adverse events (see 9.1.1) are 
assessed at each visit, documented in subject’s file, and reported to the PI for 
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7 STUDY SCHEDULE 
7.1 
Prescreening 
Potential subjects who respond to the study advertisement will undergo a brief 
(5 to 10 minute) phone screening by research assistant to assess potential 
eligibility prior to Visit 1. The prescreening will require potential subjects to 
respond verbally to approximately 10 yes/no medical history questions in order 
to determine whether a screening visit should be scheduled. 
Subjects who seem eligible and available for the duration of the study will be 
scheduled for a screening visit at OCNS. 
7.2 
Enrollment/Baseline Screening (Visit 1) 
This visit will occur at the Oppenheimer Family Center for Neurobiology of 
Stress. It will take about 3 hours to complete the screening and device training 
process. The research team will verify OEF/OIF Veteran status (i.e. DD 214) 
before study enrollment if the subject identifies as a Veteran. The potential 
subjects will first review and sign ICF and HIPAA Authorization with either the 
RN, FNP, or MD. All are certified to obtain informed consent (nursing or 
physician license). Subjects will be identified by the PI, Dr. Tillisch, as possibly 
eligible after the clinic visit and the study questionnaires have been completed 
and scored. Medical history will be reviewed and a physical will be performed 
as well. The assessment questionnaires include: 
• A standardized psychiatric evaluation (MINI) 
• Hospital Anxiety and Depression Scale (HADS) 
• Mental Health Continuum Short Form (MHC-SF) 
• Patient Reported Outcomes Measurement Information System 
(PROMIS-29) 
• Positive and Negative Affect Schedule Short Form (PANAS-SF) 
• Connor-Davidson Resilience Scale (CD-RISC) 
• Perceived Stress Scale (PSS) 
• Patient Health Questionnaire (PHQ) 
 
 

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• Columbia-Suicide Severity Rating Scale (C-SSRS) Self Report Screener 
- Recent 
We will use the HADS to assess symptom severity defined as normal range (0-
7), mild (8-10), moderate (11-14) or severe (15-20). Subjects with impaired 
emotional wellbeing as defined as a minimum combined HADS score of 14 will 
be included. Subjects who score >15 will be excluded in the study and will be 
given referrals to their personal provider or community mental health resources. 
(See “Reporting Suicidal Ideation” Section 5.4) 
Subjects who express interest in participating and meet the inclusion criteria will 
be trained to use the CES device. They will be instructed that the device is set 
to a low level that should not be detectable. Subjects will have their first 1 hour 
treatment at OCNS (commencing Week 1 of the study). Subjects who tolerate 
the device treatment will then have blood drawn for baseline biological 
measures. They will be informed that this is a randomized controlled trial and 
they may or may not have an active device kit. Subjects will be sent home with 
a device, instructions for daily treatment, and a patient diary to track usage and 
side effects if applicable. 
7.3 
Intermediate Study Visit (Visit 2) 
This visit will occur at the Oppenheimer Family Center for Neurobiology of 
Stress. This visit will take approximately 1 hour and will occur Week 4 ± 1 week. 
Subjects must complete this set of study questionnaires: 
• Hospital Anxiety and Depression Scale (HADS) 
• Positive and Negative Affect Schedule Short Form (PANAS-SF) 
• Perceived Stress Scale (PSS) 
• Columbia-Suicide Severity Rating Scale (C-SSRS) Self Report Screener 
- Since Last Contact 
• Patient Reported Outcomes Measurement Information System 
(PROMIS-29) 
Subjects will have vital signs and weight measured by a nurse. Adverse events and 
concomitant medication report will be collected as well. The study coordinator will 
collect the tracking diary for weeks 1-4 and provide another tracking diary to complete 
for weeks 5-8.  
7.4 
Final Study Visit (Visit 3) 
This visit will occur at the Oppenheimer Family Center for Neurobiology of 
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treatment, Week 8 + 1 week. Subjects will be asked to bring the CES device to 
return. The study coordinator will collect the tracking diary for weeks 5-8. The 
subjects must complete the final set of questionnaires: 
• Mini International Neuropsychiatric Interview (MINI) 
• Hospital Anxiety and Depression Scale (HADS) 
• Mental Health Continuum Short Form (MHC-SF) 
• Patient Reported Outcomes Measurement Information System 
(PROMIS-29) 
• Positive and Negative Affect Schedule Short Form (PANAS-SF) 
• Connor-Davidson Resilience Scale (CD-RISC) 
• Perceived Stress Scale (PSS) 
• Patient Health Questionnaire (PHQ) 
• Columbia-Suicide Severity Rating Scale (C-SSRS) Self Report Screener 
- Since Last Contact 
• Impression of Global Improvement Scale 
The subjects will have vital signs and weight measured and have the final blood 
draw performed by a nurse. Adverse events and concomitant medication report 
will be collected as well. 

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8 STUDY PROCEDURES/EVALUATIONS 
8.1 
Study Procedures/Evaluations 
Electronic assessment questionnaire data will be collected from subjects during 
the visits at UCLA OCNS using SurveyMonkey (www.surveymonkey.com) and 
unique subject identifiers. Survey Monkey states they utilize some of the most 
advanced technology for Internet security commercially available today. Unique 
usernames and passwords are required and must be entered each time a user 
logs on. When a user accesses secured areas of our site, Secure Sockets 
Layer (SSL) technology protects user information using both server 
authentication and data encryption, ensuring that user data is safe, secure, and 
available only to authorized persons. Servers are kept in a locked cage. Digital 
surveillance equipment monitors the data center. A firewall restricts access to 
all ports except 80 (http) and 443 (https). Intrusion detection systems and other 
systems detect and prevent interference or access from outside intruders. 
QualysGuard network security audits are performed weekly. McAfee SECURE 
scans performed daily. 
The subjects will complete the aforementioned study questionnaires above (see 
“Study Schedule” Section 7) and the assessments will be scored per published 
guidelines. 
All paper source data collected at UCLA will only contain unique subject ID 
numbers. Research staff will know matching of ID with subject for data 
collection purposes but this will not be written on documents in the field. The 
documents will be coded before being stored in subject’s file. Files will be 
secured in a locked cabinet in a locked room. 
8.2 
Laboratory Procedures/Evaluations 
8.2.1 
Sample Draws 
Sample blood draws will be done by either the nurse coordinator or nurse 
practitioner. 8 mL BD Vacutainer® CPT™ Cell Preparation Tubes with 
Sodium Citrate will be used to store the blood draws. 8 mL of blood will be 
drawn during visit 1 and visit 3, so 16 mL of blood total will be drawn from 
each subject. 
The blood draws will be performed at the OCNS clinic, CHS 42-128, 10833 
LeConte Ave Los Angeles, CA 90025 and transferred immediately to the 
Inflammatory Biology Core (IBC) Laboratory, 300 Medical Plaza, Room 
3160, for processing and storage. 

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8.2.2 
Pre-Visit Sample Processing 
• Patient must be scheduled at least one week in advance by notifying 
through e-mail Stephanie, Nancy, Dr. Breen with the following: patient 
ID, date, time point of visit (pre- or post-op), and estimated time of 
delivery of blood samples. 
• If the new or rescheduled visit is less than one week away, please call 
Stephanie first at the IBC Lab phone (310-825-0302 or ext 50302) to 
confirm the ability of the lab to handle the specimens. When confirmed, 
then please email Stephanie, Nancy, Dr. Breen 
• Prepare tubes, labels (CES ID#, time point, and date), transport 
containers in advance 
8.2.3 
Study Visit Sample Processing 
1. Have the following tubes ready to be drawn in the following order: 
i. 
1 CPT tube, 8 mL (pick up as needed from IBC Lab) 
2. Complete top portion of “CES Requisition Form” for IBC Lab 
3. Have labels with participant’s study ID # and date ready 
i. 
1 x 8 mL CPT tube handling 
BE SURE TO FILL CPT TUBE COMPLETELY. 
Once the CPT tube is filled, remove from blood draw 
apparatus and immediately but gently invert tube 8 to 10 
times to mix anticoagulant additive with blood. DO NOT SHAKE. 
Vigorous mixing can cause hemolysis.  Place mixed tube upright 
in rack at room temperature in transport container; insure that 
container is closed to shield tube from light. 
NOTE: Since this BD Vacutainer® CPT™ Tube contains chemical 
additives, it is important to prevent possible backflow from the 
tube with its attendant possibility of adverse reactions to the 
patient. To guard against backflow, the following precautions 
should be taken when drawing blood into the tube: 
• Keep patient’s arm in the downward position during the 
collection procedure 
• Hold the tube with the stopper uppermost 
• Make sure the tube contents do not touch the stopper or 
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4. Deliver ASAP to IBC lab by 4 p.m. at the latest, 300 Med Plaza, third 
floor, Room 3160 (main Lab): 
• Room temperature transport container 
o Place transport container containing rack with CPT and 
requisition form on black crate just inside door 
If no lab staff is present in room 3160 where samples are dropped off, 
please check in room 3152 (opposite Deb Garet’s office) to let someone 
know samples have arrived. 
(If delayed after 4 p.m. and IBC Lab is closed, lavender top tubes may 
be held in refrigerator overnight and delivered to IBC Lab the next day; 
CPTs should be discarded) 
Blood delivered to IBC Lab will be processed and stored for CPTs = 
PBMC (pellets for future Telomere and Telomerase) 
8.2.4 
Sample Processing Directions 
Upon receipt of CPT tubes upright in rack at RT: 
1. Within two hours of blood draw, begin isolation of PBMC utilizing CPT to 
PBMC protocol—be sure to re-mix CPT tube by inverting 8 times 
before centrifugation. 
2. Count cells record number of PBMC’s on requisition. 
3. Proceed according to the following algorithm: 
a. 2x106 cells for pellet in PBS for DNA extraction. 
b. 1x106 cells for telomerase extraction in CHAPS buffer. 
4. Freeze PBMC for DNA pellet(s) at -80°C to store for future extraction. 
5. Perform telomerase extraction on fresh cells per IBC protocol. 
 
 
 
 

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9 ASSESSMENT OF SAFETY 
9.1 
Specification of Safety Parameters 
Safety assessments will include recording of AEs, which will be followed until 
the event has resolved or the condition has been deemed stable by the 
Investigator. At each visit, the Investigator will evaluate the subject to determine 
whether any AE has occurred. AEs may be directly observed, spontaneously 
reported by the subject, or obtained by questioning the subject at each study 
visit. Subjects should be questioned in a general way without asking about the 
occurrence of specific symptoms; at each visit, they will be asked standard 
questions to elicit any medically related changes in their well-being. 
All SAEs will be reported to regulatory authorities and the site IRB within 
required time frames. 
9.1.1 
Adverse Events 
The Investigator is responsible for reporting all AEs observed or reported 
during the study, regardless of clinical significance or potential causal 
relationship to study medication. 
An AE is any untoward medical occurrence in a human subject 
administered the study device, temporally associated with the subject’s 
participation in the research, whether or not considered related to the 
subject’s participation in the research. Subjects will be instructed to contact 
the Investigator at any time after randomization if any symptoms develop. 
9.1.2 
Serious Adverse Events 
An SAE is defined as any event that results in death, is immediately life-
threatening, requires inpatient hospitalization or prolongation of existing 
hospitalization, results in persistent or significant disability/incapacity or is a 
congenital anomaly/birth defect.  
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered SAEs when, based on 
appropriate medical judgment, they may jeopardize the subject and require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 
9.2 
Time Period and Frequency for Event Assessment and Follow-Up 
All AEs reported by subjects or observed during the study will be recorded. All 
AEs shall be recorded in subject’s file regardless of perceived causality. AEs 
will be assessed from the first device treatment (screening visit) to the last 
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9.3 
Characteristics of an Adverse Event 
9.3.1 
Relationship to Study Intervention 
The Investigator is obligated to estimate the relationship between the 
device and the occurrence of each AE or SAE by using his or her best 
clinical judgment. Other elements, such as the history of the underlying 
disease, concomitant therapy, other risk factors, and the temporal 
relationship of the event to the investigational product, will be considered 
and investigated.  
To assess relationship of an event to study intervention, the following 
guidelines are presented in Table 1.  
Table 1  
Assessment of Causality/Relatedness of AEs and SAEs 
Categories 
Definition 
Definitely related 
This relationship suggests that a definite causal 
relationship exists between the device treatment and the 
AE, and other conditions (concurrent illness, 
progression/expression of disease state, or concurrent 
medication reaction) do not appear to explain the event. 
Probably related 
This relationship suggests that a reasonable temporal 
sequence of the event with device treatment exists and, 
based upon the known side effects of device treatment, 
known or previously reported adverse reactions to device 
treatment, or judgment based on the Investigator’s clinical 
experience, the association of the event with the study 
device seems likely. 
Possibly related 
This relationship suggests that device treatment may 
have caused or contributed to the AE (i.e., the event 
follows a reasonable temporal sequence from the time of 
device treatment and/or follows a known response pattern 
to the study treatment but could also have been produced 
by other factors). 
Not related 
This relationship suggests that there is no association 
between the study device and the reported event. 
 
 
 

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9.3.2 
Expectedness of SAEs 
The Study PI will be responsible for determining whether an SAE is 
expected or unexpected.  An adverse event will be considered unexpected 
if the nature, severity, or frequency of the event is not consistent with the 
risk information previously described for the intervention.   
9.3.3 
Severity of Event 
The Investigator will make an assessment of severity for each AE and SAE 
reported during the study. The assessment will be based on the 
Investigator’s clinical judgment. The severity of each AE should be 
assigned to one of the categories shown in Table 2. 
Table 2  
Common Adverse Event Grading Scale 
Grade 
Definition 
Mild 
Aware of sign or symptom, but easily tolerated 
Moderate 
Discomfort enough to cause interference with usual activities 
Severe 
Incapacitating, with inability to work or perform usual activities 
An AE that is assessed as severe should not be confused with a SAE. 
Severity is a category used for rating the intensity of an event (such as 
mild, moderate, or severe), and both AE(s) and SAE(s) can be assessed 
as mild, moderate, or severe. An event is defined as serious when it meets 
one of the predefined outcomes described in 9.1.2. 
9.4 
Reporting Procedures 
AE’s that meet the criteria for reporting per the UCLA IRB guidelines are 
reported to the IRB within 10 working days of awareness where the UCLA IRB 
is the responsible IRB, and is determined by the UCLA PI to be either: 
• Unexpected, and related or possibly related to the research activity, and 
serious (i.e. placing subjects art greater risk of harm than previously known) 
or 
• Expected and related to but indicating a higher severity or frequency of 
occurrence (i.e. a trend) than was known or described in the current 
approved ICF and therefore anew identified risk. 
SAEs or deaths that are unanticipated, serious, and possibly related to the 
study intervention will be reported to the UCLA IRB in accordance with their 
requirements which is within 3 working days of awareness. 

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10 STATISTICAL ANALYSIS PLAN 
10.1 
Sample Size 
G*Power 3.1 was employed to calculate the number of subjects needed per 
group to detect a large group differences, slightly less than a 1 standard 
deviation difference (Cohen’s effect, size, d=.80) in the effect of daily CES 
treatment on emotional well-being and PBMC telomerase activity. Based on a 
one tailed superiority test of improvement (active > sham CES treatment) and 
an alpha = .05, 22 subjects per group are required to provide adequate 
statistical power (80%) for the analysis (Noncentrality parameter=2.59, Critical t 
(40)=1.68. To meet this criteria we will include 22 completed subjects per group. 
10.2 
Assessment of Primary and Secondary Outcomes 
Intention to treat and completed group analyses will be performed for the 
behavioral measures. Because the utility of CES in effecting telomerase, 
telomere length, or CRP has not been established, the biological measures will 
be assessed only for those subjects who have both pre and post treatment data 
points. 
10.2.1 Primary Outcomes 
One tailed t-tests for independent groups will be performed to test the 
hypothesis that active CES device will be superior to sham in decreasing 
the combined HAD score. This will be accomplished by Contrast analysis 
within the framework of a random effects  general linear mixed effects  (RE 
GLMM) model.  
10.2.2 Secondary Outcome 
One tailed t-tests for independent groups will be performed to test the 
hypothesis that participants using the active vs sham CES device will have 
smaller reductions in telomere length and higher telomerase levels at post 
compared to pre-treatment. 
10.2.3 Exploratory Outcomes 
• 
One tailed t-tests of independent groups will be performed to test the 
hypotheses that active CES device will be superior to sham in improvement of 
PROMIS domains, MHC-SF, CD-RISC, PSS, PHQPANAS-SF and impression 
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11 ETHICS/PROTECTION OF HUMAN SUBJECTS 
11.1 
Institutional Review Board 
The protocol, Informed Consent Forms, recruitment materials, and all subject 
materials will be submitted to the IRB for review and approval. Approval of both 
the protocol and the Informed Consent Form must be obtained before any 
subject is enrolled.  Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented in the study.   
11.2 
Informed Consent Process 
Informed consent is a process that is initiated prior to the individual agreeing to 
participate in the study and continues throughout study participation. Before 
coming to the clinic, the study is explained via phone screening using the IRB-
approved prescreening script. All interested volunteers are offered a copy of the 
consent form beforehand in order to review and ponder the consent by 
themselves or with family, friends or advisors before their screening date. At 
every stage of the process, they will be given opportunity to ask questions or 
voice concerns that they may have.  
The informed consent and study documents will be in English language only 
therefore only persons fluent in reading English will be eligible to enroll into the 
study. The consent is written to ensure comprehension at a 6th-8th grade level. 
No vulnerable persons, as defined by the Office of Protection of Research 
Subjects (OPRS/IRB), will be targeted. The PI and research personnel (co-
investigator, RNs, research assistant) will be responsible for inviting subjects to 
participate. The study will be explained in detail and they will be allowed as 
much time as needed to read, comprehend and ask any pertaining questions. 
After the subject has read the consent form at the UCLA OCNS private clinic 
exam room area, the investigator will review the study and answer any 
questions or concerns regarding participation. Subjects will be asked to 
summarize the information provided to ensure comprehension. It will be 
explained that they are allowed to withdraw consent at any time without 
retribution. The consent process will be documented in the research record.   
11.3 
Subject Confidentiality 
Subject’s names and study information will be kept on a password protected 
database, and will be linked only with a unique 4-digit study identification 
number for this research. The only people who will have access to the data or 
the codes will be research team associated with this study. All other data is 
stripped of personal identifiers and stored in an encrypted Microsoft Access 
database. All electronic data in the computer database is password protected. 
Paper source documents are stored in a locked office with locked cabinets in a 
secured office location. Only authorized research personnel will have access to 
the locked office and cabinets.  

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11.4 
Future Use of Stored Specimens and Other Identifiable Data 
These procedures will be taken to protect the confidentiality of the subjects who 
donate samples. The procedures by which samples will be stored including the 
information that will be attached to samples. The process by which the donor’s 
identity will be protected (process of coding and de-identifying samples) 
including the location where the information that links a sample to the identity of 
the donor is kept and who has access to this information. 
Although the samples containing genetic material will be coded and no subject 
identifiers will be attached to the samples, the codes will be maintained by the 
PI or the research assistant in the records along with the date of collection on 
the tube containing genetic material and in the specimen log book. This will 
allow protecting the identity of the donor from anybody who has access to the 
storage, but is not working on the study. The Samples will be coded but not 
anonymous. Therefore the policy will read: 
Policy: Samples will be coded to protect the identity of the donor from anybody 
who is not a part of the research team. The link will be maintained between 
subject identifiers and stored samples in the PI’s records. Samples will be 
stored in a manner that optimizes the viability of the specimen and the utility of 
the cells for research. All equipment used in preparation or storage of human 
specimens shall be subject to routine maintenance to ensure optimal 
preservation of specimens. 
Process: The participant will specify within the consent form whether they would 
like to the samples stored for future research.  On receipt of a sample the PI or 
study coordinator will assign a code to the sample and record the code and the 
date of collection on the tube containing genetic material and in the specimen 
logbook. This will be the only link between the samples and the subjects 
accessible only to the PI and members of the research team. The sample will 
then be processed in accordance with the research needs of the study. The 
samples will not be shared. 
Sharing: The participant sample will not be shared with other researchers 
outside the research team. Since the sample will only be shared within the 
research team, the only set process for sharing (within the team) will be a 
written request to the PI.  Only after approval by the PI, will the samples be 
release to the co-investigators. Only the subjects ID will accompany the sample. 
Processing of sample upon leaving UCLA: In the event that the PI leaves 
UCLA, then the samples will be destroyed.     

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12 DATA HANDLING AND RECORD KEEPING 
12.1 
Data Management Responsibilities 
Data collection and accurate documentation are the responsibility of the study 
staff under the supervision of the investigator.  All source documents and 
laboratory reports must be reviewed by the study team and data entry staff, who 
will ensure that they are accurate and complete.  Unanticipated problems and 
adverse events must be reviewed by the investigator.   
12.2 
Data Collection 
Paper source documents with data collected at UCLA will be coded and kept in 
locked cabinets. A coding key and any collected identifiers (e.g., phone, 
address) will be kept in a separate locked cabinet by the PI. All data will be 
coded upon storing and before data analysis. 
Electronic data collected at UCLA will be done using SurveyMonkey and will be 
coded. All data will be stripped of personal identifiers and stored in an 
encrypted Microsoft Access database. All data in the computer database will be 
password protected. Only authorized research personnel will have access to 
the password protected computer database. 
12.3 
Study Records Retention 
Upon completion of the study, the coding key and all identifiers will be 
destroyed, rendering the data anonymous. 
With subject permission, we may store specimen data with or without subject’s 
name or identifying information for future use. Retention of blood specimens 
after the end of the study for use in future research must be granted permission 
from the subject on the ICF. Subjects will give permission on the ICF if they 
agree to keep their name and other identifying information with their specimens. 
See 11.4 for future use of stored specimens plan. 
 
 
 
 

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13 RESULTS:  
13.1 Feasibility: This was a feasibility study, initially powered for a sample size of 44.  
We fell far below the recruitment goals, despite 2 years of recruitment, finding a lack of 
interest for this intervention from the desired patient population. Therefore we consider 
the feasibility goal to have been a failure. The results should be interpreted with caution 
as the study was likely underpowered and the real world acceptability of the intervention 
in the context of this study was not desirable enough to recruit participants.  
13.2 Baseline values and demographics:  
11 subjects completed the Sham treatment and 13 completed the active treatment. No 
baseline differences in age, body mass index, HAD anxiety, HAD depression, or 
telomere length were identified between subjects randomized to the sham or active 
device groups.  Both groups had 5 Veterans. Two subjects did not have baseline BMI 
measured. 1 subject did not have sufficient sample to complete the Telomere length.  
No baseline differences were noted in age, BMI, anxiety, depression between Veterans 
and non-Veterans (all p>.05)  
 
 

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13.4 Secondary outcome: Telomeres 
13.4.1 Telomere length 
No differences in telomere length were noted in pre to post treatment phase,p=.33. 
 
13.4.2 Telomerase activity 
The results of the telomerase assay showed unacceptably high intra and inter-subject 
variability, multiple outliers, and non-normal distribution (baseline values skewness 3.1,  
kurtosis 10.7; end values skewness 2.1, kurtosis 4.1).  It is unclear whether this was 
secondary to natural population variations or assay unreliability but it was determined 
that analysis of this small sample was unlikely to result in an interpretable finding.  
13.5 Exploratory outcomes 
These outcomes were not measured due to the lower than expected sample size.  
 

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14 CONCLUSIONS AND INTERPRETATION 
The study was considered a feasibility failure due to failure to recruit subjects in general 
and Veteran subjects in particular. There are multiple potential reasons for this.  First, 
the study site was not located at the Veterans clinic, it was at UCLA which requires 15-
30 minutes drive or bus ride.  The study compensation was low for the time that the 
participants were involved. There was not an advertising budget to reach a larger group 
of eligible individuals. The treatment interventions required an hour of use per day which 
may have been unacceptable to this young population.  
Analysis of the anxiety and depression combined score showed a small benefit of the 
active over the sham device. This is consistent with other studies and supports the 
possibility that the intervention has benefit on negative affect in young men. Larger 
studies will be required to confirm this.  
Analysis of the telomere lengths did not show differences between subject groups.  Due 
to the small sample this is hard to interpret, but may represent a lack of effect of mildly 
improved mood on telomere length in young men.  

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15 REFERENCES 
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Permanent imprint or reversible process?: An overview of the current evidence, 
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2. Simon NM, Smoller JW, McNamara KL, Maser RS, Zalta AK, Pollack MH, et al. 
Telomere shortening and mood disorders: preliminary support for a chronic stress 
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3. van Ockenburg SL, de Jonge P, van der Harst P, Ormel J, Rosmalen JG. Does 
neuroticism make you old? Prospective associations between neuroticism and 
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5. Jergovic M, Tomicevic M, Vidovic A, Bendelja K, Savic A, Vojvoda V, et al. Telomere 
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8. Taylor AG, Anderson JG, Riedel SL, Lewis JE, Bourguignon C. A randomized, 
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activity in brain pain processing regions in individuals with fibromyalgia. Explore 
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9. Feusner JD, Madsen S, Moody TD, Bohon C, Hembacher E, Bookheimer SY, et al. 
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Behav. 2012;2(3):211-20. PMCID: 3381625. 
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11. Bystritsky A, Kerwin L, Feusner J. A pilot study of cranial electrotherapy stimulation 
for generalized anxiety disorder. J Clin Psychiatry. 2008;69(3):412-7. 
12. Winick RL. Cranial electrotherapy stimulation (CES): a safe and effective low cost 
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13. Lichtbroun AS, Raicer MM, Smith RB. The treatment of fibromyalgia with cranial 
electrotherapy stimulation. J Clin Rheumatol. 2001;7(2):72-8; discussion 8. 
14. Kirsch DL, Nichols F. Cranial electrotherapy stimulation for treatment of anxiety, 
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15. Gilula MF, Barach PR. Cranial electrotherapy stimulation: a safe neuromedical 
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16. Suman AL, Biagi B, Biasi G, Carli G, Gradi M, Prati E, et al. One-year efficacy of a 3-
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17. Barclay TH, Barclay RD. A clinical trial of cranial electrotherapy stimulation for 
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18. Zhang ZJ, Ng R, Man SC, Li TY, Wong W, Tan QR, et al. Dense cranial 
electroacupuncture stimulation for major depressive disorder--a single-blind, 
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19. Schrader LM, Cook IA, Miller PR, Maremont ER, DeGiorgio CM. Trigeminal nerve 
stimulation in major depressive disorder: first proof of concept in an open pilot trial. 
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20. Lande RG, Gragnani C. Efficacy of cranial electric stimulation for the treatment of 
insomnia: a randomized pilot study. Complement Ther Med. 2013;21(1):8-13. 
21. Taylor AG, Anderson JG, Riedel SL, Lewis JE, Kinser PA, Bourguignon C. Cranial 
electrical stimulation improves symptoms and functional status in individuals with 
fibromyalgia. Pain Manag Nurs. 2013;14(4):327-35. 
22. Lee SH, Kim WY, Lee CH, Min TJ, Lee YS, Kim JH, et al. Effects of cranial 
electrotherapy stimulation on preoperative anxiety, pain and endocrine response. J 
Int Med Res. 2013;41(6):1788-95. 
23. Schutte NS, Malouff JM. A meta-analytic review of the effects of mindfulness 
meditation on telomerase activity. Psychoneuroendocrinology. 2014;42:45-8. 
24. Monson CM, Gradus JL, Young-Xu Y, Schnurr PP, Price JL, Schumm JA. Change in 
posttraumatic stress disorder symptoms: do clinicians and patients agree? Psychol 
Assess. 2008;20(2):131-8. 
25. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr 
Scand. 1983;67(6):361-70. 
26. Amorim P, Lecrubier Y, Weiller E, Hergueta T, Sheehan D. DSM-IH-R Psychotic 
Disorders: procedural validity of the Mini International Neuropsychiatric Interview 
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1998;13(1):26-34. 
27. Lamers SM, Westerhof GJ, Bohlmeijer ET, ten Klooster PM, Keyes CL. Evaluating 
the psychometric properties of the Mental Health Continuum-Short Form (MHC-SF). 
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28. Kim NW, Wu F. Advances in quantification and characterization of telomerase 
activity by the telomeric repeat amplification protocol (TRAP). Nucleic Acids Res. 
1997;25(13):2595-7. PMCID: 146790. 
29. Valenzuela HF, Effros RB. Divergent telomerase and CD28 expression patterns in 
human CD4 and CD8 T cells following repeated encounters with the same antigenic 
stimulus. Clin Immunol. 2002;105(2):117-25. 
30. Cawthon RM. Telomere measurement by quantitative PCR. Nucleic Acids Res. 
2002;30(10):e47. PMCID: 115301. 
31. Rickabaugh TM, Kilpatrick RD, Hultin LE, Hultin PM, Hausner MA, Sugar CA, et al. 
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SUPPLEMENTAL MATERIALS 
• Phone Prescreening Script 
• Informed Consent Form 
• HIPAA Authorization 
• Mini International Neuropsychiatric Interview (MINI) 
• Hospital Anxiety and Depression Scale (HADS) 
• Mental Health Continuum Short Form (MHC-SF) 
• Patient Reported Outcomes Measurement Information System (PROMIS-29) 
• PTSD Check List - Military (PCL-M) 
• Positive and Negative Affect Schedule Short Form (PANAS-SF) 
• Connor-Davidson Resilience Scale (CD-RISC) 
• Perceived Stress Scale (PSS) 
• Adverse Childhood Experiences (ACE) 
• Patient Health Questionnaire (PHQ) 
• Columbia-Suicide Severity Rating Scale (C-SSRS) Self Report Screener – Recent 
• Columbia-Suicide Severity Rating Scale (C-SSRS) Self Report Screener – Since 
Last Contact 
• Expectancy for Improvement Scale 
• Impression of Global Improvement Scale 
• Tracking Diary 
• Instructions for Daily Use 
• Alpha-Stim Brochure 
• CES Requisition Form 
• Internet Ad Posting 
• Internet Ad Flyer 
• Tear-Off Flyer