Management of Chronic Pain and PTSD in Gulf War Veterans With tDCS+Prolonged Exposure
Phase: NA
Conditions: Chronic Pain, PTSD
Sponsor: The University of Texas Health Science Center, Houston

IRB NUMBER: HSC-MS-19-0960 
IRB APPROVAL DATE: 03/26/2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Management of Chronic Pain and PTSD in Gulf War Veterans With tDCS+Prolonged Exposure 
 
NCT04236284 
 
Version Date: 03/26/2020 
 
 

IRB NUMBER: HSC-MS-19-0960 
IRB APPROVAL DATE: 03/26/2020 
 
1. ABSTRACT (provide a one-paragraph summary of the current seed project) 
Veterans with co-morbid chronic pain and PTSD utilize healthcare services at a higher rate than those with pain 
or PTSD alone. Unfortunately, there are no integrated treatments for Pain and PTSD. Moreover, non- 
pharmacological treatments for pain such as Cognitive Behavioral Therapy are useful in only about 50% of 
cases. Transcranial direct current stimulation (tDCS) may be an effective treatment for pain, and has been 
recently used to ameliorate PTSD symptoms. Prolonged Exposure Therapy (PE) is highly effective in treating 
PTSD symptoms. Therefore, we propose to (a) integrate & (b) gather feasibility data for home-based tDCS + 
PE for Pain and PTSD with 15 Veterans. 
2. PRIMARY HYPOTHESES AND SPECIFIC AIMS (provide an NIH-style set of primary hypotheses about the 
project outcomes, and the specific aims that will be accomplished) 
Chronic pain is one of the most prevalent health conditions among Americans, affecting about a third of the 
general population1. In Veterans, chronic pain is even more common, with a prevalence of about 50%2,3,4,5. For 
instance, the pain-related fibromyalgia diagnosis is part of Gulf War Syndrome and is highly comorbid with other 
common military service-related health problems such as Posttraumatic Stress Disorder (PTSD)6. Moreover, 
lack of effective, integrated, and available alternative treatments for chronic pain contributes to the opioid 
epidemic7.Combat veterans are more likely to develop PTSD than civilians, with 20-30% of Vietnam-era Veterans, 
15-25% of Operation Desert Storm Veterans, and 11-25% of Operation Enduring Freedom, Operation Iraqi 
Freedom, and Operation New Dawn (OEF/OIF/OND) Veterans experiencing significant PTSD symptoms8,9 The 
number of veterans with chronic pain and PTSD is expected to grow given the return of personnel from recent 
OEF/OIF/OND conflicts9,10. Veterans with co-morbid chronic pain and PTSD utilize healthcare services at a 
higher rate than those with pain or PTSD alone, leading to an increased burden on healthcare systems 
throughout the United States. Furthermore, opioid medications have been used more frequently to treat chronic 
pain among OEF and OIF Veterans with PTSD, and these Veterans are more likely to incur harmful 
consequences during the course of their care due to these medications12. 
The Overall Aim of the present proposal is to integrate, refine and investigate the feasibility (e.g., pilot testing, 
recruitment, attrition, assessment) of tDCS for treating chronic pain with a best practices evidence-based 
treatment for PTSD (i.e., Prolonged Exposure: PE) in 15 veterans, a group for which both pain and PTSD are 
particularly problematic. 
SA1: Integrate the home-based tDCS+PE Treatment. The investigative team is comprised of Pain, PTSD, and 
salivary biomarker experts who will integrate tDCS into the 12 session PE treatment protocol. 
H1: The 12 session PE protocol will yield itself well to tDCS component integration based on participant feedback. 
SA2: Test the feasibility of both the integrated intervention and key study design features, including translational 
research features such as biomarker assessment in a non-randomized trial with 15 Veterans assessed at 
baseline and post-treatment. Feasibility of the home-based tDCS+PE intervention will be measured in terms of 
recruitment metrics, assessment burden, successful biomarker collection, specification of biomarker relationship 
to hypothesized mechanisms of change, treatment attrition, rates of missing data at each measurement time 
point, participant satisfaction, and ratings of treatment face validity. Post treatment key informant interviews will 
be conducted where suggestions for treatment enhancement and satisfaction will be systematically collected 
and analyzed. 
H2 is given in terms of Specific Pre-Defined Milestones for Success, including: 75% of Veterans experiencing 
chronic pain and PTSD who enroll will complete at least 8 sessions of the integrated treatment, and both 
completers and dropouts will offer actionable suggestions in exit interviews for improving the delivery of the 
intervention. SA2) Feasibility metrics will be acceptable for recruitment rate (two per month), treatment 
completion of 8 sessions (75%), assessment completion (90%), and good to excellent satisfaction (95%). 
3. BACKGROUND AND RATIONALE (provide evidence for the importance of the scientific/clinical problem, 
and how this project will address the problem, including new knowledge to be gained) 
Chronic Pain: Chronic pain is common in Veterans, with a prevalence of about 50%2,3,4,5. Moreover, pain is 
highly comorbid with other common military service-related health problems such as Posttraumatic Stress 
Disorder (PTSD)6. Pain is an exceedingly costly condition, with estimates from the Institute of Medicine at $560 
to $635 annually for healthcare costs, disability days, and lost wages in the United States10. Moreover, lack of 
effective, integrated, and available alternative treatments for chronic pain is a contributor to the opioid epidemic7. 

IRB NUMBER: HSC-MS-19-0960 
IRB APPROVAL DATE: 03/26/2020 
 
Post-Traumatic Stress Disorder: PTSD is characterized by intrusion symptoms, persistent avoidance 
behaviors, negative alterations in cognition and/or mood, and alterations in arousal and reactivity11. Combat 
veterans are more likely to develop PTSD than civilians, with 20-30% of Vietnam-era Veterans, 15-25% of 
Operation Desert Shield and Desert Storm Veterans, and 11-25% of Operation Enduring Freedom, Operation 
Iraqi Freedom, and Operation New Dawn (OEF/OIF/OND) Veterans experiencing significant PTSD symptoms8,9. 
3.1. 
Chronic 
Pain 
and 
PTSD: 
Potential 
for 
 Mutual 
Symptom 
Figure 1 
Exacerbation Avoidance of stimuli associated 
with a traumatic event, as well as hypervigilance 
(with concomitant increased pain perception) are 
diagnostic features of PTSD. Patients with 
chronic pain often exhibit avoidance behaviors 
secondary to perceived pain related to physical 
activity, leading to inactivity and weakened 
overall health status. Indeed, the presence of 
shared avoidance behaviors may predict poor 
outcomes for individuals experiencing co-morbid 
pain and PTSD12,13. Research focused on 
treatment approaches that address this shared 
avoidance may be fruitful, given the impact that 
co-morbid pain and PTSD have on veterans. 
Hyperarousal and hypervigilance to bodily sensations are also found independently in chronic pain and in PTSD, 
although they likely have an additional synergistic effect on maintaining the negative impacts of both conditions 
when they are comorbid12. Additionally, other PTSD symptoms such as numbness and detachment from others 
are also frequently associated with chronic pain14. Figure 1 presents a thematic diagram illustrating the 
interaction between core characteristics of PTSD and comorbid pain targeted in the present proposal. 
3.2. Transcranial direct current stimulation (tDCS). Noninvasive brain stimulation, such as transcranial direct 
current stimulation (tDCS), has received significant attention for the treatment of pain in chronic conditions owing 
to its neuromodulatory effects in the central nervous system15.tDCS involves the application of low-amplitude 
direct electric current to the head in a noninvasive and painless manner, which modulates the resting membrane 
potentials of neurons, altering the excitability of the targeted cortical area. tDCS is categorized as a “non- 
significant risk” device by the U.S. Food and Drug Administration16,17. Hundreds of clinical trials have 
demonstrated tDCS to be safe and well tolerated within the established current intensities and durations18. For 
pain treatment, stimulation is typically delivered multiple times with the anode electrode placed over the primary 
motor cortex and with the cathode electrode placed over the supraorbital region. In particular, a panel of experts 
of the International Federation of Clinical Neurophysiology published evidence-based guidelines in which they 
recommended 20-minute tDCS using 2 mA electrical current intensity for possible efficacy among populations 
with chronic pain19. Our group and others have shown that this stimulation produces analgesic effects by 
activating afferents or efferents that connect structures involved in pain processing or by facilitating descending 
pain modulation and improves pain system function through direct effects on the motor, somatosensory, and 
frontal cortices implicated in pain sensitivity20,21. 
3.3. tDCS may potentiate treatment outcomes achieved from PE. Since tDCS is a noninvasive and safe 
approach to facilitate neuroplasticity22, it may enhance the brain’s ability to adaptively reorganize in response to 
other clinical interventions23, including PE. Because the therapeutic effects of PE are at least partially due to 
adaptive changes in pain-related brain function, pairing tDCS with PE may augment the adaptive brain changes 
that occur with PE and further reduce pain and PTSD symptoms. 
3.4. Saliva as a non-invasive Biomarker source for innovative Pain & PTSD related measures: Saliva 
contains numerous biomarkers including proteins, peptides, mRNA, DNA, and miRNA of both human and oral 
microbial origin24,25,26,27. Molecules such as nerve growth factor (NGF), substance P, dehydroepiandrosterone 
(DHEA), opiorphin28 and calcitonin-gene related peptide (CGRP) are secreted in saliva in response to chronic 
stress and pain29,30. For instance, molecules such as cortisol, DHEA, Substance P, norepinephrine, salivary 
alpha amylase and estrogen have long been proposed to be useful in diagnosis of PTSD31,32,33,34. The following 

IRB NUMBER: HSC-MS-19-0960 
IRB APPROVAL DATE: 03/26/2020 
 
are biomarkers that have been proposed to be indicative of development of PTSD symptoms, however not all of 
them were tested in the saliva (reviewed in Andrews, & Neises35): 1) Neuropeptide Y, released from sympathetic 
 
neurons during chronic and sustained stress36 2) CD14, associated with TBI, stroke and microglial activity37,38 3) 
S100A8, marker of microglia and macrophages and elevated in TBI39 4) S100A10, shown to be reduced in level 
in PTSD when compared with controls40,41 5) TNF, a potent inflammatory response initiator elevated in PTSD42 
(6) IL-1, associated with local and systemic inflammation, elevated in PTSD43,44 7) IL-6, a pleiotropic cytokine 
elevated in PTSD45,46 and 8) GS, a key intracellular signaling molecule associated with depression and suicide47. 
Recently salivary alpha amylase has been proposed to be a marker for pain in epilepsy48 and cancer49; salivary 
cortisol and sTNFαRII have been to some degree associated with pain intensity and pain unpleasantness in 
healthy individuals50; salivary chromogranin A level increases after massage therapy suggesting it could be a 
marker for reduced pain perception51. Evidence shows the relevance of tDCS and salivary biomarkers. These 
studies show that tDCS stimulates salivary proteomic changes, especially related to inflammation and stress. 
For instance, IL-10, IL-6, TNF-alpha, CRP, Cortisol, and beta-endorphin have been shown to modify after tDCS 
treatment52,53. As the usefulness of these biomarkers has not yet been fully established in PTSD54,34 further 
validation is critical. 
 
4. INNOVATION 
The means by which the current proposal addresses a widely prevalent problem (i.e., Pain comorbid with PTSD), 
and a national crisis (i.e., opioid addiction following pain treatment), is highly innovative, both in terms its 
treatment integration, and in terms of its use of select biomarkers to specify mechanisms of improvement. 
 
5. METHODS (describe the primary plan for data collection, measurement tools, and timelines) 
Design Overview and Project Timeline: The study team will first integrate home-based tDCS into two of the 
early weeks of the 12 week sessions of PE protocol. The reasoning to conduct tDCS in this way related to PE 
are three folded: first, controlling signaling of pain to engage into trauma treatment may reduce dropout from PE; 
second, research shows some cognition improvement with tDCS which may help patients to understand and 
more adequately participate in aspects PE treatment particularly as the complete understanding of the rationale 
of PE at the beginning of the treatment is very important to set the stage for treatment expectation and prevent 
dropout, and finally the hypothesized model of interaction of chronic pain and PTSD symptomatology, tDCS may 
help to reduce avoidance behavior modulated by pain and PTSD symptoms. This will be followed by a repeated 
measures single group design wherein each of the 15 Veteran participants serves as their own control, with 
major assessments of feasibility, clinical and biomarker indices at pre, mid and post-treatment (week 13), 
complemented by weekly assessments of key pain and PTSD symptoms. The study will also include with open 
ended key informant interviews following treatment with the 15 participants to derive suggestions for improving 
the integrated treatment 
5.1. Study team: Dr. Hernandez Tejada, Principal Investigator, is an Associate Professor at the Department of 
Psychiatry, Trauma Resilience Center at UTHealth Houston and an affiliate Research Health Scientist at the 
Ralph H. Johnson VAMC in Charleston, SC. She is both a clinical psychologist and a health administrator and 
is currently site PI for a large Dept. of Defense PTSD treatment outcome study. Her work has centered on 
addressing dropout from evidence-based PTSD treatment and telemental health delivered psychotherapies for 
veterans. Dr. Fries is Assistant Professor at the Department of Psychiatry and Behavioral Sciences at UTHealth 
and an investigator at the Translational Psychiatry Program. Dr. Fries has a broad background in psychiatry, 
molecular biology, genetics, and biochemistry, with specific interest and training in epigenetics, bipolar disorder, 
and stress. Over the past few years he has been working on the search for the biological underpinnings of mood 
disorders, with an emphasis on epigenetics and biochemical mechanisms. He will be responsible for processing 
and analyzing the saliva samples. Dr. Little, is a professor in the Department of Psychiatry and the director of 
research for the Trauma and Resilience Center. Her current work involves Gulf War Veterans and focuses on 
the mechanisms that underlie risk for neurodegenerative disease secondary to brain trauma; development of 
diagnostic tests using high field magnetic resonance imaging for those who have been exposed to toxins during 
military service; and development of early interventions for PTSD. Dr. Little will facilitate with recruitment. Dr. 
Ahn is an Associate Professor in the Department of Research at the UTHealth Cizik School of Nursing and a 
board-certified nurse practitioner and nurse scientist with a strong background in electrical and computer 
engineering, and has produced more than 40 peer-reviewed publications (27 as first author). In particular, he 
has acquired professional training and earned certificates in neuromodulation (transcranial magnetic stimulation 

IRB NUMBER: HSC-MS-19-0960 
IRB APPROVAL DATE: 03/26/2020 
 
and tDCS) and neuroimaging (multimodal brain imaging and fNIRS). He will be responsible for the tDCS 
component of this feasibility study. 
5.2 Participants & Inclusion / Exclusion Criteria: Participants will be Veterans, age 18 years and older, 
presenting with PTSD and Pain. Inclusion Criteria are: 1) Presence of chronic non-cancer pain and pain 
interference, defined as scoring 1 standard deviation above PROMIS55 normative data on both the 3-item 
PROMIS Pain Intensity 3a scale55 and the 8-item PROMIS Pain 8a Interference scale55 (see Measures below). 
Symptoms will be required to be of six-month duration or longer; 2) Diagnosis of PTSD assigned on the basis of 
the Clinician Administered PTSD Scale56. Exclusion Criteria are: 1) Having a household member who is already 
enrolled in the study; 2) Active psychosis or dementia at screening; 3) Suicidal ideation with clear intent; 4) 
Current substance dependence; 5) current opioid medication for pain 6) being pregnant. 
5.3. Recruitment and Retention Procedures: will be addressed in the larger proposal derived from pilot. 
5.4. Minority and Female Recruitment: At least 25% of the sample will be non-white and 10% female. 
5.5. Description of the Informed Consent Process: Informed consent will be administered in private UTH 
TRC offices by approved individual trained in human subjects regulations and informed consent procedures. If 
any participants are illiterate, the consent will be read and explained in the presence of a witness. Teleconsent 
will also be used when the potential participant is unable to come to the office for the first visit of enrollment 
and to address unforeseeable circumstances, such as the current covid19 crisis. The potential participant will 
digitize (scan or photograph) a version of the consent they sign, or use a digital signature such as that found in 
Adobe to sign the consent document. This digitized document and signature will then be sent via email, or the 
hard copy will be sent via US postal service mail to the person consenting the potential participant. 
5.6. Attrition and Retention efforts: Will be addressed in the larger proposal derived from this pilot. 
5.7. Medication Stabilization. Patients will be asked to maintain medications at current dosages for at least 4 
weeks prior to starting the trial. 
5.8. Participant Payment: All participants will receive $30 for baseline and $30 for midpoint, $30 for the post- 
treatment clinical and biomarker assessments (insufficient time for follow-up), $15 for tDCS turn over and 
assessment, and $25 for the feasibility interview. Transportation/parking in the amount of $12 will be designated 
for the four in person visits. 
5.9. Treatment: tDCS and PE Integration: 
Overview of tDCS: tDCS is a non-invasive neuromodulation technique that has been used to improved cognitive 
functions. will be administered with a constant current intensity of 2 mA57 for 20 min per session/ 10 sessions 
total daily for 2 weeks (Monday to Friday), the device is a Soterix 1x1 tDCS mini-CT Stimulator (Soterix Medical 
Inc., NY) with headgear and 5 _ 7 cm saline-soaked surface sponge electrodes. The sponge electrodes snap 
into the custom headgear, which is secured to the participant’s head for simple and fail-safe electrode 
preparation. This single-position headgear with clearly labeled sponge markers eliminated room for user error 
and helped conserve the placement of the montage. Participants will administer a stimulation session via the 
Soterix 1x1 tDCS mini-CT Stimulator only after being provided a single-use code to unlock the device by the 
research staff once proper contact quality is achieved (only the on/off button will be adjustable by the study 
participants; they will not be able to adjust the device settings). After the participant enters the unlock code, the 
screen on the device will show a timer that counted down the minutes until the end of the session. After 20 min, 
the device will turn off automatically, and the study staff will instruct the participant to remove the headset and 
discard the sponges and to safely store all materials for the next session. 
Overview of PE: Prolonged Exposure has been extensively researched, including by the present team (see 
Acierno et al.58), and is an effective treatment for PTSD59 that includes the following components: a) psycho- 
education about the common reactions to traumatic events and presentation of the treatment rationale (sessions 
1 and 2), b) repeated in vivo exposure to traumatic stimuli (in vivo exercises are assigned as homework during 
sessions 3 through 11), c) repeated, prolonged, imaginal exposure to traumatic memories (imaginal exposure is 
implemented during sessions 3 through 11; patients listen to session audiotapes for homework between 
sessions), and d) relapse prevention strategies and further treatment planning (session 12). The manual for PE 
is publicly available. 
Integration of tDCS and PE: Participants will come in person to the clinic office to complete the baseline visit and 
the in-person training for the use of both home-based self-administered tDCS and the home-based telehealth 
device (iPad) for the PE sessions. They understand that they will start the sessions of tDCS once they start the 
in vivo and imaginal exposures assignments at home. They will self-administer (under televideo supervision) the 

IRB NUMBER: HSC-MS-19-0960 
IRB APPROVAL DATE: 03/26/2020 
 
tDCS session before doing in vivo and/or imaginal exposures assignments. The participants will be remotely 
supervised by trained research staff at each stimulation to ensure the technique is correct and to monitor any 
adverse events. We will provide secure videoconferencing software (e.g., WebEx) and ensure the participants 
are comfortable using the telehealth software. 
5.10 Dependent Measures / Feasibility, Biomarker, and Clinical (note description has been eliminated) 
1. Demographics (pre-treatment only): age, race, ethnicity, sex, marital status, education, disability status, 
income, and employment information will be collected via a study specific demographic form. 
2. Recruitment Metrics: defined as the rate of participant enrollment per week. 
3. Biomarker Sample Collection: defined as the % of samples collected at major assessment points. 
4. Feasibility of establishing biomarker relationship to hypothesized mechanisms of change: defined as ability to 
collect viable samples for analysis. 
5. Treatment Attrition: defined as the % of participants dropping out prior to completing 12 sessions of the 
intervention protocol. We will also collect number of sessions completed. 
6. Rate of Missing Data: defined as % of missing data (# missing items aggregated across all self-report 
measures divided by total number of possible items) at each measurement time point. 
7. Treatment Satisfaction: as measured by the Charleston Psychiatric Outpatient Satisfaction Scale: CPOSS60. 
8. Treatment Credibility: defined as an overall scale rating from 0 to 10 with 0 being ‘not credible, I did not think 
this treatment would help either my PTSD or Pain symptoms’ to 10 being “completely credible, I was very sure 
this treatment would help both my PTSD and Pain symptoms”. 
9. Treatment Acceptability: defined as an overall scale rating from 0 to 10 with 0 being ‘not acceptable, this 
treatment should not be offered to veterans, those in pain, or those with PTSD’ to ‘completely acceptable’ “this 
treatment is perfectly suited to veterans and others with Pain and PTSD symptoms.” 
10. General Pain Information (Major Assessments): general information about chronic pain will be gathered to 
include location of pain site(s), duration of chronic pain at each site, current and prior treatment approaches for 
chronic pain, medical visits related to pain management, and past pain medications. 
11. PROMIS Pain 3a Intensity Scale55 (Weekly during Treatment + Major Assessments) 
12. PROMIS PAIN 8a Interference Scale55 (Weekly during Treatment + Major Assessments) 
13. The Clinician-Administered PTSD Scale 5 (CAPS-5)61 (Major Assessments) 
14. PTSD Checklist-5 (PCL-561) (Major Assessments) 
15. PHQ-962 (Weekly during Treatment + Major Assessments) 
16. World Health Organization Quality of Life – Short Form (WHOQOL-BREF)63 (Major Assessments) 
To permit comparison with prior pain research, but to limit participant burden, the following 
additional pain related scales will also be used only at major assessment points: 
17. The West Haven-Yale Multidimensional Pain Inventory: (Major Assessments) (WHYMPI/MPI)64 
18. The Tampa Scale of Kinesiophobia-Revised (TSK-R)65 (Major Assessments) 
19. Pain Catastrophizing Scale (PCS)66  (Major Assessments) 
20. Homework Diary (Weekly During Treatment): Daily records of tDCS and PE homework completion will be 
maintained so as to permit ‘dose as delivered’ effects of treatment. 
21. Biomarker Assessments (Baseline, Mid-Point, Post-Treatment and Follow-ups): Salivary levels of the 
biomarker panel (cortisol, substance P, DHEA, IL-1, and IL-6) using enzyme-linked immunosorbent assays 
(ELISA). 
Saliva Sample Collection (All major assessments): Saliva samples will be collected through a passive drool 
method at the beginning and end of Baseline (first week), Mid-Point (week 6), and Post (week 12)-Treatment. 
Saliva will be naturally allowed to accumulate in the oral cavity and the participant will discharge it into the 
specimen tube (2 mL capacity) with lid. 
Immediately after collection the collected saliva samples will be placed on ice and store at -80 degree C until 
analysis. 
Salivary Biomarker Measurement (All major assessments): Owing to their possible involvement in pain and/or 
PTSD (see Background section), the following biomarker panel will be assessed in saliva: cortisol, substance P, 
DHEA, IL-1, and IL-6. 
5.11. Post treatment Key informant interview procedures and Integration of Feedback 
A standardized series of queries will be used to prompt participants to comment on various aspects of the 
intervention integration and how it might be approved. Additional information will be provided in the larger 
proposal derived from this pilot. 

IRB NUMBER: HSC-MS-19-0960 
IRB APPROVAL DATE: 03/26/2020 
 
5.12. Treatment Providers / Interviewers / Consent Procedures: Project therapist will have a master’s degree 
or higher in clinical psychology, counseling, or social work and be certified to deliver PE. All treatment sessions 
will be audio-taped and 15% of these will be randomly selected and rated for adherence. The PI or Research 
Assistant will conduct the consent procedures and initial eligibility (i.e., baseline) diagnostic assessments for the 
study. The Research Assistant will conduct all major assessments. All assessments will be audio-taped and 
study personnel will listen to a randomly selected 20% to ensure reliability of CAPS diagnosis over the course of 
the study. Pilot trials of this assessment battery indicate that major assessments will take between 75 and 90 
minutes. 
5.13.  DATA ANALYSIS PLAN (provide a detailed description of how the data will be analyzed, 
focusing specifically on how the data analytic approach is suited to answer the study aims) 
Analysis Sets & Treatment of Missing Data: Participants who terminate early will be asked to complete follow- 
up interviews and their data will be included in analyses following intent to treat standards. 
Descriptive Analyses Putative prognostic variables that will be investigated through these descriptive analyses 
include: demographic factors, number/type of comorbid diagnoses, participation in non-study treatment for 
comorbid psychopathology, medications (by class), and initial (baseline) intensity/severity levels for the primary 
outcome variables: pain severity, pain interference, and intensity of PTSD (PCL), avoidance behaviors, and 
whether non-study treatments were received for psychopathology symptoms. To investigate potential limits on 
generalizability, we will compare demographic characteristics of those who decline to participate with those who 
participate. 
Primary Feasibility Analyses Feasibility Hypothesis SA1) 75% of Veterans experiencing Pain and PTSD who 
enroll in the Pilot will complete the integrated treatment (at least 8 sessions) and both completers and dropouts 
will offer actionable suggestions in focus groups for improving the delivery of the intervention. We will report the 
% of veterans who complete the integrated tDCS+PE protocol. We will report the rate of treatment completion, 
including a description of number of sessions completed prior to dropping out at the patient level (with 12 
sessions completed being 100% treatment complete/not dropout). In addition to overall measures of treatment 
completion (i.e., session attendance), we will also collect measures of treatment adherence, as measured by 
percent of returned, completed homework record forms for tCBS and exposure practices in terms of actual daily 
assignments completed. All these measures will also be reported in terms of Race and Sex. Feasibility 
Hypothesis SA1) Feasibility metrics will be acceptable for recruitment rate (2 per month), treatment completion 
(75%), assessment completion (90%), and good to excellent satisfaction (95%). A key feature of the proposed 
feasibility study is demonstration that recruitment of eligible participants is possible for a future large scale RCT. 
Thus, we will report all aspects of CONSORT data in addition to the number of referrals obtained each week. 
Finally, we will report the overall % of missing data at the item level, and the rate of assessment completion and 
partial completion at each time point to examine if assessment timing is optimal. SA1 also includes effective 
collection and use of stress biomarker samples. Finally, Descriptive data on rates / scores for satisfaction, 
credibility, and acceptability will be reported. 
 
6. SUMMARY and SPECIFIC AIMS for ENSUING GRANT APPLICATION (Page 6) 
SPECIFIC AIMS 
Overview: Chronic pain is among the most pervasive and expensive health complaints in the United States67,68. 
Veterans, especially those who present with Post-Traumatic Stress Disorder (PTSD), are particularly likely to 
experience chronic pain69,70. Moreover, pain in the form of fibromyalgia diagnosis is actually a component of Gulf 
War Syndrome, and is highly comorbid with other common military service-related health problems such as 
Posttraumatic Stress Disorder (PTSD)6. While effective non-pharmacological treatments for each disorder exist 
independently71,72, there are no integrated treatments for Pain and PTSD; this despite recognition of the primacy 
of pain complaints in combat Veteran populations69. Moreover, evidence-based non-pharmacological treatments 
for pain, per se, are effective in only about 50% of cases, with recent meta-analysis findings indicating no 
significant maintenance of effects at 6 or 12-month followup73. Therefore, we propose to (a) refine & (b) gather 
feasibility data for an integrated mind-body intervention for Pain and PTSD: tCBS+Prolonged Exposure, with 
the prediction that integrating these treatments will enhance overall efficacy. 
Given its frequent co-occurrence with mental health conditions, pain is often conceptualized within a 
biopsychosocial model to explain the multiple dynamic and complex influences that impact its presentation and 
exacerbation73. Extending this model to PTSD supports the conceptualization of a mutual maintenance loop 
between pain and PTSD, and suggests the potential benefit, or perhaps, necessity of an integrated treatment for 

IRB APPROVAL DATE: 03/26/2020 
 
both disorders, as common mechanisms may underlie symptom exacerbations for both Pain and PTSD74. 
Indeed, integrating innovative, non-pharmacological, non-invasive interventions such as tDCS with an evidence- 
based treatment for PTSD may produce short-term and long-term benefits in both PTSD and pain symptoms by 
addressing shared mechanisms. 
 
Thus, the Overall Aim of the present proposal is to integrate, refine and investigate the feasibility (e.g., pilot 
testing, recruitment, randomization, attrition, assessment, etc.) of combining a non-pharmacological, non- 
invasive and short technique for treating pain (tDCS) and a best practices evidence-based treatment for PTSD 
(i.e., Prolonged Exposure: PE) in Veterans. Establishing feasibility will justify future work directed toward 
assessing the ability of the combined treatment to ameliorate the impact of shared hyperarousal and avoidance 
symptoms (e.g., pain mediated avoidance and anxiety/fear mediated avoidance; hyperarousal driven pain 
intensification). Moreover, standard psychological PROMIS measures of pain and PTSD will be complemented 
by stress-related salivary biomarkers before, during, and after treatment to test feasibility and relevance of these 
measures on pain ratings and PTSD symptoms. Whereas PE and the tDCS techniques already exist, the 
integration of these strategies into a treatment of acceptable duration, interaction and character must first be 
achieved and pilot tested as proposed here. 
Toward this end, the Specific Aims of the present proposal are to: 
SA1a: Integrate and Pilot the tDCS+PE treatment. The investigative team is comprised of Pain, PTSD, and 
salivary biomarker experts who will integrate tDCS and PE into a 12 session tDCS+PE treatment which will 
undergo subsequent pilot testing with 15 Veterans with significant ratings of pain and PTSD diagnosis. Post 
treatment key informant interviews will be conducted where suggestions for treatment enhancement and 
satisfaction will be systematically collected and integrated into the intervention. 
SA1b: Test the feasibility of both the intervention and key study design features. The investigators will evaluate 
the feasibility of the integrated tDCS+PE intervention in treating Pain and PTSD measured in terms of recruitment 
metrics, randomization processes, assessment burden, salivary biomarker collection, specification of biomarker 
relationship to hypothesized mechanisms of change, treatment attrition, rates of missing data at each 
measurement time point, participant satisfaction, and ratings of treatment face validity.. 
SA2: Observe a preliminary signal of treatment effects in terms of Pain and PTSD symptoms. We will derive 
preliminary effect size approximations associated with intervention and comparison conditions in terms of 
primary symptom outcome measures. 
Specific hypotheses include: SA1a) 75% of Veterans experiencing pain and PTSD who enroll in the Pilot 
phase will complete the integrated treatment and both completers and dropouts will offer actionable suggestions 
in focus groups for improving the delivery of the intervention. SA1b) Feasibility metrics will be acceptable for 
recruitment rate (4 per month), successful randomization (100%), treatment completion (75%), assessment 
completion (90%), and good to excellent satisfaction (95%). SA2) A preliminary signal based on baseline to post- 
treatment symptom changes for pain and PTSD measures will be acquired. 
 
 
REFERENCES 
 
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10.1016/j.jpain.2010.07.002. 
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Kerns, R.D., Otis, J., Rosenberg, R., & Reid, M.C. (2003). Veterans' reports of pain and associations with ratings 
of health, health-risk behaviors, affective distress, and use of the healthcare system. Journal of Rehabilitation, 
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