Cognitive Rehabilitation for Gulf War Illness
Phase: NA
Conditions: Gulf War Illness
Sponsor: VA Office of Research and Development

 
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Protocol Title:  
Cognitive Rehabilitation for Gulf War Illness (GWI) 
PI: 
Lisa McAndrew, PhD 
NCT02161133 
 
War Related Illness and Injury Study Center 
 
Version 8 –  08/02/2018 
 
Background  
 
Gulf War Illness (GWI) is a complex multi-dimensional illness which causes disability. Previous 
clinical trials (i.e. cognitive behavioral therapy and graded exercise) for GWI have sought to 
improve disability by increasing activity regardless of symptom presentation. These previous 
trials for GWI have shown limited efficacy and poor adherence.  An innovative treatment 
approach is to target a specific component of GWI, namely problem-solving ability, known to be 
associated with disability.  
 
Impairment in problem-solving ability affects Gulf War Veterans (GWV) with GWI and is 
prospectively related to greater risk of disability. This impairment is also related to poorer 
adherence to medical regimes, making it difficult for GWVs to manage other aspects of GWI. 
Problem-solving is considered one of the most complex of cognitive abilities and is related to 
complicated behaviors such as setting goals, sequencing and multi-tasking. Despite published 
reports documenting these deficits, there are no treatments that target the problem-solving 
deficits of GWI in order to reduce disability. 
 
Problem-Solving Therapy  
 
Problem-solving therapy (PST) is a targeted treatment to compensate for the problem-solving 
deficits of GWI and thereby reducing disability. PST, a top down approach, teaches patients 
skills to overcome problems like cognitive dysfunction or physical symptoms that impact 
problem-solving. Compensating for problem-solving deficits would reduce disability and provide 
information on the effect of treating one component of GWI on other symptoms of GWI.  
 
PST is a treatment approach that teaches patients strategies to address real-life problems. It refers 
to the process by which people identify and implement effective means to cope with problems 
encountered in their lives. PST has been developed for individuals with problem-solving deficits. 
Traditionally, PST for cognitive rehabilitation has been 24 weeks long and is provided in group 
settings. PST for cognitive rehabilitation is split into two parts: problem-solving orientation 
phase and problem-solving skill phase and has been delivered over the phone to reduce attrition.  
Aim 1: To determine the impact of telephone delivered Problem-Solving Therapy on disability in 
GWV with GWI. H1: Among Veterans with GWI, telephone delivered Problem-Solving Therapy 
will produce greater improvement in disability as compared to telephone delivered health 
education.  
Aim 2: To determine the effect of Problem-Solving Therapy on problem-solving ability in GWV 
with GWI. H2a & H2b: Among Veterans with GWI, telephone delivered Problem-Solving 
Therapy will produce greater improvement in (H2a) self-reported problem-solving ability 
(measured with the Problem-Solving Inventory) and (H2b) objective problem-solving ability 
(measured with a neuropsychological battery) as compared to telephone delivered health 
education. 

 
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H2c & H2d: Improvement in (H2c) self-report problem-solving ability and (H2d) objective 
problem-solving ability will mediate the effect of telephone delivered Problem Solving Therapy 
on disability. 
Exploratory Aim 3: To determine the effect of Problem-Solving Therapy on other symptoms of 
GWI. Problem-Solving Therapy may help GWV with GWI better compensate for other 
symptoms (e.g. avoid over exertion) which may improve other symptoms of GWI.    
Exploratory H3a – H3b Among Veterans with GWI, telephone delivered Problem-Solving 
Therapy will produce greater improvement in (H3a) self-reported pain and (H3b) fatigue as 
compared to telephone delivered health education. 
Study Population 
 
We will screen up to 2,000 Veterans to obtain a final sample of up to 300 Veterans from the Gulf 
War who screen positive for GWI.  
 
Inclusion: 
(a)  deployed to first Gulf War and meets Kansas definition for GWI (see definition in measures 
section);  
(b) scores at least a half a standard deviation worse than the mean on the World Health 
Organization Disability Schedule (WHO-DAS II).  
 
Exclusion:  
(a) current suicidal/homicide intent or plan assessed by The Columbia Suicide Severity Rating 
Scale, schizophrenia or current psychotic symptoms  
(b) self-reported diagnosis of a degenerative brain disorder or serious psychiatric or medical 
illness which may limit generalizability of the findings, limit safety or account for the 
symptoms of GWI.  
Exclusionary medical illnesses include: Class 3 and 4 heart failure, cancer diagnosed within 
the past year and/or undergoing active treatment (chemotherapy or radiation therapy), 
chronic renal insufficiency, hospitalization due to myocardial infarct, stroke in the past year, 
a neurodegenerative disorder, or another medical or psychiatric disorder that may limit 
generalizability, limit participants safety or account for the symptoms of GWI at the 
discretion of the PI. 
(c) a disability that would preclude telephone use. 
 
Methods 
 
The study is a collaborative randomized controlled trial with two arms: telephone delivered PST 
(treatment group) versus telephone delivered health education (control). Veterans with GWI will 
be recruited from all three sites: East Orange VA in New Jersey, Bedford VA in Massachusetts, 
and Canandaigua VA in New York. The East Orange VA will conduct all the telephone-
delivered sessions. As needed, all sites, including East Orange VA, Bedford VA and 
Canandaigua VA, will assist with all parts of the study, e.g., mail follow-up questionnaires.  
 
 
 
 
 
 

 
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a. Recruitment and Screening 
 
Potential participants (subjects) will be identified primarily via the Managerial Accounting 
Office (MCAO), VINCI, the Defense Manpower Data Center (DMDC) of the Department of 
Defense (DoD), and the VA Office of Public Health Gulf War Registry. We will ask the  VINCI, 
the DoD, and the VA Office of Public Health Gulf War Registry to provide a list of Veterans 
who possibly meet our inclusion and exclusion criteria and also who reside in  Region 1, and as 
needed nationally.  
 
We will also use the following methods to identify and recruit potential participants: Referrals, 
standard mail, telephone, flyers, and advertisements. This includes via 1. planned conferences, 
satellite broadcasts, and other educational workshops for providers or Veterans; 2. VA facilities 
and affiliated ambulatory services including community-based outpatient clinics (CBOCs); 3. 
community locations (e.g., Home Depot); 3. Veteran related events such as job fairs; 4. 
newspapers/newsletters; 5. websites relevant to Gulf War Veterans (e.g., American Legions); 
and 6. VA social media; 7. WRIISC Clinical and Operations Database. We may also work with 
Veteran Service Organizations (VSO) to develop a recruitment plan. Veterans may be recruited 
from anywhere in the Nation.  
 
Once potential participants are identified, introduction letters will be mailed to their addresses. 
Approximately after two weeks of mailing the introduction letter to Veterans, research staff will 
contact potential participants to inform them about the study, obtain verbal consent for and 
conduct initial screenings over the phone. For Veterans who contact us over the phone or in-
person, (e.g., after reading a posted flyer), we will obtain verbal consent for and conduct intial 
screenings in person or over the phone.  
 
If a Veteran is screened as eligible to participate in the study, a date and time will be scheduled 
for the Veteran to come into one of the three study sites (East Orange VA, Canandaigua VA or 
Bedford VA) to be consented into the study and complete the baseline questionnaires and 
neuropsychological assessments.  
 
b. Sessions 
 
Once consented and baseline assessments (described below) are completed, therapy sessions will 
be scheduled with a Study Provider from the East Orange VA.  Study providers will be a 
licensed provider, e.g., psychologist, nurse, social worker, or a trainee e.g., working under a 
licensed provider, at the East Orange VA. A Study Provider from the East Orange VA will 
provide the sessions via phone with all participants from all VA sites (East Orange VA, 
Canandaigua VA, and Bedford VA). We will have a standardized assessment regimen that all 
Study Providers will adhere to. Therapy sessions will be scheduled weekly, and may be adjusted 
to accommodate the Veteran’s schedule and/or needs. 
 
The telephone sessions with the Study Provider will generally be 1 hour. Most telephone 
sessions will be voice recorded and transcribed for quality assurance, i.e., fidelity to study 
protocols, length of sessions, engagement of participants. Coding of telephone sessions will 
occur by our off site collaborators once proper approvals are in place (i.e., DUA). 
 
Study Arms 

 
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Veterans will be randomized either to the PST (treatment) or Health Education group (control).  
 
If randomized to the PST (treatment):  
A state of the art evidence-based 12 session PST intervention with a structured five step 
sequential approach to teaching problem-solving will be used. Our goal is to reduce disability 
(i.e., limitations in daily activities and participation). Study Providers will first work with 
participants to increase participation in the activities of their choosing. This could include 
increasing social activities, hobbies, physical activities, etc. Participants are then taught problem-
solving skills and encouraged to problem-solve to overcome the barriers with increasing activity.  
A 5-step problem-solving approach is employed whereby, 1) the problem is defined and goals 
are created, 2) possible solutions are generated, 3) these possible solutions are evaluated and one 
is selected, 4) the chosen solution is implemented in a step-by-step approach, and finally, 5) the 
outcome of the implemented solution is measured for success. Participants are introduced to the 
steps incrementally and each is reinforced by working with the Study Provider.  
Participants will be given or mailed a PST workbook after the baseline assessment. For 
participants enrolled at the Bedford VA and Canandaigua VA, the Study Coordinator from the 
East Orange VA may mail the PST workbook. The content in the PST workbook will help guide 
participants through each session. The workbook also includes worksheets that are completed 
during each session and during the participant’s own time. The workbooks will then be reviewed 
with the Study Provider during each session. At the Study Provider’s or PI’s discretion, the 
treatment or protocol may vary in order to meet a Veteran’s needs (e.g., changing the order of the 
information given, having an additional session if feasible).  During the sessions, participants 
will regularly be asked questions about their perception of the sessions, treatment, and if they 
have any new health concerns. 
 
If randomized to the Health Education group (control):  
 
Every week participants will receive up to an hour of didactic information and discussion about a 
variety of health concerns. Sessions will be highly structured and will emphasize the learning 
and analysis of key concepts in the presentations. This intervention will also be delivered over 
the telephone. 
 
Participants will be given or mailed a Health Education workbook after the baseline assessment. 
For participants enrolled at the Bedford VA and Canandaigua VA, the Study Coordinator from 
the East Orange VA may mail the Health Education workbook. The Health Education workbook 
will be used in conjunction with the sessions. The content in the Health Education workbook 
includes didactic information on a variety of health topics pertinent to GWVs, i.e., pain, 
improving cognition, sleep, diet and physical activity. This information will also be reviewed 
with the Study Provider during each session. Similar to those randomized to the PST group, at 
the Study Provider’s or PI’s discretion, the Health Education protocol may vary in order to meet 
a Veteran’s needs (e.g., changing the order of the information given, having an additional session 
if feasible).  
 
Participants who are assigned to the health education control condition may be offered the 12-
session PST program at the end of the study. 

 
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During the sessions, participants will regularly be asked questions on their perception of the 
sessions, treatment and if they have any new health concerns. 
 
Reducing Attrition 
 
To reduce attrition and the burden on the Veteran, all therapy sessions are done over the phone or 
video to phone if available. In addition, we plan to make phone calls to remind participants about 
their scheduled appointments (similar to the VA’s automated appointment reminder system). 
PST has been successfully implemented over the telephone. Prior to starting the treatment, the 
participant and Study Provider may determine the time that is best for the Veteran (including 
nights and weekends) and may determine ground rules (for example, not having anyone else in 
the room, shutting off other telephones to remove distractions). The Study Provider and Veteran 
may also establish verbal signals to substitute for non-verbal cues, for example, “that’s great” or 
“can I interrupt.”   
 
Participants will be allowed to begin or continue with their existing medical regimen throughout 
the course of the trial and make changes to their existing treatments. Adherence to medical 
protocols and participation in alternate treatments will be evaluated by a questionnaire at the 
assessments and this will be controlled for in analyses. The Study Provider may make additional 
recommendations for additional health care if needed or as appropriate. 
 
We will make a concerted effort to contact participants for their appointments and assessments 
through phone calls and letters. We will not reach out to Veterans who do not wish to continue in 
the study.  
 
Consent Procedures 
 
Informed consent is an ongoing process.  At the phone screening, Veterans will provide a verbal 
consent. At the baseline assessment, when the Veteran is considering enrolling in the study, 
information will be presented in-person to enable the Veteran to voluntarily decide whether or 
not to participate as a research participant. The Investigator, study coordinator or research 
assistant will review and explain the study’s purpose, experimental procedures, alternatives, 
risks, benefits and duration of the study in terms that the potential participant can understand. 
The Investigator or study team member will be available to address any concerns and answer any 
questions the Veteran might have regarding the study and the informed consent. After all 
questions have been answered and concerns addressed, the Veteran may sign the Consent Form. 
A signed copy will be provided to the Veteran and the original copy will be placed in the 
Veteran’s study folder and scanned into his/her CPRS record. 
 
Participant Compensation 
 
Participants may receive a total of $200 for their participation in the study as follows: $30 for 
completion of the baseline assessments; $70 for completion of the 12th session questionnaires 
and neuropsychological assessments. We will contact participants after the 4th session and also at 
6 months post-treatment to complete written questionnaires – participants will receive $50 for 
completing each of these questionnaires. For compensation, participants will complete and sign a 
voucher, and a check will be mailed within 6-8 weeks.  If the subject does not want to continue 

 
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in the study, s/he may come to an assessment site and complete a study exit visit and assessment; 
they will still receive $70.  
 
Our budget includes funds to pay for participant travel  as needed.  
 
c. Assessment Methods 
 
In this section we summarize all of the assessment instruments/procedures used to determine 
eligibility, assess neuropsychological functioning, and disability.  
 
Table 2 outlines the study procedures that are described below: assessments, mailed 
questionnaires, qualitative interviews, and therapy sessions with the study provider.  
 
 
 
Weeks 
Months  
 
Baseline 1 2 3 4 
5 6 7 8 9 10 11 12 6 
Questionnaires 
X  
 
 
 
X   
 
 
 
 
 
 
X  
X 
Neuropsychological 
Assessments  
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Qualitative Phone 
Interview  
X 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
Baseline and 12th Week Assessments 
 
Baseline and 12th week assessments will be conducted in-person at any one of the study sites: 
East Orange VA, Canandaigua VA or Bedford VA. The baseline and 12th session assessments 
include completing written questionnaires and participating in neuropsychological assessments.   
 
If the need arises (e.g., from fatigue) during the baseline or after the 12th session assessment, 
participants may have the option to complete the questionnaires at home and return them via 
mail in a prepaid envelope or complete the questionnaires via phone at a time and date that is 
convenient for him/her.   
 
Participants  may be provided the option of completing the written questionnaires and qualitative 
assessments only – and not completing the neuropsychological assessments. Questionnaire 
packets will still be mailed to them to complete and return to us in prepaid envelopes. 
Questionnaires may also be completed via phone with a study staff member at a time and date 
that is convenient for the participant. In addition, participants may be offered the opportunity to 
travel into one of the three study sites to complete the in-person baseline and 12th week 
assessments. We have budgeted this cost into the grant proposal. 
 
Special considerations for the Baseline Assessment only 
The baseline only will include full consenting into the study. Participants will also be asked to 
complete a mental health provider form as part of their baseline assessment. They will be 
encouraged to talk to their mental health provider and this provider form will be used to 
document it.  
 
We will obtain the names of participants’ primary care providers (PCP) from their medical 
records or form they will complete. We are asking for this information so we may inform PCPs  

 
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of their patients’ participation in the study. This will enable a PCP to notify us of any health 
concerns s/he may have about his/her patient’s participation in the study. At the PI’s and/or 
Study Provider’s discretion, we may also contact participants’ health care providers at any time 
during the study if we have a concern about the Veteran’s health and/or safety. 
 
4th week and 6th month Assessment 
 
We will mail or provide written questionnaires to all participants before or after the 4th session 
and also before or after 6 months post-treatment (see Table 1). All questionnaires will also be 
returned to the East Orange VA.  Participants who wish, may also complete the questionnaires 
over the phone with a study staff member at a date/time that is convenient for the participant. 
 
Qualitative Interviews 
 
Participants may be asked to participate in 2 qualitative interviews. The qualitative interview will 
be conducted via phone by a study staff member from one of the sites at a date/time convenient 
for the participant after the baseline assessment and after the 12th session assessment. 
Participants will be asked about their perceptions of GWI and intervention methods. The 
qualitative interviews will be recorded using either a digital recording device or recorded directly 
onto a VA computer. Upon completion of all interviews, the recordings will be transferred to the 
secure shared network folder. The qualitative interviews will also allow us to modify the 
treatment in the future. 
 
Assessment Instruments 
 
a. Screening 
 
The screening questionnaires will be used to determine inclusion and exclusion criteria. These 
questionnaires will be administered over the phone to determine a potential participant’s 
eligibility, given exclusion and inclusion criteria, to enroll into the study. In addition to the listed 
questions we will ask potential participants about exclusionary medical and psychiatric 
conditions. 
 
1. Case Definition of GWV’ Illness (GWI) – Kansas Case Definition. The Institute of Medicine 
has recommended the use of the Kansas definition of Gulf War Illness(Steele, 2000). This 
definition was derived from a population-based survey of over 2,000 Veterans who served 
during the 1900-1991 Gulf War and whose symptoms began during or following 
deployment. The Kansas Case Definition identifies 6 symptom domains and inclusion 
requires that Veterans endorse moderately severe and/or multiple symptoms in at least 3 of 
those domains. The 6 symptom domains are: fatigue, pain, neurological/cognitive/mood, 
skin, gastrointestinal, and respiratory. To meet the case definition, Veterans must also 
indicate that each of those symptoms first became a problem during or after the Gulf War. 
Self-report of physician diagnosis of chronic conditions (e.g., cancer) that are not associated 
with Gulf War service, but that can produce diverse symptoms similar to those affecting 
GWVs (e.g., pain) are excluded under the Kansas Case Definition. This definition also 
excludes individuals with conditions that might interfere with respondents’ ability to 
accurately report their symptoms (e.g., drug use). To develop the Kansas Case definition a 
narrow definition of conditions that might produce diverse symptoms was used. To improve 

 
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generalizability, we will only exclude participants with a clear disorder that could account for 
the GWI (e.g., multiple sclerosis).  
 
2. World Health Organization Disability Assessment Schedule (WHO-DAS 2.0): The WHO-
DAS 2.0 measures disability due to physical and mental health conditions (Ustun et al., 
2010). The WHO-DAS 2.0 is a 36 item measure that focuses upon six life tasks: 
a. Understanding and communicating,  
b. Self-care 
c. Mobility (getting around)  
d. Interpersonal relationships (getting along with others)  
e. Work and household roles (life activities)  
f. Community and civic roles (participation) 
These six life tasks reflect two underlying constructs: Activity limitations and Participation 
deficits.  The WHO-DAS 2.0 is based off of the International Classification of Functioning, 
Disability and Health (ICIDH-2), which categorizes disability into three categories: 
physiological, activities and participation. The WHO-DAS 2.0 has been translated into 15 
languages and tested in 13 countries. The six domains have a factor loading of 0.82 to 0.98 
and all load onto the general disability factor. Participants will be asked to complete this at 
all time points. We will use the WHO-DAS 2.0 screener which is a 12 item measure at 
screening. The WHO-DAS 2.0 screener explains 86% of the variance in the full measure and 
will reduce burden at screening. As the WHO-DAS is the primary outcome measure, we will 
use the full, and more valid, 36 item measure during the study. 
 
3. Columbia-Suicide Severity Rating Scale (C-SSRS): The C-SSRS is the gold standard for 
suicide assessment. It is used by the VAs Center of Excellence for Suicide Prevention. The 
C-SSRS was developed by Columbia University and is used extensively across primary care, 
clinical practice, surveillance, research, and institutional settings. The C-SSRS in one study 
showed 100% sensitivity and specificity in identifying individuals who attempted suicide. 
Across three major randomized controlled trials, the C-SSRS demonstrated convergent, 
divergent, and predictive validity; sensitivity to change; sensitivity and specificity of the 
instrument; and internal consistency of the intensity subscale.(Posner et al., 2011) is part of a 
national and international public health initiative involving the assessment of suicidality, 
including general medical and psychiatric emergency departments, behavioral health 
organizations, medical homes, community mental health agencies, primary care, clergy, 
hospices, schools, college campuses, US Army, National Guard, VAs, Navy and Air Force 
settings, frontline responders, substance abuse treatment centers, prisons, juvenile justice 
systems, and judges to reduce unnecessary hospitalizations. At the screening and 12th session 
visit, this questionnaire will be administered by a member of the research staff.  
 
 
b. Questionnaires 
 
The questionnaires described by construct below will be administered at certain time points. 
Questionnaires may be administered in person at baseline and after the 12th session.  
 
Questionnaires will be mailed or administered via phone after the 4thsessions, as well as 6 
months post-treatment.  
 

 
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1. Case Definition of GWV Illness (GWI) – Kansas Case Definition (described above). 
 
2. The Fatigue Severity Scale (FSS): The FSS is designed to differentiate fatigue from clinical 
depression, since both share some of the same symptoms (Takasaki & Treleaven, 2013). The 
FSS consists of a short questionnaire that requires the participant to rate his or her own level 
of fatigue. This measure has demonstrated good reliability, with a higher Cronbach’s alpha 
indicated for the newer severity scale, as well as a correlation of 0.976 between the initial and 
current Fatigue Severity scales for a sample of 235 participants in seven groups. The FSS 
will be used to capture fatigue as a secondary outcome.  
 
3. Pain Disability Index  (PDI) & Pain Inventory (MPI): We will assess pain with 10 questions 
from two measures. We will first include the 7 item Pain Disability Index that assesses 
disability from pain. This measure has been found to be valid, have adequate test-retest 
reliability and be responsive to change in clinical trials (Soer et al., 2012; Tait et al., 1990). 
We will also use the 3 item West Haven Yale Pain Inventory that measures pain severity 
which has excellent test-retest reliability (0.74), internal consistency (.80), criterion validity, 
construct validity (Kerns et al., 1985). Both of these are commonly used together to 
characterize the suffering associated with pain.  
 
4. Patient Health Questionnaire (PHQ-15): The PHQ is a self-administered questionnaire 
yielding algorithmic diagnoses of psychiatric illness. We will give the somatic symptoms (15 
items) module. Patients are instructed to code each symptom based on whether it bothered 
them over the preceding 2 weeks: “not at all”, “several days”, “more than half the days”; or 
“nearly every day”.  The PHQ-15 was validated on a sample of 6,000 and found to be 
reliable, valid and responsive to change (Kroenke et al., 2002). 
 
5. MOS Sleep Scale and Insomnia Severity Index (ISI):  Medical Outcomes Study measure of 
sleep. This short version of the sleep scale is used to screen for sleep difficulties and social 
support. The internal reliability is .86 and there is adequate convergent and divergent validity 
(Hays et al., 1995). The ISI measures insomnia it has been shown to be reliable and valid 
(Gagnon et al., 2013). Together with the MOS Sleep Scale it provides an adequate measure 
of sleep disturbance in participants.  
 
6. World Health Organization Disability Assessment Schedule (WHO-DAS 2.0): (described 
above) 
 
7. Veterans Rand 12 item Health Survey (VR-12): The VF-12 is a multidimensional measure of 
disability that is commonly used among Veterans to understand impairment in activities. The 
VR-12 explains over 90% of the variance in the SF-36, a gold standard measure of disability. 
Test-retest correlations were excellent (.089 and .76) validity estimates were also excellent 
(Ware, Jr. et al., 1996).  
 
8. USER-P (activity frequency and satisfaction): The USER-P captures satisfaction with 
activities and frequency of engaging activities, critical components of disability. The USER-
P has been found to have adequate test-retest reliability. Further, in a comparison of three 
rehabilitation measures of disability, the USER-P was the measure most liked by participants 
(van der Zee et al., 2010) 
 

 
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9. MOS Social Support: The MOS Social Support measure captures if participants feel that they 
have access to available support to deal with and address problems in their life. This is 
another method to assess satisfaction with participation. The MOS Social Support is the best 
used measure of social support (2,500 citations to date) and has high convergent and 
divergent validity in addition to excellent reliability (Sherbourne & Stewart, 1991) 
 
10. Problem Solving Inventory (PSI): The PSI is a commonly used self-report measure of 
problem-solving. It is the measure that has been most used to assess changes in problem-
solving during and after Problem-solving Treatment. The PSI measures self-assessed ability 
to deal with problems. The PSI has good internal consistency (alpha=.88) and excellent 
convergent and divergent validity (Sahin N et al., 1993). 
 
11. Behavioral Responses to Illness Questionnaire (BRIQ): The BRIQ was developed to assess 
how individuals problem-solve medically unexplained symptoms. Internal reliability is above 
.80, test-re-test reliability is acceptable (.60-.87) and it is able to predict the onset of 
medically unexplained symptoms (Spence et al., 2005). 
 
12. Demographic Survey & Healthcare Access: This is a brief questionnaire designed to elicit 
basic demographic information including: sex, age, marital status, self-identified racial and 
ethnicity group, educational level, income level, sources of current income, and current 
employment status, health insurance and health care utilization. The information obtained 
through this survey will be used to assess demographic differences between groups and 
identify potential control variables. We will also ask for self-report of medical conditions and 
medication.  
 
13. The Brief Traumatic Brain Injury Screen (BTBIS): The VA/DOD BTBIS assesses TBI by 
asking if the participant has had an injury and if the injury resulted in a symptom. It will be 
used as a control variable in analyses. 
 
14. Patient Health Questionnaire  (PHQ-8): The PHQ is a self-administered questionnaire 
yielding algorithmic diagnoses of psychiatric illness. It was specifically developed and 
validated for use in primary care settings. We will administer the 8 item depression 
questionnaire. Patients are instructed to code each symptom based on whether it bothered 
them over the preceding 2 weeks: “not at all”, “several days”, “more than half the days”; or 
“nearly every day”. Depression is a common comorbid condition among Gulf War Veterans 
with Gulf War Illness.  
 
15. Post Traumatic Stress Disorder Checklist (PCL): The 21 item National Center for PTSD 
Checklist of the VA will be used to assess PTSD.  When compared to the gold standard for 
assessing PTSD, the Clinician Administered PTSD scale (CAPS), the PCL has been shown 
to be a valid and reliable measure of PTSD symptoms. PTSD is a common comorbid 
condition among Gulf War Veterans with Gulf War Illness.  
 
16. Alcohol Use Disorders Identification Test (AUDIT-C): a 4-item alcohol screen used to 
identify patients with hazardous drinkers or have alcohol use disorders. The AUDIT is used 
in the VA to screen patients with alcohol use disorders.  
 
 

 
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17. Illness Perception Questionnaire: The illness perception questionnaire is a well validated and 
reliable measure of patient’s illness cognitions. We have previously used this measure among 
Gulf War Veterans and found that it predicts adherence and satisfaction with medical care. 
We will use it to determine if the intervention changes cognitions. The illness perception 
questionnaire was developed to be modified for different populations and we have modified 
the questionnaire for use with this population. The Illness Perception Questionnaire has good 
internal reliability and long term test retest reliability. The IPQ also has good discriminant 
and predictive validity (Moss-Morris et al., 2002). 
 
18. Patient Global Impression of Change (PGIC): This 2 item scale is widely used in clinical 
trials to gauge patient satisfaction. The scale asks the patient to rate status change since the 
beginning of treatment. It has been recommended as a core outcome among patients with 
medically unexplained symtpoms. This will be asked at the follow up time points only 
(Geisser et al., 2010).   
 
19. Working Alliance Inventory (WAI) – Self: The working alliance is one of the most powerful 
predictors of change in therapy. It assess the participants perception of their relationship with 
their study provider.  The working alliance has excellent reliability (.80) and convergent 
validity (Munder et al., 2010).  
 
20. Target Complaints Questionnaire (GOALS): The measures ask participants what their current 
goals for treatment are and then if they meet them. This will enable us to understand the 
changes and if the treatment worked.  
 
21. Clients Satisfaction with Treatment: This short validated measure (8 items) asks about 
clients’ satisfaction with treatment. It is regularly used to assess satisfaction in clinical trials.  
 
22. MOS – Adherence Scale: Assesses participants’ perceptions of adherence to 
recommendations. This will assess if participants are following the treatment. The MOS 
Adherence Scale had adequate reliability and validity (Hays et al., 1995).  
 
 
After the baseline visit and after the 12th session, participants may be asked about their 
perceptions of GWI and intervention methods. The qualitative interviews will be up to 45 
minutes. This qualitative interview will also allow us to modify the treatment in the 
future.Qualitative interviews may be conducted on a subset of subjects enrolled over the duration 
of the project to achieve thematic saturation.  
  
Qualitative assessments and interviews may be recorded, transcribed, and coded for further data 
analyses. Personal identifiers will not generally be transcribed from the voice recordings.  
 
Additionally, we will review participants’ medical records and collect information on previous 
and future medical treatment including physical and mental health treatment, diagnoses and 
medication. 
 
c. Neuropsychological Measures   
 

 
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These measures capture Problem-solving Ability or Executive Function. These measures will be 
administered in-person at the baseline assessment visit and after the 12th session assessment visit. 
Problem-solving, an executive function refers to the ability of an individual experiencing an 
undesirable situation to move to a more desirable one when no response is immediately apparent 
or available.  Problem-solving is considered the most complex of all cognitive functions as it 
requires the use and integration of other cognitive functions like attention, processing speed, 
effort, and impulse control as well as other executive functioning skills like mental flexibility 
and abstract thinking. Neuropsychological testing can be used to measure participants' 
functioning in the entire range of cognitive skills that problem-solving demands. We propose to 
use 5 neuropsychological instruments to measure functioning in the following cognitive areas: 
Attention, processing speed, impulse control, effort, mental flexibility and abstract thinking.  
 
1. Halstead Category Test, Russell Revised Version: The Category Test is an objective test of 
problem-solving ability, specifically abstract thinking and mental flexibility. The test takes 
30-40 minutes to administer. Our previous work has shown that the Category Test is able to 
differentiate Veterans with GWI from Gulf War Veterans without GWI. The Category Test 
has acceptable test-retest reliability and has been used as an outcome in cognitive 
rehabilitation treatments. 
 
2. The Conner’s Continuous Performance Test-3 (CPT-3): The CPT-3 is a measure of ability to 
alternate attention,inhibit impulses and mental flexibility. The CPT-3 is a valid and reliable 
measure that and this version includes norms for adults with brain disorders as well as 
attentional disorders. It can and has been used in treatment efficacy trials.  
 
3. Stroop Color and Word Test: The Stroop Test is a well-used measure of executive 
functioning and asks participants to read the color word (e.g., green) that is printed in black 
ink. Next, participants are asked to identify the color ink that “XXXX” is printed in (e.g., 
red). Finally, participants are asked to identify the color of the ink in which a word is printed 
(e.g., green) regardless of the color term being represented (e.g., blue). It is a measure of 
impulse control. 
 
4. Trails Making Test A and B (TMT): Trails A and B asks participants to connect sequentially 
circles with different numbers and letters within them. It assesses processing speed a key 
component of problem-solving. . 
 
5. Rey-15, Memorization of 15-Items: The Rey-15 is a short test of effort that instructs 
participants to look at and then remember 15 pieces of information. It is used as a control to 
ensure that participants are fully participating.  
 
d. Study Provider Measures 
 
At each assessment point, we will ask Study Providers to answer questionnaires about their  
views about the treatment for each Veteran they are providing treatment.  
 
1. Working Alliance Inventory (WAI) – Therapist: The working alliance is one of the most 
powerful predictors of change in therapy. It has never been assessed among Gulf War 
Veterans and rarely in remote therapy. It assesses the relationship between the Study 

 
Page 13 
 
Provider and participant. It is best assessed by asking both the provider and participant 
(Munder et al., 2010).  
 
2. SOFTA Questions: The SOFTA asks Study Providers to answer questions about the 
behavioral indicators of the relationship between the Study Provider and participant. 
 
3. Target Complaints Questionnaire (GOALS): The measures ask participants what their current 
goals for treatment are and then if they meet them. We have to capture what Veterans want to 
see changes in to understand if the treatment worked.  
 
4. Patient (Therapist) Global Impression of Change (PGIC): We will adapt this measure for 
providers to measure their participant’s impression of change to assess whether there is 
concordance between the provider’s and participant’s impressions. 
  
5. Concordance: These measures assess whether a Study Provider’s views of GWI are the same 
as the participant’s views.  
 
Subject Confidentiality/Data Safety and Monitoring 
 
This is a collaborative clinical study that involves various components being administered from 
one of 3 sites: East Orange VA, Bedford VA, and Canandaigua VA. Recruitment will occur from 
all three sites. In addition, Veterans will consent and complete the baseline assessment and 12th 
session assessment in-person at one of the three sites. East Orange VA will provide the PST or 
health education via phone to all participants in the study.  As needed, all sites, including East 
Orange VA, Bedford VA and Canandaigua VA, will assist with all parts of the study.  
 
Data from all sites (East Orange VA, Canandaigua VA, and Bedford VA) will be kept on a 
VANJHCS server in a shared network folder created by IRM in East Orange, NJ. All data and 
study materials, including PHI from screening and recruitment, questionnaire data, 
neuropsychological data, and qualitative recordings and transcriptions will be stored and shared 
by all three sites via the shared network folder. This folder will have restricted access to study 
personnel approved on the protocol. Data will be collected in accordance with the protocol and 
under supervision of qualified personnel. Data may also be placed on the VA VINCI platform for 
data analysis.   
 
There exists the possible risk of loss of confidentiality. We minimize these risks by assigning 
participants a unique study ID that is coded and which we will use on all electronic files resulting 
from their participation. The “link” or key that matches the ID code with participants’ personal 
information will be kept in an electronic study folder on the server administered by IRM in East 
Orange in the IRM server room with access granted only to the PI and study staff across study 
sites.  
 
In addition, all other paper documents, including signed consent forms, forms that ask for contact 
information, hard copies of data, and completed questionnaires, will be kept in a locked cabinet 
in room 11-198. 
 
All recorded data from the therapy sessions and qualitative interviews will be stored on the  
network shared folder on the secure VA server with access limited to the research team. Before 

 
Page 14 
 
being uploaded to the server, audio recorders will be stored in a locked cabinet with access to 
only study team members. The recordings may then be transcribed, with transcriptions stored on 
the same limited-access server. Transcriptions will generally contain no identifying information; 
basic information on gender and age range will be attached to each subject in the transcript, who 
will be identified with the assigned unique ID number (e.g., 10012). 
 
The PI and study team members only will have access to the data and no confidential data will be 
shared with individuals outside of this team. Once a member of the study team leaves the study, 
s/he wil no longer have access to any of the data or study folders. 
 
Data use agreements and proper approvals will be put into place with collaborators from outside 
institutions for data analyses. 
 
Incident Reporting: 
In the case that any digital recorders, electronic data, or hard copies of any research files and 
study data are compromised (e.g., lost, theft, unauthorized access, non-compliance with security 
controls), the PI will report the incident to the appropriate authorities/committees, including the 
VA NJHCS Information Security Officer and Privacy Officer within 1 hour of discovery, and 
will assist in the investigation and/or remediation of the incident. 
 
Plan for destruction/return of data: 
Study records will be destroyed in accordance with VHA RCS 10-1, and no less than 6 years past 
the date of study closure.  All study records that are kept at the VA, including the links, will be 
destroyed in accordance with VHA RCS 10-1 and no less than 6 years past the date of study 
closure. 
Data Analysis 
 
a. Data  
 
Data analyses will be conducted both on-site by study investigators and with proper approvals, 
including DUAs, at our affiliate institutes by current and future study investigators. All analyses 
will be primarily performed on an intention-to-treat basis. The statistical significance will be 
defined by a p value < 0.05, unless specified otherwise. Calculations of the means, standard 
deviations, proportions, histograms, etc., will be conducted to explore the distributions of the 
data, identify outliers, and calculate correlations between variables. We will also determine 
confounders that need to be controlled for in our analyses. We will particularly examine if we 
need to control for depression measured with the PHQ-8 or PTSD symptoms measured with the 
PCL based characteristics that exhibit differences at the baseline (pre-intervention).  
 
Due to repeated measures, we will analyze the data using mixed model analysis, with 
participants nested within therapists modeled by random effects. To address H1, disability 
(WHODAS II scores) will be treated as the dependent variable, and treatment assignment [PST 
vs. Health education], time [pre- vs. post-intervention] and their interaction will be modeled as 
fixed effects. Differences in the improvement of disability between Problem-solving therapy and 
Health education will be evaluated by the treatment by time interaction. Linear contrasts will be 
constructed to evaluate the improvement in disability for each treatment separately. Variables 
such as age, gender, education and the confounders identified in the preliminary analysis will be 
controlled as covariates in the statistical analyses. Data transformations (e.g., square root, log, 

 
Page 15 
 
etc.) will be used to normalize data where necessary. The same mixed model analysis strategy 
will be applied to address H2a, H2b, H3a and H3b. We will also explore, using this same mixed 
model strategy, the impact of PST therapy on each of the four individual neuropsychological 
tests scored as a composite and scored individually (Category Test, CPT 3, Stroop Test, and 
TMT). We will use the same data analysis strategy to examine all secondary outcomes. These 
will be reported as secondary outcomes and will primarily be used to generate hypotheses.  
 
To address the H2c and H2d, we will establish a mediational model to explore whether the PST 
produces greater improvement in disability through its effects on problem-solving ability 
(measured by either the self-report (H2c) or the objective measurements (H2d)), following the 
recommendations of Baron and Kenny. The same mediational model will be used to explore 
whether participants views of treatment (e.g., relationship with therapist) also mediates the 
relationship between PST and disability. The statistical analysis will be performed using the 
mixed model analysis. Using these general methods we will also examine the impact of the 
treatment on other outcomes of interest, the relationship between variables and other potential 
moderators and mediators; we will also explore the relationship between variables of interest 
assessed concurrently.  
 
b. Qualitative Data 
 
Qualitative interviews will be transcribed and analyzed using standard qualitative research 
methods.  The data to be analyzed are the participants’ own words and narratives.  Several 
members of the study team will perform an initial independent read through of interview notes 
and transcripts and generate a list of domains to create the initial coding scheme. Initial domains 
are expected to parallel the major themes or questions in the discussion and interview guides. 
Initial codes will be used to inform ongoing interviews and coding schemes.  Once codes have 
been finalized, the coding scheme, interview notes and transcripts for interviews will be entered 
into an Excel or a qualitative software package. Study team members will apply the codes and 
labels to text.  
 
Risks and Benefits 
 
Risks 
 
The risks of this study include: 
1. Loss of confidentiality 
2. Emotional distress. Some Veterans could find some of the questionnaires and the phone 
sessions  upsetting.  
3. As part of the study, Veterans will be encouraged to increase activities of their choosing. 
Examples of activities may include hobbies, household chores, social activities, or physical 
activity. Since the activities are personalized, the exact risks are not known. Participants are 
encouraged to talk with their primary care providers before engaging in activities. Study 
Providers will use clinical judgment to reduce risks as appropriate. Increasing activity 
(behavioral activation) is a standard component of cognitive and behavioral treatments. 
 
Veterans in the Health education component will be provided with didactic health 
information. All Veterans will be encouraged to talk with their PCPs prior to implementing 
any changes.  
 

 
Page 16 
 
Benefits 
 
This study will enable us to learn more about treatments that may help individuals with GWI. 
Some participants may experience improvement in the disability associated with GWI.  
 
 

 
Page 17 
 
Reference List 
 
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Geisser, M. E., Clauw, D. J., Strand, V., Gendreau, R. M., Palmer, R., & Williams, D. A. (2010). 
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Hays, R. D., Sherbourne, C. D., & Mazel, R. (1995). User's Manual for the Medical Outcomes 
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Kerns, R. D., Turk, D. C., & Rudy, T. E. (1985). The West Haven-Yale Multidimensional Pain 
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Page 19 
 
 
Summary List of Measures and Timeline 
 
 
Domain
Study Instruments
# of Items
Screening 
Baseline
4 week
12 week
24 week    
(6 month)
General Screening Questionnaire
27
X
Columbia Suicide Severity Rating Scale [C-SSRS]
26
X
X
Mini International Neuropsychiatric Interview [MINI]
23
X
World Health Organization Disability Assessment Schedule- 12 items [WHO-DAS]
12
X
Estimated Completion Time for Screening Domain: 35-45 minutes
Problem Solving Inventory [PSI]
32
X
X
X
X
Behavioral Responses to Illness Questionnaire [BRIQ]
19
X
X
X
X
Estimated Completion Time for Problem-Solving Domain: 9 minutes
Fatigue Severity Scale [FSS]
9
X
X
X
KANSAS Questionnaire [KANSAS]
29
X
X
Patient Health Questionnaire 15-items [PHQ-15]
15
X
X
X
X
Pain Disability Inventory [PDI] & Pain Inventory [MPI]
10
X
X
X
MOS Sleep Scale [MOS-Sleep] & Insomnia Severity Index [ISI]
19
X
X
Estimated Completion Time for Gulf War Illness Domain: 16 minutes
World Health Organization Disability Assessment Schedule- 36 items [WHO-DAS]
36
X
X
X
X
Veterans RAND 12 Item Health Survey [VR-12]
12
X
X
USER-P (activity satisfaction and frequency) [USER-P]
21
X
X
X
MOS Social Support [MOS-SS]
8
X
X
X
Estimated Completion Time for Disability Domain: 14 minutes
Alcohol Use Disorders Identification Test Alcohol Consumption Questions [AUDIT-C]
4
X
X
Post Traumatic Stress Disorder Checklist [PCL-5]
20
X
X
X
Patient Health Questionnaire 8 items [PHQ-8]
9
X
X
X
Brief Traumatic Brain Injury [BTBIS]
4
X
Demographics [Demo]
30
X
X
X
Healthcare Access [HCA]
17
X
X
X
Estimated Completion Time for Characterization Domain: 12 minutes
Working Alliance Inventory (Self) [WAI]
12
X
X
Target Complaints Questionnaire [GOALS]
6
X
X
MOS Adherence Scale [MOS-Adhere]
5
X
X
Patient Global Impression of Change [PGIC]
2
X
X
Client Statisfaction Scale [Client Sat]
8
X
Veterans Perceptions of Gulf Illness Perceptions Questionnaire [IPQ]
60
X
X
Estimated Completion Time for Perceptions Domain: 10 minutes
Total Estimated Completion  for Questionnaires
35-45 mintue 70 minutes
20 mintues
70 minutes
35 minutes
Halstead Category Test Short Form: Russell Revised Short Version [RCat]
X
X
Stroop Test
X
X
Trail Making Test Part A & B [TMT]
X
X
Continuous Performance Task [CPT-III]
X
X
Rey-15
X
X
Estimated Completion Time for Neuropsychological Assessments: 50 minutes
Qualitative Interviews
X              
(After 
Baseline is 
completed)
X              
(After Follow 
up is 
completed)
Estimated Completion Time for a Qualitative Interview: 45 minutes
Screening
Problem-Solving 
Neuropsychological 
Assessments
Participant Characterization
Disability
Gulf War Illness
Problem-Solving
Veterans Perceptions of 
Problem-Solving and Health 
Education
Estimated Completion Time for Treatment Perceptions Domain: 8 minutes