Using fMRI to Understand Response to an Integrative Treatment for Pain and Anxiety in Pediatric Functional Abdominal Pain Disorders (FAPD)
Phase: NA
Conditions: Functional Abdominal Pain Syndrome, Anxiety
Sponsor: Michigan State University

 
Neural Mechanisms of Treatment Response Protocol 1 of 45 
Version 6.0 
 
 
04 August 2020 
USING FMRI TO UNDERSTAND RESPONSE TO AN INTEGRATIVE 
TREATMENT FOR PAIN AND ANXIETY IN PEDIATRIC FUNCTIONAL 
ABDOMINAL PAIN DISORDERS (FAPD) 
 
Principal Investigator:   
Natoshia Cunningham, PhD 
Assistant Professor of Family Medicine 
College of Human Medicine 
Michigan State University 
 
Supported by:  
The National Center for Complementary and Integrative Health 
K23AT009458 
 
 

 
Neural Mechanisms of Treatment Response Protocol 2 of 45 
Version 6.0 
 
 
04 August 2020 
Revision History 
Version Number: 1 
Version Date:  12/7/18 
Version Number:  2 
Version Date:  3/22/18 
Summary of Revisions Made:  A detailed procedure for monitoring and recording adverse events 
and severe adverse events was added. The number of assessment visits for each time point 
(baseline and post assessment) has been changed from 2 to 1.  The protocol was revised so that 
the CDI will be administered at screening so that all eligibility criteria are met by participants 
prior to starting the baseline assessment.  The protocol also now states that the PI of the study 
will be blind to group assignment and Dr. Kashikar-Zuck will provide clinical supervision.  A 
table about blinding and additional explanatory text was added.  The randomization procedures 
were changed.  Lastly, measures including the adverse event query form, menstruation query 
form, Parent Pain Visual Analog Scale, and Concomitant Medications Form were added to the 
table of events and the Anxiety Diagnostic Interview Schedule was removed.    
Version Number:  3 
Version Date:  4/30/18 
Summary of Revisions Made: The protocol was revised so that the Functional Disability 
Inventory (FDI) and Visual Analog Scale for Pain Intensity (VAS) will be administered at the 
screening visit in addition to the baseline and post assessment visits. Additional eligibility 
requirements were included in the inclusion criteria including at least moderate disability (FDI ≥ 
8) and a highest reported pain of at least 3/10 in the past 2 weeks according to the VAS. 
Additionally, participants and their parents will have the option to complete baseline and follow 
up assessment measures at home prior to their scheduled visit using their own electronic devices. 
We will provide them with a RedCap link to the measures via email within a few days of their 
scheduled visit. This option would reduce the length of the in-person assessment visits and thus 
reduce participant burden. If participants do not choose to complete measures prior to their visit, 
they will be administered during the assessment visit. Text detailing this was added to the 
protocol.  The number of participants we plan to approach was also adjusted for accuracy.  
Version Number:  4 
Version Date:  5/15/18 
Summary of Revisions Made:  The protocol reformatted to comply with the NCCIH protocol 
guidelines. 
Version Number:  5 
Version Date:  8/15/18 
Summary of Revisions Made: The screening procedures were amended such that in 
circumstances in which the FDI, SCARED, or Numeric Rating Scale (NRS) are unavailable in 

 
Neural Mechanisms of Treatment Response Protocol 3 of 45 
Version 6.0 
 
 
04 August 2020 
EPIC, any participant approached will be consented and administered all three measures. We 
have noted that if the scores from the three measures indicate study ineligibility, the remaining 
screening measures will not be given. Moreover, the protocol now allows for anyone interested 
in the study who was unable to meet in-person with study staff during their outpatient visit to set 
up a screening appointment outside of an office visit. FAPD will be confirmed with the provider 
using the EMR and/or direct communication with the provider. Abdominal migraine was added 
to the description of the Rome IV FAPD Diagnosis Checklist. The explanation of the water load 
symptom provocation task (WL-SPT) was revised to state that the WL-SPT has been used in 
adult studies. The protocol now states that the Adverse Event Query Form will be administered 
during ADAPT session 2 and post-assessment for participants randomized to the ADAPT 
treatment group. The protocol was also revised to explain that participants randomized to the 
waitlist will receive the Adverse Event Query Form at post-assessment, and if they choose to 
participate in ADAPT after the waitlist period, they will receive the Query during ADAPT session 
2 and over the phone after ADAPT session 6. We have clarified that the Numeric Rating Scale 
(NRS) will be used for screening, while the baseline and post-assessments will primarily use the 
Visual Analog Scale (VAS). If the VAS cannot be obtained because of technical difficulties with 
the slider, we will use the NRS instead. The protocol now explains that we will allow up to 8 
weeks to complete ADAPT, rather than 6 weeks. Several typographical errors were corrected, 
including in sections 6.2.3, 6.2.4, 7.2, 7.3, and 11.2. We also updated the Menstruation Query, 
Concomitant Medications, and Baseline/Post Demographic Information forms to include 
clarifying questions and language. For the Baseline/Post Demographic Information Forms under 
the "School Information" section, "Not Applicable" responses were added to increase clarity. 
The Menstruation Query for baseline and post assessment were revised to include a question 
about current pain levels due to menstruation. The FDI-Child and FDI-Parent Forms had item 8 
modified to increase clarity for participants and caregivers whose children are not currently in 
school. The fMRI Pain and Anxiety Ratings Form was updated to add a clarifying "not 
applicable" option to an item along with a notes section to explain any unusual circumstances 
such as the need to conduct a fMRI rescan due to significant participant movement. Updated 
version numbers were added to revised measures. An "Other Pain" measure was added to 
assess alternative pain sources and better contextualize imaging data. This measure will be 
administered during baseline and post assessment. The Contact Information form was modified 
to allow for more clarifying information. The Adverse Event Query, Adverse Event Detail, and 
Serious Adverse Event forms have also been updated to reflect more accurate administration 
time points (ADAPT Sessions 2 and 6, Post Assessment). 
 
Version Number: 6 
Version Date: 08/04/2020 
Summary of Revisions Made: The protocol has been revised in response to the PI’s change in 
institution. At the present site—Michigan State University (MSU)—the study team will 
collaborate with Helen DeVos Children’s Hospital (HDVCH)/Spectrum Health (SH). Participants 
will be recruited from pediatric GI clinics at HDVCH and the fMRI portion of the study will be 
conducted at SH. The study team roster has been updated to reflect the change in research 
staff. We anticipate actively enrolling participants over the next two years, though the 
anticipated number of participants to enroll and complete the study have not been changed. The 

 
Neural Mechanisms of Treatment Response Protocol 4 of 45 
Version 6.0 
 
 
04 August 2020 
inclusion criteria have been adjusted to no longer include greater than minimal levels of 
disability and pain as requirements to qualify for the study. During our initial launch of the study 
we found that pain levels and pain-related disability at the time of recruitment were not generally 
reflective of pain levels at the time of neuroimaging. Therefore, discounting participants due to 
current pain levels at the time of their GI visit seemed unnecessary. Further, we removed the 
criterion regarding disability levels, as disability levels widely fluctuate in this population and are 
not an outcome of this study.  The method of reimbursement has changed, though the amount 
has not been altered.  A few COVID-19 related modifications have also been made: 
Recruitment can occur virtually.  Secondly, participants will now complete all ADAPT sessions 
virtually, using a HIPAA compliant videoconference platform or phone. Measures of parent and 
child COVID-related distress have been added to the study. Finally, the ACEs caregiver 
measure has been added to the baseline and post-assessments of the study. 
 

 
Neural Mechanisms of Treatment 
5 of 45 
Response Protocol, Version 6.0 
 
TABLE OF CONTENTS 
Page 
PROTOCOL TITLE PAGE ........................................................................................................ 1 
Revision History ......................................................................................................................... 2 
TABLE OF CONTENTS ............................................................................................................. 5 
STUDY TEAM ROSTER........................................................................................................... 8 
PRÉCIS ..................................................................................................................................... 10 
1. STUDY OBJECTIVES ........................................................................................................... 12 
1.1 
Primary Objective ......................................................................................................... 12 
1.2 
Secondary Objectives.................................................................................................... 12 
2. BACKGROUND AND RATIONALE .................................................................................. 12 
2.1 
Background on Condition, Disease, or Other Primary Study Focus ............................ 12 
2.2 
Study Rationale ............................................................................................................. 14 
3. STUDY DESIGN ..................................................................................................................... 14 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS .............................................. 16 
4.1 
Inclusion Criteria .......................................................................................................... 17 
4.2 
Exclusion Criteria ......................................................................................................... 17 
4.3 
Study Enrollment Procedures ....................................................................................... 18 
5. STUDY INTERVENTIONS .................................................................................................. 18 
5.1 
Interventions, Administration, and Duration ................................................................ 18 
5.2 
Handling of Study Interventions ................................................................................... 19 
5.3 
Concomitant Interventions ............................................................................................ 19 
5.2.1 
Allowed Interventions ............................................................................................... 19 
5.2.2 
Required Interventions .............................................................................................. 19 
5.2.3 
Prohibited Interventions ............................................................................................ 19 
5.4 
Adherence Assessment ................................................................................................. 19 
6. STUDY PROCEDURES ........................................................................................................ 19 
6.1 
Schedule of Evaluations ................................................................................................ 20 
6.2 
Description of Evaluations ............................................................................................ 21 
6.2.1 
Screening Evaluation ................................................................................................ 21 
6.2.2 
Enrollment, Baseline, and Randomization................................................................ 22 
 

 
Neural Mechanisms of Treatment 
6 of 45 
Response Protocol, Version 6.0 
 
6.2.3 
Blinding..................................................................................................................... 25 
6.2.4 
Adverse Event Queries/Additional Measures ........................................................... 27 
6.2.5 
Completion/Final Evaluation .................................................................................... 28 
7. SAFETY ASSESSMENTS ..................................................................................................... 29 
7.1 
Specification of Safety Parameters ............................................................................... 31 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters .... 32 
7.3 
Adverse Events and Serious Adverse Events ............................................................... 32 
7.4 
Reporting Procedures .................................................................................................... 33 
7.5 
Follow-up for Adverse Events ...................................................................................... 33 
7.6 
Safety Monitoring ......................................................................................................... 33 
8. INTERVENTION DISCONTINUATION ........................................................................... 34 
9. STATISTICAL CONSIDERATIONS .................................................................................. 34 
9.1 
General Design Issues ................................................................................................... 34 
9.2 
Sample Size and Randomization .................................................................................. 35 
9.3  
Definition of Populations .............................................................................................. 37 
9.4 
Interim Analyses and Stopping Rules ........................................................................... 37 
9.5 
Outcomes ...................................................................................................................... 38 
9.5.1 
Primary Outcome ...................................................................................................... 38 
9.5.2 
Secondary Outcomes ................................................................................................ 38 
9.6 
Data Analyses ............................................................................................................... 38 
10. DATA COLLECTION AND QUALITY ASSURANCE .................................................. 39 
10.1 
Data Collection Forms .................................................................................................. 39 
10.2 
Data Management ......................................................................................................... 39 
10.3 
Quality Assurance ......................................................................................................... 40 
10.3.1 
Training ..................................................................................................................... 40 
10.3.2  Quality Control Committee .......................................................................................... 40 
10.3.3 
Metrics ...................................................................................................................... 40 
10.3.4 
Protocol Deviations. .................................................................................................. 40 
10.3.5 
Monitoring ................................................................................................................ 40 
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY ................................................... 40 
11.1 
Institutional Review Board (IRB) Review .................................................................... 40 
11.2 
Informed Consent Forms .............................................................................................. 40 
11.3 
Participant Confidentiality ............................................................................................ 41 
11.4 
Study Discontinuation ................................................................................................... 41 

 
Neural Mechanisms of Treatment 
7 of 45 
Response Protocol, Version 6.0 
 
12. COMMITTEES..................................................................................................................... 41 
13. PUBLICATION OF RESEARCH FINDINGS .................................................................. 41 
14. REFERENCES ...................................................................................................................... 42 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Neural Mechanisms of Treatment 
8 of 45 
Response Protocol, Version 6.0 
 
STUDY TEAM ROSTER  
Natoshia Cunningham, PhD 
Assistant Professor of Family Medicine 
College of Human Medicine 
Michigan State University 
15 Michigan St NE 
Grand Rapids, MI 49503 
natoshia@msu.edu 
(616) 234-2821 
 
Brittany Barber Garcia, PhD 
Pediatric Psychologist 
Pediatric Behavioral Health 
Helen DeVos Children’s Hospital 
35 Michigan St NE 
Grand Rapids, MI 49503 
Brittany.BarberGarcia@helendevoschildrens.org 
(616) 267-2830 
 
David Zhu, PhD 
Professor of Radiology, Psychology, Electrical & Computer Engineering and Biomedical 
Engineering 
Michigan State University 
846 Service Rd 
East Lansing, MI 48824 
zhuda@msu.edu 
(517) 884-3345 
 
Judith Arnetz, PhD, MPH, PT 
Professor; Associate Chair for Research, Director of Faculty Development in Research 
College of Human Medicine 
Michigan State University 
15 Michigan St NE 
Grand Rapids, MI 49503 
arnetzju@msu.edu  
(517) 884-0436 
 
Mathew Reeves, PhD 
Professor of Epidemiology and Biostatistics 
Michigan State University 
909 Wilson Rd 
East Lansing, MI 48824 
reevesm@msu.edu 
(517) 353-8623 

 
Neural Mechanisms of Treatment 
9 of 45 
Response Protocol, Version 6.0 
 
PARTICIPATING STUDY SITE 
Natoshia Cunningham, PhD 
Michigan State University 
Department of Family Medicine 
15 Michigan Street NE 
Grand Rapids, MI 49503 
(616)243-2821 
STUDY MEMBER EXPERTISE 
 
Staff Member 
Role 
Demonstrated Qualifications 
Dr. Natoshia Cunningham 
Candidate/PI 
-Research faculty in the department 
of family medicine 
-Licensed clinical psychologist 
-Research: Assessment and 
treatment of pediatric pain and 
anxiety; Neuroimaging to 
understanding pain and tx response 
Dr. David Zhu 
Co-Primary Mentor 
(Neuroimaging) 
-Director and MR physicist, MSU 
Cognitive Imaging Research Center  
-24 years MRI research experience 
-15 years neuroimaging experience 
with multidisciplinary teams 
(including psychologists and 
neuroscientists) 
Dr. Judy Arnetz 
Co-Primary Mentor 
(Health systems research) 
-Associate Chair for Research in 
MSU’s Department of Family 
Medicine (where PI is housed) 
-Health systems research expertise 
(i.e., examining organizational 
determinants of healthcare safety) 
Dr. Brittany Barber Garcia 
Consultant (Primary 
Interventionist) 
-Licensed clinical psychologist 
-Specialty in pediatric pain 
management 
Dr. Mathew Reeves 
Consultant (Statistical 
Analysis) 
-Statistical analysis for clinical 
trials & health outcomes research in 
individuals with chronic conditions 
 
 
 
 
 
 
 
 

 
Neural Mechanisms of Treatment 
10 of 45 
Response Protocol, Version 6.0 
 
PRÉCIS  
Study Title  
Using fMRI to understand response to an integrative treatment for pain and anxiety in 
pediatric functional abdominal pain disorders (FAPD).  
Objectives  
Aim 1. Left AMY-PFC functional connectivity will be significantly diminished (i.e., 
evidence of decreased hyperconnectivity) during the water load symptom provocation 
task (WL-SPT) post ADAPT vs. waitlist. 
Aim 2. Brain activations associated with cognitive (PFC), affective (pgACC, AMY), 
and visceral afferent (INS, thalamus, aMCC, S1 & S2) pain will significantly be more 
diminished after ADAPT vs. waitlist. 
Exploratory Aim.  Changes in functional connectivity and brain activations following 
ADAPT will correspond to reductions in pain (intensity and unpleasantness) and 
anxiety ratings.  
 
Design and Outcomes   
In this study, brain mechanisms implicated in the modulation of pain during a 
symptom provocation task in relation to response to a psychological intervention for 
pediatric FAPD will be investigated. Participants with FAPD and comorbid anxiety 
will complete a screening to assess eligibility.  Next, they will complete a baseline 
assessment where they will undergo an fMRI to explore changes in functional 
connectivity during visceral pain induction (via the water load symptom provocation 
task; WL-SPT).  Participants will then be randomized to either ADAPT or waitlist 
control.  A post assessment will be conducted approximately 6 weeks later where 
participants will again undergo an fMRI and complete the WL-SPT. Changes in 
functional connectivity and brain activations will be observed and compared for 
participants in each treatment condition (ADAPT intervention or waitlist control).  
It is expected that Left AMY-PFC functional connectivity will be significantly 
diminished (i.e., show evidence of decreased hyperconnectivity) during the WL-SPT 
post ADAPT vs. waitlist (Aim 1).  In addition (Aim 2), brain activations associated 
with cognitive (PFC), affective (pgACC, AMY), and visceral afferent (INS, thalamus, 
aMCC, S1 & S2) pain will significantly be more diminished after ADAPT vs. 
waitlist.  Finally, we predict changes in functional connectivity and brain activations 
following ADAPT will correspond to reductions in pain (intensity and 
unpleasantness) and anxiety ratings (exploratory Aim).  
Conventional blood oxygenation level dependent (BOLD) fMRI will be used to 
assess functional connectivity to capture moment-to-moment fluctuations in activity 
(Aim 1). In Aim 2, changes in regional brain activation for those receiving ADAPT 
will be compared to those in the waitlist condition.  The novel arterial spin label 
(ASL) MRI technique will be used to gain inferences into regional brain activity since 
these activations represent a relatively steady-state. In line with the NCCIH funding 
priorities, this study seeks to increase understanding of the mechanisms through 
which mind and body approaches impact clinical outcomes in chronic pain and 

 
Neural Mechanisms of Treatment 
11 of 45 
Response Protocol, Version 6.0 
 
anxiety. Results will advance the field by providing crucial information needed for 
the refinement and testing of a tailored mind body intervention for FAPD and 
comorbid anxiety. 
 
 
 
 
 
 
 
 
Interventions and Duration  
In this study, a psychological intervention, Aim to Decrease Anxiety and Pain 
Treatment (ADAPT), was developed and will integrate mindfulness meditation with 
cognitive behavioral therapy approaches for managing pain and anxiety to improve 
patient outcomes. ADAPT is a remotely delivered individual therapy with caregiver 
involvement that consists of 2 video-recorded  sessions with an interventionist (60 
minutes) once per week for the first two weeks, followed by 4 weeks of self-paced 
web modules (45 minutes per week) in conjunction with interventionist support (15 
minutes per week). Of note, participants will complete the ADAPT program through 
a HIPAA compliant video platform (Zoom) or over phone calls as an alternate 
delivery method. Zoom sessions will be video recorded to measure interventionist 
adherence and for training purposes. The duration of ADAPT is 6 weeks, although up 
to eight weeks will be permitted to account for scheduling conflicts and participant 
illness. Preliminary testing has shown that ADAPT successfully reduces pain and 
anxiety over time.   
Participants randomized to ADAPT will be actively involved in the study for a 
~10 week period (from screening to post assessment). Those who are randomized to 
the waitlist control and then opt to receive ADAPT afterwards will be involved for 
~16 weeks.   
Sample Size and Population  
The target population is male and female youth between the ages of 11-16 with 
functional abdominal pain disorders (FAPD) and clinically significant anxiety.  Youth 
will be recruited from pediatric gastroenterology clinics at Helen DeVos Children’s 
Hospital.  We aim to have between 17 – 25 participants in each arm for a total N of 
34 - 50 participants in the study. Gender and age will be used as blocking variables in 
randomization.  
Screening 
Baseline 
Randomization 
 
Waitlist Control 
Session 1 
Zoom 
Session 2 
Zoom 
Session 3 
web/phone 
Session 5 
web/phone 
Session 6 
web/phone 
Session 4 
web/phone 
ADAPT 
Post Assessment 
ADAPT 
Therapist support 

 
Neural Mechanisms of Treatment 
12 of 45 
Response Protocol, Version 6.0 
 
1. STUDY OBJECTIVES 
1.1 
Primary Objective 
Left AMY-PFC functional connectivity will be significantly reduced (i.e., decreased 
hyperconnectivity) post ADAPT vs. waitlist. 
 
1.2 
Secondary Objectives 
Brain activations associated with cognitive (PFC), affective (pgACC, AMY), and visceral 
afferent (INS, thalamus, aMCC, S1 & S2) pain will be significantly more diminished after 
ADAPT vs. waitlist. 
Exploratory Aim.  Changes in functional connectivity and brain activations following 
ADAPT will correspond to reductions in pain (intensity and unpleasantness) and anxiety 
ratings.  
 
2. BACKGROUND AND RATIONALE 
2.1 
Background on Condition, Disease, or Other Primary Study Focus 
Functional abdominal pain disorders (FAPD) are the most common chronic pain 
conditions of childhood and are associated with significant functional disability. 
FAPD impacts >10% of youth in community samples1,2 and accounts for up to 50% 
of gastroenterology (GI) visits3,4. FAPD is associated with significant functional 
impairment5-7, including psychological problems, such as anxiety and depression8,9. 
Youth with FAPD are more prone to social and academic difficulties7, including 
school refusal/absences, poor academic performance, and social problems10.  
Impairment and disability are likely to persist, with 25%-45% affected after 5 years 
11,12. Increased healthcare utilization and medical costs are substantial and include 
invasive and unnecessary medical procedures13, such as blood work-up (92%), 
endoscopic studies (51%), and abdominal x-rays (39%). Such work-ups are common, 
costly ($6,104 per patient), and are associated with medical complications. Although 
the total cost of pediatric FAPD is unknown, the cost in adults is estimated to be $20 
billion a year14. Given that a substantial proportion of youth continue to experience 
symptoms over time and may even develop other chronic pain conditions15, the total 
cost of pediatric FAPD is likely substantial. Early and effective intervention may play 
a key role in preventing long-term problems.  
Anxiety is highly prevalent and predicts poor outcomes. A large proportion of 
youth with FAPD meet criteria for a concurrent anxiety disorder8,9,16. Anxiety 
disorders are characterized by extreme distress and worry and may be generalized or 
result from specific triggers, such as separation from attachment figures or social 
situations17. In youth with FAPD presenting to GI clinics, anxiety disorders are 
estimated to affect 42% to 85%18-20. Further, prior research18,21,22 has found that 
clinically significant anxiety is common and predicts increased functional 
impairment20,23. Clearly, youth with FAPD and clinical anxiety are the most common 
and most clinically complicated manifestation of FAPD.   

 
Neural Mechanisms of Treatment 
13 of 45 
Response Protocol, Version 6.0 
 
Conventional treatments are ineffective for many youth with FAPD. 
Pharmacologic treatments (i.e., antispasmodic agents, low-dose psychotropics) for 
FAPD have limited evidence and efficacy24. Cognitive behavioral therapy (CBT) for 
pain is a conventional non-pharmacologic treatment that uses cognitive strategies 
(e.g., reducing catastrophic thinking about pain) and behavioral approaches (e.g., 
activity pacing, behavioral activation) to improve functioning and reduce pain 
symptoms in youth with chronic pain such as FAPD25,26. However, a substantial 
proportion (~40%) fail to respond27 and the presence of elevated anxiety can attenuate 
response to pain-focused CBT28. Including specific treatment components to manage 
clinical anxiety29,30 is the next logical step for these patients. 
Mindfulness may amplify the efficacy of conventional treatments. Mindfulness 
includes attending to experiences in the present moment and using a nonjudgmental 
attitude, and is effective for managing pain31,32 and anxiety33,34. Pain reduction 
following mindfulness in healthy adults has been shown to be related to changes in 
activation of the primary sensory cortex (S1), insula (INS), anterior cingulate cortex 
(ACC), and prefrontal cortex (PFC) brain regions35. Moreover, improvements in 
anxiety following mindfulness are characterized by enhanced PFC connectivity with 
the amygdala (AMY) during resting state36 and changes in the ACC, PFC, and INS in 
healthy adults37. 
In general, the neurobiological underpinnings of visceral pain in FAPD are poorly 
understood although anxiety is likely to play a crucial role in understanding 
psychological treatment response for pain. Research suggests pain is experienced 
through the pain connectome38, a whole-brain-wide network that integrates cognitive, 
affective, and sensorimotor aspects. Recent reviews of prior neuroimaging studies in 
IBS, the most common subtype of FAPD, suggest that common areas of activation in 
response to pain include regions associated with visceral afferent processing, such as 
the thalamus, INS, anterior midcingulate cortex (aMCC)39, and the primary and 
secondary sensory cortices (S1 & S2)40. Interestingly, brain regions associated with 
emotional arousal, including the pregenual anterior cingulate cortex (pgACC) and 
AMY, are also activated by pain induction in FAPD, but not in healthy controls 39. In 
adolescents with FAPD (IBS), structural abnormalities were observed in the INS and 
S1, in addition to structural and functional abnormalities in the PFC, and posterior 
cingulate (PCC)41. Although brain regions associated with anxiety may play an 
important role in the expression of pain (i.e., FAPD), there is limited hypothesis-
driven research examining the role of anxiety41. Anxiety alone is associated with 
AMY hyperactivations and PFC hypoactivations42-44.  
Neural mechanisms may offer insights on response to a tailored intervention for 
youth with FAPD. There have only been two research studies examining neural 
mechanisms of treatment response to non-pharmacologic interventions for FAPD (in 
adults with IBS). However, these studies use an invasive and potentially risky pain 
induction technique (rectal distention), though less invasive methods (such as water 
loading) to induce visceral pain are available45.The first found that improvements in 
pain using cognitive therapy were associated with reduced rectal distention-induced 
activations in the AMY and the pgACC46. However, functional connectivity analysis 
was not undertaken. The second47 compared hypnotherapy for pain to an educational 
control and found that the brain response to rectal distension after treatment was 

 
Neural Mechanisms of Treatment 
14 of 45 
Response Protocol, Version 6.0 
 
similar to that observed in HCs, suggesting that the treatment had a normalizing effect 
on the central processing abnormality of visceral pain signals in IBS. Hypnosis 
responders demonstrated a BOLD attenuation in posterior INS while education 
responders had a BOLD attenuation in prefrontal cortex. Moreover, in a pediatric pain 
sample, a positive response to an intensive integrated treatment for complex regional 
pain syndrome was related to a reduced hyperconnectivity between the lAMY and 
regions including the PFC48; but research specific to pediatric FAPD is needed.  Dr. 
Cunningham’s pilot study has shown lAMY-PFC changes in functional connectivity 
following a symptom provocation task.  Further, CBT for pediatric pain (migraine) 
alters interactions between affective regions (AMY) and structures involved in 
cognitively driven pain modulation (PFC).  Thus, the AMY might represent an 
important mechanism linking anxiety to sensory processing mechanisms. 
These findings suggest that complex neuromechanistic processes account for 
response to psychological interventions. However, there is no research to our 
knowledge that distills the mechanism of the effect in a psychological intervention for 
youth with FAPD and comorbid anxiety. It is plausible that a psychological 
intervention tailored to anxiety and pain symptoms in FAPD would impact 
neuromechanisms that link cognitive and visceral afferent processing with emotional 
arousal (i.e., lAMY-PFC connectivity). Determining such information is critical for 
identifying brain mechanisms of effective treatments. For example, if lAMY-PFC 
connectivity is significantly altered following ADAPT (e.g., reduced 
hyperconnectivy), this evidence would offer further support for the importance of 
targeting anxiety and pain in youth with FAPD.  
 
2.2 
Study Rationale 
Given this research evidence, Aim to Decrease Pain and Anxiety Treatment 
(ADAPT) was developed.  ADAPT is a cognitive behavioral approach to manage 
pain and anxiety for youth with FAPD and comorbid anxiety49.  For the current study, 
ADAPT is enhanced with mindfulness meditation. Thus, ADAPT focuses on 
decreasing attention to pain and anxiety using conventional strategies (CBT), as well 
as training in mindfulness meditation techniques, such as mindful breathing, 
developing a mindful awareness of bodily sensations, recognizing the impact of stress 
on functioning. ADAPT utilizes a blend of 2 interactive sessions with a psychological 
provider (1 hour, via videoconference) and 4 web-based, self-paced modules (45 
minutes) with therapist support videoconferencing and/or phone calls (15 minutes).  
The  Zoom-based ADAPT sessions will be video-recorded. The ADAPT intervention 
period is approximately 6 weeks (up to eight weeks will be allowed for scheduling 
flexibility).  Based on our prior research50, there are no known risks associated with 
the ADAPT intervention. 
3. STUDY DESIGN 
• Type/design of trial: Masked clinical trial 
• Specific statement of the primary and secondary outcomes: The primary outcome is that 
left AMY-PFC functional connectivity will be significantly reduced (i.e., decreased 

 
Neural Mechanisms of Treatment 
15 of 45 
Response Protocol, Version 6.0 
 
hyperconnectivity) post ADAPT vs. waitlist.  The secondary outcome is that brain activations 
associated with cognitive (PFC), affective (pgACC, AMY), and visceral afferent (INS, 
thalamus, aMCC, S1 & S2) pain will be significantly more diminished after ADAPT vs. 
waitlist.  We will also explore whether changes in functional connectivity and brain 
activations following ADAPT correspond to reductions in pain (intensity and unpleasantness) 
and anxiety ratings. 
• Study population and groups/arms including sample size: The target population is male 
and female youth between the ages of 11-16 with functional abdominal pain disorders (FAPD) 
and clinically significant anxiety.  Youth will be recruited from pediatric gastroenterology 
clinics at Helen DeVos Children’s Hospital. We aim to have between 17 – 25 participants in 
each arm for a total N of 34 - 50 participants in the study. Gender and age will be used as 
blocking variables in randomization. 
• Study location: The study is located Helen DeVos Children’s Hospital/Spectrum Health. 
• Approximate duration of enrollment period and follow-up:  Participants will be recruited 
from GI clinics and enrolled in the study during that visit (immediately).  They will then come 
in for the baseline assessment, which will occur approximately one week after enrollment 
(though up to six weeks after enrollment will be allowed to account for MRI scanner 
availability).  Following that visit, they will then be randomized to either the ADAPT group or 
a waitlist control group (each six weeks in duration) and will be informed of group assignment 
within a week of their baseline assessment, and will begin ADAPT/waitlist approximately one 
week after group assignment (with up to three weeks allowed to begin ADAPT).  Up to eight 
weeks will be permitted for the six ADAPT sessions to account for potential scheduling 
conflicts and participant illness. Upon completion of ADAPT or waitlist control, participant 
outcomes will be reassessed at the post assessment visits (approximately six weeks after 
ADAPT/waitlist). After completing the post assessment visit, participants in the waitlist 
control group will be given the opportunity to complete ADAPT.   
Participants randomized to ADAPT will be actively involved in the study for a ~10 week 
period (from screening to post assessment). Those who are randomized to the waitlist control 
and then opt to receive ADAPT afterwards will be involved for ~16 weeks.   
It is anticipated that we will be actively enrolling participants for 2 years. After study 
completion, three additional months will be allotted for data analysis.   
• Description of intervention and administration. In this study, a psychological intervention, 
Aim to Decrease Anxiety and Pain Treatment (ADAPT), was developed and will integrate 
mindfulness meditation with cognitive behavioral therapy approaches for managing pain and 
anxiety to improve patient outcomes. ADAPT is an individual therapy with caregiver 
involvement that consists of 2 interactive sessions with a psychological provider (60 minutes) 
once per week for the first two weeks, followed by 4 weeks of self-paced web modules (45 
minutes per week) in conjunction with interventionist support (15 minutes per week).  
Participants will complete the ADAPT program virtually (e.g., using HIPPA compliant 
videoconferencing or phone).  The duration of ADAPT is 6 weeks, although up to eight weeks 
will be permitted to account for scheduling conflicts and participant illness. Preliminary 
testing has shown that ADAPT successfully reduces pain and anxiety over time.   
Participants randomized to ADAPT will be actively involved in the study for a ~10 week 
period (from screening to post assessment). Those who are randomized to the waitlist control 
and then opt to receive ADAPT afterwards will be involved for ~16 weeks.   

 
Neural Mechanisms of Treatment 
16 of 45 
Response Protocol, Version 6.0 
 
• Randomization, blinding:  Participants will then be randomized to either ADAPT or waitlist 
control.  Gender and age will be used as blocking variables in randomization.  For further 
detail on randomization, see 9.2 Sample Size and Randomization.  The PI (Cunningham), data 
analyst (Reeves), and outcome assessors (post-baccalaureate research coordinator) will be 
blinded to intervention group assignment.  The study statistician (Reeves), PI (Cunningham), 
and mentorship team (Zhu and Arnetz) will be blinded to the primary mechanistic outcome 
measure.  For further detail on blinding, see 6.2.3 Blinding. 
• Other protocol specific details:  Participants with FAPD will be recruited from 
gastroenterology clinics. We will work with Dr. Brittany Barber Garcia (who already provides 
outpatient clinical/psychological care for patients in the GI clinics) to identify potentially 
appropriate patients. Of note, the GI section chair, Dr. Cloney is supportive of the project and 
has agreed to facilitate clinical recruitment and consultation efforts for the study. Dr. Cloney, 
along with the other GI physicians of the section, are close collaborators of Dr. Brittany 
Barber Garcia. With Dr. Brittany Barber Garcia’s established relationships within GI, we will 
be able to work broadly with members of the GI team at HDVCH.  
     Potentially appropriate participants will be contacted by a member of the medical team and/or 
by a study staff member.  They will be described the study in detail and participants will have 
the opportunity to ask questions and voice concerns.  If the patient/family is agreeable, 
informed consent/assent will be obtained and participants will be screened for study 
eligibility. Qualifying patients will then be scheduled to complete the baseline assessment 
visit (clinical measures/WL-SPT with fMRI).  After this visit, participants will be randomized 
to either the ADAPT treatment group or a waitlist control (each condition will last for 
approximately 6 weeks).  The post assessment will be similar in format to the baseline 
assessment. Those randomized to waitlist will be eligible to receive ADAPT after the post 
assessment. 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS  
The study population is male and female youth between the ages of 11-16 diagnosed with 
functional abdominal pain disorders (FAPD) and clinically significant anxiety.  We plan to 
approach approximately 124 participants, ages 11-16 years.  Of those, we expect 75% will agree 
to participate (n=93) based on our pilot fMRI study.  Of those, we expect approximately 65% 
will qualify.  Thus, we anticipate recruiting n=60 to complete a baseline assessment. Based on 
our previously RCT, we expect 85% of those recruited in clinic will complete the baseline 
assessment (n = 50) and the majority will be retained in the study (90%, n=45).  Based on our 
fMRI pilot study, we expect to lose approximately 10% of participant data to movement artifacts 
yielding n=40 with usable data.  The minimum number of total completed participants allowed 
will be 34 and the maximum will be 50. 
We will recruit males and females to participate in this study.  While FAPD is more common 
in females, we have found that we are easily able to recruit males as well.  Based on our prior 
research projects, we expect that we will recruit a sample of youth with FAPD that is 65% 
female and 35% male.  The PI (Cunningham) will check in with the mentorship team (Arnetz 
and Zhu) quarterly regarding enrollment and gender breakdown in a blinded fashion.  If the 
gender breakdown is skewed (>85% females or >60% males), the PI (Cunningham) will problem 
solve with study mentors (Arnetz and Zhu) to ensure the sample is representative of the 

 
Neural Mechanisms of Treatment 
17 of 45 
Response Protocol, Version 6.0 
 
population.  Recruitment efforts would target candidates from underrepresented gender until the 
sample is more representative of the FAPD population. 
4.1 
Inclusion Criteria 
Participants must meet all of the inclusion criteria to participate in this study. 
• Children (males and females) between 11 and 16 years of age and their 
parent/primary caregiver will participate in the study. 
 
Child Criteria 
• Meets criteria for FAPD based on physician diagnosis of FAPD and ROME IV 
FAPD criteria (see Description of Evaluations section for additional details). 
• Meets criteria for presence of clinically significant anxiety (based on the Screen 
for Child Anxiety Related Disorders [SCARED] total cut-off score ≥ 25; see 
Description of Evaluations section for additional details).  
Child and Caregiver Criteria 
• Youth and caregiver must have sufficient English language ability necessary to 
complete study measures and protocol. 
4.2 
Exclusion Criteria 
All candidates meeting any of the exclusion criteria at screening will be excluded 
from study participation.  
Child Criteria 
• Children with a significant medical condition(s) with an identifiable organic cause 
including those that may include abdominal pain symptoms (e.g., Inflammatory 
Bowel Diseases).   
• Children with a documented developmental delay(s), autism spectrum disorder, a 
previously diagnosed thought disorder (i.e., psychosis), or bipolar disorder.  
• Significant visual, hearing, or speech impairment.  
• Organic brain injury.  
• Participants who are currently in psychological therapy for pain or anxiety. 
• Participants with severe depressive symptoms (T score ≥ 80) or current active 
suicidal ideation reported on the CDI. 
• Exclusionary criteria specific to the fMRI component of the study: 
• Participants with an implant such as a cochlear implant device, a pacemaker or 
neurostimulator containing electrical circuitry or generating magnetic signals. 
Participants with any significant ferrous material in their body that could pose the 
potential for harm in the fMRI environment or cause signal suppression of key 
regions (i.e. orthodontia).  
• Female participants who report current/suspected pregnancy. 
• Participants with evidence of claustrophobia. 
 
Child and Caregiver Criteria 
• Inability or unwillingness of individual or legal guardian/representative to give 
written informed consent. 

 
Neural Mechanisms of Treatment 
18 of 45 
Response Protocol, Version 6.0 
 
4.3 
Study Enrollment Procedures  
• 
Method for identifying and recruiting candidates for the trial. Eligible 
participants with FAPD will be identified for the study from new or existing 
patients seen at the outpatient pediatric GI clinics. 
• 
Procedures for documentation of reasons for ineligibility and for non-
participation of eligible candidates.  A screening log will be maintained with 
eligible candidates contacted/approached for study recruitment.  This log will 
detail reasons for ineligibility and/or reasons for disinterest in study participation 
if applicable.  Once consented, participant names and ID numbers will be 
recorded in a secured enrollment log.  A separate log will track participant 
progress throughout the study.   
• 
Consent procedures. FAPD patients will be introduced to the study in person (or 
virtually if an in-person option is not available) by a medical staff member and/or 
study staff member who will explain the study to the patient and the primary 
caregiver in greater detail.  Participants will be assured that their usual medical 
care will not be affected based upon whether or not they choose to participate. 
Written consent from the primary caregiver and written assent from the child will 
be obtained by study staff.  All participants will be notified that screening is 
necessary and study entry is not guaranteed at this point.  If the child is not 
eligible and the family is interested in the child receiving mental health services, 
contact information for the psychology service at HDVCH will be provided. 
• 
Randomization procedure for assigning a participant to an intervention 
group.  Following the baseline visit, patients will then be randomized to either the 
ADAPT group or a waitlist control group (each six weeks in duration) and will be 
informed of group assignment within a week of their baseline assessment, and 
will begin ADAPT/waitlist approximately one week after group assignment (with 
up to three weeks allowed to begin ADAPT).  Gender and age will be used as 
blocking variables in randomization.   
5. STUDY INTERVENTIONS  
5.1 
Interventions, Administration, and Duration  
Participants will either begin ADAPT in the week following the treatment group 
assignment or after completing the post assessment (waitlist control).  The duration of 
ADAPT is 6 weeks (although up to 8 weeks will be allowed for scheduling 
flexibility) and a total of 6 hours of intervention will be administered.  Participants 
will be reminded via text message to complete their respective ADAPT web modules. 
Based on our prior research, the risk for potential for adverse events is low. 

 
Neural Mechanisms of Treatment 
19 of 45 
Response Protocol, Version 6.0 
 
5.2 
Handling of Study Interventions  
ADAPT will be primarily delivered by a trained interventionist (Dr. Barber 
Garcia, licensed clinical psychologist). Dr. Barber Garcia is a trained provider with 
expertise in pediatric pain management and telehealth. In addition, a back-up provider 
will be available to deliver the intervention in the event of an absence of the primary 
provider.  
5.3 
Concomitant Interventions  
Any concomitant interventions (i.e., medical and psychological) experienced by 
the participants (either allowed or prohibited) will also be assessed for and recorded at 
baseline and post assessments.  Participants will provide the reason and duration of 
concomitant interventions at the baseline and post assessment visits. 
5.2.1 Allowed Interventions 
Participants are allowed to continue their medical care as usual (i.e., taking 
medication) throughout the duration of the study.  Participants are also allowed to 
partake in psychological therapy as long as it is not directly addressing pain or 
anxiety. 
5.2.2 Required Interventions 
There are no other required interventions. 
5.2.3 Prohibited Interventions 
Youth who are currently in psychological therapy for pain or anxiety will be excluded 
from participation. 
5.4 
Adherence Assessment  
 
The projected sample size is not adequately powered to account for differences in 
adherence.  However, data will be collected on the attendance of Zoom-based 
sessions, completion of web-based content, and completion of therapist 
videoconferencing/phone calls, in addition to completing study assessments.  We 
anticipate good adherence (>80% completion of intervention materials) based on our 
prior research.  If adherence becomes problematic during the course of the study, the 
interventionist (Barber Garcia) will communicate these concerns with the PI 
(Cunningham). 
6. STUDY PROCEDURES  
(See subsections below)

 
Neural Mechanisms of Treatment 
20 of 45 
Response Protocol, Version 6.0 
 
6.1 
Schedule of Evaluations 
Assessment 
Screening 
Baseline Assessment 
ADAPT 
Session 2 
ADAPT 
Session 6 
Post Assessment 
Post WL/ 
ADAPT*  
Participant 
Participant 
Parent 
Participant 
Participant 
Participant 
Parent 
Participant 
fMRI/Water loading measures 
 
 
 
 
 
 
 
 
Current pain intensity/unpleasantness  
 
X 
 
 
 
X 
 
 
State Anxiety (VAS)  
 
X 
 
 
 
X 
 
 
Fullness Rating Scale (during fMRI)  
 
X 
 
 
 
X 
 
 
Self-Report/Interview measures 
 
 
 
 
 
 
 
 
Screen for Anxiety and Related Disorders 
(SCARED) 
X 
 
X 
 
 
X 
X 
X 
Eligibility Criteria  
X 
 
 
 
 
 
 
 
FAPD screening measure 
X 
 
 
 
 
X 
 
 
MRI Safety and Screening  
X 
 
 
 
 
 
 
 
CDI 
X 
 
 
 
 
X 
 
 
Menstruation Query 
X 
X 
 
 
 
X 
 
 
Other Pain  
 
X 
 
 
 
X 
 
 
Petersen Pubertal Development Scale 
(PDS) (*also includes menstruation query) 
 
X 
 
 
 
X 
 
 
PROMIS Pain Interference 
 
X 
 
 
 
X 
 
 
Edinburgh Handedness Inventory 
 
X 
 
 
 
X 
 
 
Pain VAS Scale 
X 
X 
X 
 
 
X 
X 
 
Pain NRS Scale 
X 
 
 
 
 
 
 
X 
Functional Disability Inventory (FDI) 
X 
X 
X 
 
 
X 
X 
X 
Pain Catastrophizing Scale  
 
X 
X 
 
 
X 
X 
 
Affective Reactivity Index (ARI) 
 
X 
X 
 
 
X 
X 
 
Self-Efficacy Chronic Pain Scale 
 
X 
X 
 
 
X 
X 
 
Depression Anxiety Stress Scales (DASS) 
 
 
X 
 
 
 
X 
 
Demographic Information  
 
 
X 
 
 
 
X 
 
Child Pain History & Sociodemographic 
Factors 
 
 
X 
 
 
 
X 
 
Concomitant Medications 
 
 
X 
 
 
 
X 
 
Adverse Event Query Form 
 
 
 
X 
 
X 
 
X 
Child COVID-19 Related Distress 
 
X 
 
 
 
X 
 
 
Child COVID-19 Related Distress Coping 
 
 
 
 
X 
 
 
X 
COVID-19 Exposure and Family Impact 
Survey (CEFIS) 
 
 
X 
 
 
 
X 
 
Adverse Childhood Experiences (ACEs) 
 
 
X 
 
 
 
X 
 

 
Neural Mechanisms of Treatment 
21 of 45 
Response Protocol, Version 6.0 
 
6.2 
Description of Evaluations  
6.2.1 Screening Evaluation 
Consenting Procedure 
Consenting will be completed with a single informed consent form that 
describes both the screening and study procedures.  Patients with FAPD and their 
primary caregiver will be introduced to the study by a medical staff member and/or 
study staff member at their outpatient pediatric GI medical visit, or virtually if an in-
person option is not available.  If the patient expresses interest in the study after being 
introduced to the study  by their GI medical provider and research staff are unable to 
meet with them in-person for their clinic appointment, a screening appointment will 
be made outside of the office visit. FAPD diagnosis will be confirmed with the 
patient’s provider using the EMR and/or direct communication. A member of the 
research staff will explain the study to the patient and primary caregiver in greater 
detail.  Participants will be assured that their usual medical care will not be affected 
based upon whether or not they choose to participate. Participants and caregivers will 
be informed about the importance of confidentiality and will agree that they will not 
share any personal or health information about other study participants.  If interested, 
the patient and their caregiver will complete the consent, and assent.  All consent and 
assent forms will be stored in a secure location within the Secchia Center. 
Screening 
Patients are consented and screened within the same study visit. Immediately 
upon providing assent/consent, participants will complete the Screen for Child 
Anxiety and Related Disorders (SCARED), the Functional Disability Inventory 
(FDI), the Numeric Rating Scale (NRS) for pain intensity, and the Children’s 
Depression Inventory (CDI) before leaving their GI clinic appointment.  If the 
patient does not qualify based on their scores from the anxiety measure, they will not 
be administered the remaining screening measures. For potentially eligible 
participants, the participants and families will answer questions to ensure the child 
can safely enter the scanner and undergo fMRI and study procedures.  Additionally, 
study staff will complete the ROME IV FAPD diagnostic checklist with the 
participant’s gastroenterology provider to ensure that the child meets FAPD criteria. 
These procedures will ensure that eligibility is determined prior to assessment or 
randomization.  Participants who can complete the fMRI protocol procedures, 
evidence clinical anxiety, do not evidence severe depressive symptoms (T score ≥ 
80) and meet FAPD criteria will be considered eligible for participation. If eligible, 
we will inquire whether females have achieved menarche.  If yes, we will query the 
date of their last menstrual cycle and inform them that we will schedule the 
neuroimaging on a date when they are not having pain due to menstruation. If the 
patient expresses interest in the study after being introduced to the study in-person 
by their GI medical provider and research staff are unable to meet with them in-
person for their clinic appointment, a screening appointment will be made outside of 
the office visit. FAPD will confirmed with the patient’s provider using the EMR 
and/or direct communication.  

 
Neural Mechanisms of Treatment 
22 of 45 
Response Protocol, Version 6.0 
 
 
Screening Measures: 
• Screen for Child Anxiety Related Disorders, SCARED 51. Child reported anxiety 
in the past 3 months; ≥25 is clinical anxiety. This measure has been 
recommended for use by the American Academy of Pediatrics 52 and has been 
validated in pediatric chronic pain 51,53,54 and used in pediatric FAPD 
samples20,28. 
• Rome IV FAPD Diagnosis Checklist (physician report).  FAPD criteria based on 
the Rome IV.  FAPD include irritable bowel syndrome (IBS), functional 
dyspepsia, abdominal migraine, and FAPD- not otherwise specified.  To meet 
criteria for FAPD, a child must endorse continuous or episodic pain at least 4 
times in a month that do not exclusively occur during a physiological event 
(e.g., eating, menses) for a periods of 2 months or longer that cannot be fully 
explained by another medical condition after appropriate evaluation.  This 
questionnaire will allow us to group our sample into specific diagnostic 
subtypes of FAPD.   
• MRI Safety and Screening.  Research staff to determine if patient can safely 
complete fMRI protocol. 
• Children’s Depression Inventory 2 (CDI)55.  A validated and reliable measure of 
depressive symptoms in the past 2 weeks. 
• Menstruation Query.  Female participants will be asked if they have achieved 
menarche.  If participants indicate that they have, we will query the date of their 
last menstrual cycle and inform them that we will schedule the neuroimaging on 
a date when they are not having pain due to menstruation.  This may include 
pain that a child reports occurs in the days prior to menstruation if applicable. 
• Functional Disability Inventory (FDI)56. 15-item measure of physical/daily 
function in last few days.  This measure has been validated in pediatric chronic 
pain 57 and used in pediatric FAPD samples20,28. 
• Numeric Rating Scale (NRS)71 for pain.  Average, highest, and lowest pain 
levels in the past week will also be assessed. 
 
 
6.2.2 Enrollment, Baseline, and Randomization 
Enrollment 
A research team member will attend GI clinics at Helen DeVos Children’s 
Hospital when possible.  They will consult with a physician about whether attending 
patients may meet criteria for the study.  If patients potentially meet criteria and are 
interested, our research team will approach/contact patients after the physician has 
introduced the study.  For those families who may be interested/potentially eligible 
but are not available at the time of their medical visit, a follow up visit will be 
scheduled with the patient/family to determine eligibility. 
Enrollment is defined as the date all of the screening criteria are met and the 

 
Neural Mechanisms of Treatment 
23 of 45 
Response Protocol, Version 6.0 
 
individual agrees to participate.  This date will be recorded on a CRF.   
Baseline Assessments 
Qualifying participants and their respective caregivers will be scheduled to complete an in-
person baseline assessment.  Participants will complete additional study measures.  Caregivers 
will complete several measures pertaining to their child’s pain and child’s worries in addition to 
a measure of their own psychological symptoms.  Participants and caregivers will be given the 
option to either complete these measures during their baseline assessment visit or before this visit 
using their own electronic device (to reduce the length of the in-person visit).  Participants will 
enter the MRI scanner, where scans of brain structures and cerebral blood flow will be performed 
while participants provide current pain ratings. Participants will then exit the scanner to undergo 
the WL-SPT, a validated non-invasive procedure for youth ages 8-16 to create visceral pain 
sensations (40). This task has also been used in adults with FAPD70. 
 Participants will ingest water until they have achieved complete fullness 
eliciting discomfort (~5 minutes). Then, participants will re-enter the scanner and 
resume functional imaging.   
• 
Imaging:  Pre-WL-SPT.  During imaging, the first 10 minutes will consist 
of positioning the participant and collecting structural images.  BOLD and 
PCASL acquisitions will be obtained.  Post-WL-SPT. Following the WL-SPT, 
BOLD AND PCASL acquisitions will also be obtained.  
Participants will then be randomized within one week of their baseline 
assessment.  Approximately one week after randomization, participants will complete 
either 6 weekly sessions of ADAPT or 6 weeks of waitlist.   
Families will receive payment for this study in the form of an Amazon gift card. 
We will reimburse participants $100 for each assessment visit (baseline and post 
assessment for up to $200 total).   
 
Baseline participant measures: 
• Functional Disability Inventory (FDI)56. 15-item measure of physical/daily 
function in last few days.  This measure has been validated in pediatric chronic 
pain 57 and used in pediatric FAPD samples20,28. 
• Visual Analog Scale (VAS)58 for pain.  Average, highest, and lowest pain levels 
in the past week will also be assessed. 
• Numeric Rating Scale (NRS). Administered only during instances where the 
electronic or physical VAS slider cannot be used (e.g. technical difficulties).   
• Self-Efficacy Pain Scale- Child Version59.  A valid and reliable measure of child 
self-efficacy when in pain. 
• Affective Reactivity Index (ARI)- Self- Report60.  A valid 7-item measure of 
irritability in the last 7 days. 
• Pain Catastrophizing Scale for Children61. A valid measure of maladaptive 
beliefs about pain and feelings experienced when in pain. 
• NIH PROMIS Pain Interference62.  A valid measure of functional impairment 
due to pediatric pain in the past 7 days.  
• Peterson Pubertal Developmental Scale (PDS)63. A valid and reliable pubertal 
status assessed via clinician interview. 

 
Neural Mechanisms of Treatment 
24 of 45 
Response Protocol, Version 6.0 
 
• Menstruation Query.  Female participants will be asked if they have achieved 
menarche.  If participants indicate that they have, we will query the date of their 
last menstrual cycle, and inform them they we will schedule the neuroimaging 
on a date when they are not having pain due to menstruation.  This may include 
pain that a child reports occurs in the days prior to menstruation if applicable. 
• Other Pain.  Participants will be queried about other pain sources besides 
abdominal pain.  
• Edinburgh Handedness Inventory64.  A validated measure that assesses the 
dominance of a person’s right or left hand in everyday activities.  For the 
purposes of this study, one original item was removed (striking a match) given 
our pediatric sample. 
• Child COVID-19 Related Distress.  An item assessing the child’s distress in 
relation to the COVID-19 pandemic.   
 
Baseline caregiver measures: 
• Child Pain History & Sociodemographic Factors. Demographic factors, 
school absences, pain duration, location, and concomitant psychological 
treatments 
• Depression Anxiety Stress Scales65.  A validated and reliable measure of 
parent depression, anxiety, and tension/stress. 
• Visual Analog Scale (VAS)58.  Parent reported average pain experienced by 
their child over the past 2 weeks.  
• Numeric Rating Scale (NRS). Administered only during instances where the 
electronic or physical VAS slider cannot be used (e.g. technical difficulties).   
• Parent Pain Catastrophizing Scale (PCS)66. Validated measure of 
maladaptive beliefs about child pain. 
• Screen for Child Anxiety Related Disorders- Parent Report, SCARED51.  
Parent-reported child anxiety symptoms over the past three months; ≥25 is 
clinical anxiety.  This measure has been used in pediatric FAPD samples20,28. 
• Functional Disability Inventory (FDI)- Parent Report56. 15-item measure of 
child physical/daily functioning in the past few days.  This measure has been 
used in pediatric FAPD samples20,28. 
• Self-Efficacy Chronic Pain Scale- Parent Version59.  Parent reported child 
self-efficacy during pain.  This measure has been validated.  
• Affective Reactivity Index (ARI)- Parent- Report60.  A valid and reliable 7-item 
measure of child irritability. 
• Concomitant Medication Form.  Concomitant medication information 
(medication name, reason for taking, unit, frequency, route, etc.) and therapies 
will be obtained via chart review prior to the baseline visit.  Study staff will 
confirm with caregivers that the information is correct and up to date at the 
baseline and post assessment visits.  Any changes in medication from baseline 
to post assessment will be documented. 
• COVID-19 Exposure and Family Impact Survey (CEFIS)67. A measure from 
the Center for Pediatric Traumatic Stress to capture the impact of the COVID-
19 pandemic on families and caregivers. 

 
Neural Mechanisms of Treatment 
25 of 45 
Response Protocol, Version 6.0 
 
• Adverse Childhood Experiences (ACEs)68. A valid, 9-item measure used by 
the National Survey of Children’s Health that assesses for adverse events 
occurring in childhood before the age of 18.   
 
Measures administered during fMRI: 
• Pain Intensity and Unpleasantness Visual Analog Scales (VAS)58,69. Pain 
intensity is associated with nociceptive processing and is a common measure 
of treatment response26. Pain unpleasantness is related to affective network 
activity35, and is highly responsive to meditation35.  
• State Anxiety (VAS)70. 0-10 self-report of how anxious the child is feeling in 
the present moment. 
• Fullness Rating Scale45. Youth will be asked to indicate how full they felt 
after water ingestion by selecting from images representing different levels of 
fullness, from empty (coded 0) to full (coded 4).  
 
Randomization 
Following the baseline visit, patients will then be randomized to either the ADAPT 
group or a waitlist control group (each approximately six weeks in duration) and will 
be informed of group assignment within a week of their baseline assessment, and will 
begin ADAPT/waitlist approximately one week after group assignment (with up to 
three weeks allowed to begin ADAPT).  For additional details, see 9.2 Sample Size 
and Randomization. 
 
6.2.3 Blinding 
• Procedure for retaining the blind.  Blinding of study personnel will be 
employed when possible (Table 1).  Of note, our study statistician (Dr. 
Mathew Reeves) will only have access to subject IDs and Treatment A and 
Treatment B.  He will generate monitoring reports for closed sessions based 
only on Treatment A and Treatment B.  If there is an issue of serious concern 
(e.g., safety issues in one arm, differential attrition etc.) that requires complete 
unblinding, Dr Reeves will identify another statistician to run the unblinded 
reports.  Dr. Reeves will also complete final analysis only by Treatment A 
versus B and the code will be revealed only after the data has been analyzed. 
Furthermore, the PI (Cunningham) will be blinded to group assignment.  
However, Dr. Barber Garcia will not be blinded to group assignment as study 
interventionist and to ensure the safety of participants and the integrity of the 
study.  It is critical for Dr. Barber Garcia (a licensed clinical psychologist) to 
be aware of participants who are randomized to the ADAPT intervention to 
perform her role (and in the case of a back-up provider) to ensure patient 
safety (e.g., risk assessment for suicidal ideation, trauma/abuse, etc.) during 
the  study. The PI (Cunningham) and study mentors (Zhu, Arnetz) will have 
no access to post-assessment data by group assignment until after the 
completion of the study. 
• Individual authorized to break the blind.  Dr. Barber Garcia  will be 
authorized to break the blind.  She will not be blinded to group assignment 

 
Neural Mechanisms of Treatment 
26 of 45 
Response Protocol, Version 6.0 
 
and therefore can determine if the study team’s blind should be broken in 
cases where a patient’s safety is in question.  Dr. Barber Garcia’s extensive 
experience as a pediatric psychologist make her appropriately equipped to 
manage this responsibility. 
• Circumstances for breaking the blind.  The blind will be broken at the 
clinical discretion of Dr. Barber Garcia.  Circumstances for breaking the blind 
may include cases when a patient’s safety is at risk, differential attrition, or if 
a patient’s symptoms remarkably worsen throughout treatment.  
• Procedure for breaking the blind.  If the blind needed to be broken, Dr. 
Barber Garcia would communicate with our local IRB, any NCCIH members 
involved in the study, and involve our study team, included but not limited to 
the PI (Cunningham), co-mentors (Zhu, Arnetz), the biostatistician (Reeves), 
and the outcome accessors (post-baccalaureate research coordinator).    
 
Table 1.  Blinding of Study Personnel. 
 
Stake holder 
Intervention group 
assignment 
Primary Mechanistic 
Outcome Measure 
Clinical/ Functional 
Outcome Measure 
Study subjects 
Subjects will be aware 
if they are randomized 
to ADAPT versus 
waitlist. 
The subjects will 
participate in the 
collection of this data 
but will not be involved 
in the interpretation of 
the data or the analysis 
of the results. 
Subjects will provide 
such data.  As such, they 
will be aware of their 
own responses on 
clinical/functional 
outcome measures. 
Interventionists 
licensed clinical 
psychologist 
(Barber Garcia), 
backup 
interventionist  
The interventionist will 
know if participants 
are randomized to the 
intervention group. 
The interventionist will 
not be involved in 
analyses. 
The interventionist will 
not be involved in 
analyses.  
Outcome Assessors 
(post-baccalaureate 
research coordinator)  
Outcome assessors will 
be blinded as to group 
assignment.  
The outcome assessor 
will be involved in the 
collection of such data, 
but will not be involved 
in the interpretation and 
analysis of results. 
The study coordinator 
will serve as an outcome 
assessor.  However, data 
will be collected directly 
from participants using 
online forms. In 
addition, the study 
coordinator will only 
access/manage post-
assessment data that has 
been de-identified (with 
group assignment 
removed).   
Data 
Analysts/Statistician 
(Reeves) 
The study statistician 
will be blinded to the 
group assignment. 
The study statistician 
will be blinded until the 
completion of this 
study  
The study statistician 
will generate reports and 
submit data as requested 
by NCCIH or the IMC 

 
Neural Mechanisms of Treatment 
27 of 45 
Response Protocol, Version 6.0 
 
 
6.2.4 Adverse Event Queries/Additional Measures 
ADAPT Session 2: 
Participants will be queried about any experienced adverse events during their second 
session of ADAPT (if randomized to ADAPT treatment group).  This form will also 
be administered at post assessment.  For those randomized to waitlist, they will 
complete this form at post assessment, ADAPT sessions 2 and 6 (if they opt to 
complete ADAPT). 
• Adverse Event Query Form.  A form to be completed via clinician interview 
assessing for adverse events experienced by participants.   
 
ADAPT Session 6 
During the last session of ADAPT, participants (in both the ADAPT treatment and 
waitlist control groups) will be queried as to whether they found the ADAPT 
intervention helpful when coping with distress related to COVID-19.  
• Child COVID-19 Related Distress Coping.  An item assessing whether the 
intervention was helpful in improving the child’s coping with distress in 
relation to the COVID-19 pandemic. 
 
ADAPT measures for those completing the intervention after waitlist (i.e., after post 
assessment) 
Those randomized to the waitlist condition will be eligible to receive ADAPT after 
their post assessment.  Waitlist control participants who choose to complete the 
ADAPT program after their post assessments will complete brief measures (e.g., 
anxiety, disability, pain) and will be queried about adverse events during the second 
session of ADAPT and via phone or videoconferencing following their last ADAPT 
session.   
• Screen for Child Anxiety Related Disorders, SCARED51 
• Functional Disability Inventory (FDI)56 
• Visual Analog Scale (VAS)58 for pain 
for the duration of the 
study.  
Principal 
Investigator 
(Cunningham) 
and Study 
Mentors (Zhu, 
Arnetz) 
The PI will be blinded 
to intervention group 
assignment.  
The PI and her 
mentorship team will 
be blinded to post-
assessment data results 
until after the 
completion of the 
analysis.  She will 
participant in 
processing/management 
of fMRI data without 
knowledge of group 
assignment.  
The PI and her 
mentorship team will be 
blinded to post-
assessment results by 
group assignment until 
after completion of the 
analyses. 

 
Neural Mechanisms of Treatment 
28 of 45 
Response Protocol, Version 6.0 
 
• Child COVID-19 Related Distress Coping 
• Numeric Rating Scale (NRS)71 for pain (if VAS not obtained) 
• Adverse Event Query Form.   
 
 
6.2.5 Completion/Final Evaluation 
A post assessment (including fMRI) will be completed for all participants 
approximately one week after completion of treatment or waitlist.  Participants will 
complete the same assessment measures and procedures as administered at the 
baseline assessment in addition to measures that were administered at screening.  
Upon completion of this visit, participants will receive a $100 gift card (Amazon; 
described in further detail in 6.2.2. Enrollment, Baseline, and Randomization). 
 
Post assessment participant measures: 
• Screen for Child Anxiety Related Disorders, SCARED51 
• Functional Disability Inventory (FDI)56 
• Visual Analog Scale (VAS)58 for pain  
• Numeric Rating Scale (NRS)71 for pain (if VAS not obtained) 
• Rome IV FAPD Diagnosis Checklist  
• Children’s Depression Inventory 2 (CDI)55 
• Self-Efficacy Pain Scale- Child Version59 
• Affective Reactivity Index (ARI)- Self- Report 60 
• Pain Catastrophizing Scale for Children61 
• NIH PROMIS Pain Interference 62 
• Peterson Pubertal Developmental Scale (PDS)63 
• Menstruation Query  
• Other Pain  
• Edinburgh Handedness Inventory 64 
• Adverse Event Query Form  
• Child COVID-19 Related Distress 
 
Post Assessment caregiver measures: 
• Child Pain History & Sociodemographic Factors.  
• Depression Anxiety Stress Scales65.   
• Visual Analog Scale (VAS) 58.  
• Numeric Rating Scale (NRS)71 for pain (if VAS not obtained)  
• Parent Pain Catastrophizing Scale (PCS)66.  
• Screen for Child Anxiety Related Disorders- Parent Report, SCARED51.   
• Functional Disability Inventory (FDI)- Parent Report56 
• Self-Efficacy Chronic Pain Scale- Parent Version 59 
• Affective Reactivity Index (ARI)- Parent- Report 60 
• 
Concomitant Medication Form 
• 
COVID-19 Exposure and Family Impact Survey (CEFIS) 

 
Neural Mechanisms of Treatment 
29 of 45 
Response Protocol, Version 6.0 
 
• 
Adverse Childhood Experiences (ACEs) 
 
 
Measures administered during fMRI: 
• Pain Intensity and Unpleasantness Visual Analog Scales (VAS) 58,69State 
Anxiety (VAS)70 
• Fullness Rating Scale45 
7. SAFETY ASSESSMENTS  
Participant safety will be monitored once an individual is enrolled in the study.  Potential risks and 
adverse events are listed below: 
 
• Emotional Distress. Given the risk of elevated anxiety and mood problems in 
individuals with FAPD, some responses on these measures may reveal anxiety, 
depressive affect, and/or suicidal thoughts.  Youth may also find some questions 
embarrassing or uncomfortable to talk about.  To help reduce potential discomfort, the 
research protocol includes standardized measures.  Suicidal ideation may be directly queried 
during the depressive symptom screener.  Participants’ responses will be monitored to assess 
any safety issues such as suicidal ideation.  Although ADAPT online modules do not 
specifically elicit responses that may reveal depression/suicidal ideation, such symptoms 
(anxiety and mood) may arise during ADAPT.  A safety assessment will occur via 
telephone if indicated.  ADAPT is an evidence-based intervention and has not been found 
to be associated with any adverse effects. All participants will continue to receive their 
medical care as usual during the study.   
In the event that a participant reveals severe depressive symptoms or suicidal 
ideation, the following steps will be taken: (1) Dr. Barber Garcia, the co-investigator 
(licensed clinical psychologist) will address these concerns, (2) a professional and 
confidential risk assessment, including detailed information about suicidal ideation, intent 
and/or plans, access to means to hurt themselves, major stresses, availability of social 
supports, access to treatment, and plans for safety will be discussed in detail with the 
participant and their parent. The assessment will be conducted by the interventionist 
(Barber Garcia) and (3) a referral to the ER and/or a referral to the Psychiatry Division or 
an outpatient Psychology clinic, as appropriate, will be made. If the family refuses to 
follow through on the aforementioned recommendations, we will contact the appropriate 
authorities as warranted to ensure the safety of our participants. All actions will be 
documented. 
Of note, all participants will be carefully screened for depressive symptoms and 
suicidal ideation using a validated measure prior to engaging in the fMRI portion of the 
study.  Those who have high levels of depression and/or active suicidal ideation (T score 
≥ 80) will be referred for mental health care and will not be eligible for the study. 
During assessment and/or treatment procedures, participants may reveal 
experiences of abuse to the assessor or study therapist. In the event that the project staff 
becomes aware of suspected or actual abuse or neglect, Dr. Barber Garcia will be 
notified. A report will be immediately filed with the appropriate state agency when 
necessary. The informed consent/assent procedures specify that confidentiality will be 

 
Neural Mechanisms of Treatment 
30 of 45 
Response Protocol, Version 6.0 
 
breached if research staff learn that a minor is the victim or suspected victim of abuse or 
neglect.   
 
• fMRI related Risks.  fMRI has been approved for routine research and clinical applications 
and does not pose any known risk to participants. There are no known risks from exposure to 
the magnetic fields and radio waves used during fMRI data collection. However, it is not 
assured that harmful effects will not be recognized in the future. A known risk is that strong 
magnetic fields attract iron or steel metal objects, thus posing a safety risk. Prior to 
participation in the fMRI scans, participants will be given questionnaires to determine if they 
if they are eligible to complete the fMRI procedure. If they have metal objects in their bodies, 
they will be excluded from participating in the study. In addition, any removable metal (e.g., 
glasses, watch, clothes with zippers) on the day of imaging will be removed before the 
participant enters the fMRI rooms.  
 
In addition, it is possible that participants may feel uncomfortable or confined 
once inside the imaging machine.  Any participant who experiences discomfort or 
exhibits distress will be monitored visually and via microphone to ensure they are 
tolerating the procedure. In addition, an alarm system is used to monitor the temperature 
and air. As the scanner is very loud, participants’ hearing will be protected with noise-
reducing headphones specifically designed for use in the fMRI scanner. Finally, as 
participants are lying in a supine position, the child may at times feel sleepy or bored. If 
participants express a desire to leave the machine, either temporarily or permanently at 
any point, they will be removed immediately.  
 
• Time Commitment and Fatigue. The assessment visits will require approximately a two 
hour time commitment (clinical measures/fMRI visit), which may cause slight 
discomfort. Assessors will be trained to assess fatigue and will give participants a 5-10 
minute break if needed. For ADAPT sessions, there should be minimal discomfort due to 
the shorter length of these sessions (60 minutes or less).   
Participants will be informed of their right to refuse to participate in any part of the 
data collection and will be given the phone numbers of the Principal Investigator as well as 
the Institutional Review Board of MSU in the event that they desire further information or 
would like to issue a formal complaint.  
 
• The water loading task is a non-invasive and validated procedure for induction of 
abdominal discomfort in youth with FAPD. The procedure was validated by Walker and 
colleagues (2006). Children are, by design, likely to experience abdominal discomfort 
during the task.  The procedure produces symptoms similar to, but less intense, than those 
naturally experienced by children with FAPD. As noted by the authors, “This level of 
discomfort was acceptable to children and their parents” (Walker et al., 2006, p. 710). It 
will be explained to families that participation is completely voluntary and that they may 
drop out of the study at any time, for any reason, and that this will not affect the child’s 
medical care.  
 
 
There is a small risk of vomiting if children consume water beyond the point of 
feeling completely full. During the water load period, children will be asked to rate their 
fullness at 5-minute intervals – to make sure they do not push themselves to consume 
water beyond the point of perceived fullness. One child (out of 230) in Walker’s original 

 
Neural Mechanisms of Treatment 
31 of 45 
Response Protocol, Version 6.0 
 
study vomited following water ingestion. “During debriefing, the child reported that he 
had pushed himself to drink water beyond the point of feeling full. In subsequent 
administrations of the water load, children were cautioned that vomiting was a possibility 
if they continued to consume water beyond the point of feeling completely full,” (Walker 
et al., 2006; p. 707). We will caution children similarly in our study. 
 
 
Another unlikely concern is exceptionally rare occurrence of water toxicity. To 
eliminate this risk, a daily fluid maintenance formal will be used based on their weight to 
determine the maximum fluid value for each child.  The amount of water will be capped 
at that value (up to 1.5 L).  Further, allowing a specific time frame (up to 15 minutes) 
creates conditions to make water toxicity impossible. 
 
 
Study staff will be on hand to ensure the participant stops drinking water after a 
complete sensation of fullness.   We will contact the on-call GI physician at HDVCH in the 
event of any questions/concerns that may need immediate attention. In addition, participants 
will be instructed that they are free to terminate the task at any time. 
 
Risk/Benefit Analysis:  The risk/benefit ratio is favorable for this study and adverse events are 
not anticipated. Overall, the study does not significantly increase the participants’ risk of harm 
beyond those risks that are inherent in ordinary daily living.  All study procedures can be 
terminated immediately. In addition, all participants will be able to receive an evidence-based 
intervention (ADAPT).  Preliminary data suggests this intervention has a positive impact on 
symptoms associated with FAPD and comorbid anxiety.  Information obtained from this study 
will be valuable for refining behavioral interventions for the treatment of youth with chronic pain 
and comorbid anxiety. 
7.1 
Specification of Safety Parameters 
We expect no adverse events based on prior research we’ve conducted.  
However, precautions will be taken to ensure patient safety as detailed above.   
The imaging protocol used in this study includes only the minimum MR 
scanning needed to execute the tasks and paradigms for the research project. No 
report will be generated or supplied to the research participants. However, all scans 
performed for this project will be reviewed for gross abnormalities by a radiologist to 
be named prior to any subject enrollment.  All research studies at SH have a 
radiologist assigned to read images.  We will work with Dr. Mark DeLano, Director 
for the Division of Radiology and Biomedical Engineering at MSU, and Medical 
Director of Adult Radiology at SH to assure similar processes are executed for our 
study.  Moreover, our neuroimaging mentor Dr. David Zhu will provide oversight and 
has established relationships with the SH radiology team and will help ensure the 
safety of our participants and the clinical procedures.  . Although no diagnosis will be 
made, in the event that abnormal findings are identified, the investigator 
(Cunningham) will be informed and will assume responsibility for notifying the 
participants. 
In the case that abnormal findings are identified, the participant’s physician 
(identified via the patient’s electronic medical record) will be contacted by the PI 
(Cunningham), or a designee of the PI (such as the research coordinator), and the 
findings will be reported. A report generated by the identified radiologist will be 
made available to the physician if requested. 

 
Neural Mechanisms of Treatment 
32 of 45 
Response Protocol, Version 6.0 
 
For clinically significant findings of neuroimaging, the participant may choose 
to obtain appropriate clinical care or seek a second opinion. This might change the 
participant's insurability and employability as it relates to the clinical finding only. 
Seeking care may place the participant at risk for unforeseen medical costs, 
particularly for conditions that are benign.  However, the presumption is that 
detection of a potentially clinically significant finding will prove to be beneficial.  In 
the event of incidental findings, the neuroimaging mentor (Zhu) will be consulted to 
determine if the abnormal finding precludes participation.   
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
We anticipate that ADAPT will be associated with low risk based on our prior 
research50.  In addition, we will carefully monitor for adverse events, including a 
specific form administered to participants (post-assessment, ADAPT session 2, and, 
for those completing ADAPT after the waitlist period, session 6.)  
7.3 
Adverse Events and Serious Adverse Events  
An adverse event (AE) is generally defined as any unfavorable and unintended 
diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or 
disease which either occurs during the study, having been absent at baseline, or if 
present at baseline, appears to worsen. Adverse events are to be recorded regardless 
of their relationship to the study intervention.   
A serious adverse event (SAE) is generally defined as any untoward medical 
occurrence that results in death, is life threatening, requires inpatient hospitalization 
or prolongation of existing hospitalization, results in persistent or significant 
disability/incapacity, or is a congenital anomaly. 
Adverse events and unanticipated problems will be carefully monitored and 
documented at each study visit.  During all phases of the study (i.e., assessment and 
treatment), adverse events and unanticipated problems (whether or not they are 
thought to be study-related) will be monitored and documented in several ways.   
1)  During screening, assessments, and for those completing the ADAPT 
intervention, the interventionist (Barber Garcia) will maintain an individual log to 
record any increases in pain or mood-related problems during the study. Dr. Barber 
Garcia will review these logs each week.  
2)  In addition, the study team will have quarterly meetings to monitor the 
progress of the study, the integrity of the treatment, discuss the need for any protocol 
refinements, and conduct regular safety monitoring checks of adverse events and 
unanticipated problems.  Severe depressive symptoms or active suicidal ideation will 
be recorded as an adverse event.   
3) Any adverse events/unanticipated problems reported during the study including 
during the assessment (e.g., measures and fMRI/water loading) or during ADAPT 
sessions will be immediately brought to the attention of the study team. The IRB 
requires yearly renewal of study protocols, which provides additional monitoring of 
participant safety.  The study team will review study data to ensure safety compliance 
and proper reporting to the IRB. 

 
Neural Mechanisms of Treatment 
33 of 45 
Response Protocol, Version 6.0 
 
7.4 
Reporting Procedures 
Case report forms for AEs and SAEs have been developed.  An AE 
documentation form will be completed by a clinician at the second ADAPT session 
and during the post assessment.  For those randomized to waitlist control who are 
completing ADAPT after the post assessment, they will complete this information 
during session 2 and 6 of ADAPT in addition to the post-assessment query.  The form 
documents whether or not an adverse event has occurred and throughout the trial if 
any AEs/SAEs are spontaneously reported by participants. AEs will be reported by 
body system and rated by level of severity (mild, moderate, severe, life-threatening).  
The primary study team will meet regularly to monitor the progress of the study and 
safety of participants in blinded fashion.  Reportable events will also be recorded in a 
separate study database. 
For any adverse event meeting the definition of “severe” or “life threatening,” the 
study interventionist (Barber Garcia) and research coordinator will communicate with 
one another to  complete a “Serious Adverse Event” reporting form within one 
working day. Any severe or life threatening adverse event report will be sent to the 
IMC and the IRB will be notified.   
To satisfy the requirement for prompt reporting, unanticipated problems will be 
reported using the following timeline:   
• Unanticipated problems that are serious adverse events will be reported to the 
IRB, Independent Safety Monitor(s), and NCCIH within 7 days of the 
investigator becoming aware of the event.  
• Any other unanticipated problem will be reported to the IRB, Independent Safety 
Monitor(s), and NCCIH within 14 days of the investigator becoming aware of 
the problem. 
7.5 
Follow-up for Adverse Events 
A study team member will provide referrals, as appropriate, for treatment needs 
resulting from any adverse events or unanticipated problems.  In the event of any 
medical concerns that arise, the research staff will contact the on-call GI physician at 
HDVCH. 
7.6 
Safety Monitoring  
The team will also report any significant study-related or unanticipated adverse 
events to the Institutional Review Board and to the study sponsor based upon 
institutional and sponsor guidelines. In addition, there are three Independent 
Monitoring Committee (IMC) members with expertise in radiology, psychiatry, and 
biostatistics who will assess the safety and study-related concerns. Two IMC 
members have expertise in pediatric research. Specifically, the member with expertise 
in biostatistics has a program of research pertaining to the assessment and 
psychological treatment of depression in Hispanic adolescents (Dr. Brincks).  The 
member with expertise in psychiatry (Dr. Familiar) has a program of research on the 
identification of risk factors and outcomes in children and adolescents with chronic 
health conditions including HIV. Given that this study investigates the intersect of 

 
Neural Mechanisms of Treatment 
34 of 45 
Response Protocol, Version 6.0 
 
pediatric chronic health conditions and mental health functioning, this experience and 
expertise is highly complementary.  In addition, our radiologist member is well suited 
to assess MRI related issues/concerns.   Any reportable events that occur (which 
includes the occurrence of any safety issues related to the scanning procedures or to a 
breakdown of confidentiality) will be reported to the IRB immediately.  We will also 
regularly communicate with NCCIH regarding safety monitoring practices. 
8. INTERVENTION DISCONTINUATION  
• Criteria for discontinuing intervention:  A participant will be considered discontinued 
if they explicitly state that they would like to withdraw from the research study and cease 
participation in the intervention or if study staff is unable to contact the child or their 
guardian after 2 weeks. 
• Possible reasons for discontinuation:  Based on prior research, common reasons for 
discontinuing the ADAPT intervention include scheduling difficulties and the 
participants’ lack of proximity to the medical center.  It will be continually reinforced 
throughout the intervention that participation is optional.  Families will be informed if 
new treatments become available.  The intervention will be discontinued if a participant 
experiences an increase in distress and pain symptoms throughout the intervention, or if 
the interventionist (Barber Garcia) determines that a participant’s presentation warrants 
more targeted care outside of what the intervention offers. Given Dr. Barber Garcia’s 
expertise in pediatric pain psychology, she is well-suited to provide clinical oversight to 
make this determination. The intervention will be discontinued for all participants in the 
event of a study closure by the institute. 
• Participation will be discontinued at any time at participant or parent request. Participants 
will continue to be followed with their permission if study intervention is discontinued.  
Should a randomized participant prematurely discontinue participation in the study, study 
measures and endpoints will continue to be collected if possible.  Of note, based on prior 
research, if a participant discontinues the behavioral intervention it is unlikely that they 
will be retained for subsequent assessment visits.  However, every effort will be made to 
collect endpoint and study measure data. 
9. STATISTICAL CONSIDERATIONS  
9.1 
General Design Issues  
The stastistical hypotheses: 
Aim 1. Left AMY-PFC functional connectivity will be significantly diminished (i.e., 
evidence of decreased hyperconnectivity) during the water load symptom provocation 
task (WL-SPT) post ADAPT vs. waitlist. 
Aim 2. Brain activations associated with cognitive (PFC), affective (pgACC, AMY), 
and visceral afferent (INS, thalamus, aMCC, S1 & S2) pain will significantly be more 
diminished after ADAPT vs. waitlist. 
Exploratory Aim.  Changes in functional connectivity and brain activations following 
ADAPT will correspond to reductions in pain (intensity and unpleasantness) and 
anxiety ratings. 

 
Neural Mechanisms of Treatment 
35 of 45 
Response Protocol, Version 6.0 
 
 
The choice of study design (blinded clinical trial) will enable us to answer these 
research questions. 
 
Primary and secondary outcome measures are obtained from neuroimaging data.  The 
brain regions selected have been shown in prior literature to be related to chronic pain 
and response to psychological intervnetions for the management of chronic pain 
conditons48,71. 
9.2 
Sample Size and Randomization 
We’ve used the following tool 
(http://neuropowertools.org/neuropower/neuropowerinput/) to conduct sample size 
calculations for the fMRI portion of the study.  Power calculations were based on 
prior studies conducted by the PI’s previous study mentor, who collected functional 
connectivity data 1) pre and post psychological therapy for pediatric pain (migraine), 
and 2) comparing individuals with pediatric pain (migraine) to healthy controls.  
While these groups are not synonymous with those proposed in the current study 
(which aims to compare youth with FAPD who have received psychological therapy 
for pain and anxiety to those in a waitlist control condition), this preliminary data 
yields meaningful information by which we can estimate the power required for the 
proposed investigation.  The power calculations and sample size requirements are 
detailed below: 
For within group changes, we relied on the pre/post data following a 
psychological therapy for pediatric pain (migraine). Here we found that a total sample 
size of 34 would be required for power of .8 and p < 0.05.  For between group 
changes, we utilized data comparing youth with chronic pain (migraine) to healthy 
controls.  Based on these data, a total of 35 subjects are required for power of .8 and p 
< 0.05.  All comparisons were calculated using z-transformed statistical images of the 
whole brain, a cluster-forming threshold of z > 3.1 and p < 0.05, and a Gaussian 
Random Field theory-based approach for multiple comparisons. For these complex 
data, statistical power is defined as an 80% probability of correctly detecting an active 
peak for all peaks above the cluster-forming threshold. We note moderate to large 
effects observed for within and between group studies; thus, a total sample size of 40 
ensures were are adequately powered to observe at least moderate (e.g. mean effect 
size difference of 0.4 or greater) effects. 
 
Treatment Assignment Procedures 
Randomization will be generated using PROC PLAN in SAS 9.3 by a 
biostatistician who is part of the University of Cincinnati’s Center for Clinical and 
Translational Science and Training (CCTST).  The CCTST biostatistician will not 
have access to the data. This data management support service will generate 
randomization and will assign a Treatment A/Treatment B designation.  The 
randomization schedule and code sheet will be held confidentially by a senior Clinical 
Research Manager in the study mentor’s (Dr. Arnetz) lab, and the study 

 
Neural Mechanisms of Treatment 
36 of 45 
Response Protocol, Version 6.0 
 
interventionist (Dr. Barber Garcia) will contact the Clinical Research Manager to get 
the next assignment when a participant is enrolled in the study.  
Gender and age will be used as blocking variables in randomization.  Specifically, 
there will be four randomization tables for gender (male and female) by age (younger 
i.e., 11-13 years of age and older i.e., 14-16 years of age) combination:   
• 11 ≤ Age < 14, Female 
• 14 ≤ Age < 17, Female 
• 11 ≤ Age < 14, Male 
• 14 ≤ Age < 17, Male 
 
Patients will be randomized to either ADAPT or WL.  A separate randomization 
list will be produced for each of the four (4) blocks – Age x Sex.  Per study protocol, 
a list of 10 treatment / control assignments will be produced per group.  Within each 
group, a completely randomized design will be applied to allocate ADAPT or WL. 
The test randomization and final randomization will require four seed numbers, 
one for each block size. The seed numbers below are for illustration only and will not 
be used. 
• 11 ≤ Age < 14, Female: Seed = 111111 
• 14 ≤ Age < 17, Female: Seed = 222222 
• 11 ≤ Age < 14, Male: Seed = 333333 
• 14 ≤ Age < 17, Male: Seed = 444444 
 
The independent statistician will select seed numbers and will not share those 
final seed numbers with the project statistician (Reeves) nor other members of the 
project team.  The randomization identification number (rand_id) will be comprised 
of 4 digits.  The first digit will correspond to the blocks and the remaining 3 digits 
will be in sequential order, as listed below.  
• Block 1: 11 ≤ Age < 14, Female. ID numbers 1001-1010 
• Block 2: 14 ≤ Age < 17, Female. ID numbers 2011-2020 
• Block 3: 11 ≤ Age < 14, Male. ID numbers 3021-3030 
• Block 4: 14 ≤ Age < 17, Male. ID numbers 4031-4040 
 
Given that other factors such as pubertal status and subjective pain levels could 
influence the outcome, these factors will be included in the analysis as control 
covariates.  Each participant’s exact age will be recorded at assessment allowing 
personnel to control for age as an additional covariate should the need become 
apparent during preliminary analyses.    
Blinding 
• Procedure for retaining the blind.  Blinding of study personnel will be 
employed when possible (Table 1).  Of note, our study statistician (Dr. 
Mathew Reeves) will only have access to subject IDs and Treatment A and 
Treatment B.  He will generate monitoring reports for closed sessions based 
only on Treatment A and Treatment B.  If there is an issue of serious concern 

 
Neural Mechanisms of Treatment 
37 of 45 
Response Protocol, Version 6.0 
 
(e.g., safety issues in one arm, differential attrition etc.) that requires complete 
unblinding, Dr. Reeves will identify another statistician to  run the unblinded 
reports.  Dr. Reeves will also complete final analysis only by Treatment A 
versus B and the code will be revealed only after the data has been analyzed. 
Furthermore, the PI (Cunningham) will be blinded to group assignment.  
However, Dr. Barber Garcia will not be blinded to group assignment as study 
interventionist and to ensure the safety of participants and the integrity of the 
study.  It is critical for Dr. Barber Garcia (a licensed clinical psychologist) to 
be aware of participants who are randomized to the ADAPT intervention in 
order to ensure patient safety (e.g., risk assessment for suicidal ideation, 
trauma/abuse, etc.) during the study. The PI (Cunningham) and study mentors 
(Zhu, Arnetz) will have no access to post-assessment data by group 
assignment until after the completion of the study. 
• Individual authorized to break the blind.  Dr. Barber Garcia will be 
authorized to break the blind.  She will not be blinded to group assignment 
and therefore can determine if the study team’s blind should be broken in 
cases where a patient’s safety is in question.  Dr. Barber Garcia’s extensive 
experience as a pediatric psychologist  make her appropriately equipped to 
manage this responsibility. 
• Circumstances for breaking the blind.  The blind will be broken at the 
clinical discretion of Dr. Barber Garcia.  Circumstances for breaking the blind 
may include cases when a patient’s safety is at risk, differential attrition, or if 
a patient’s symptoms remarkably worsen throughout treatment.  
• Procedure for breaking the blind.  If the blind needed to be broken, Dr. 
Barber Garcia would communicate with our local IRB, any NCCIH members 
involved in the study, and involve our study team, included but not limited to 
the PI (Cunningham), co-mentors (Zhu, Arnetz), the study statistician 
(Reeves), and the outcome accessors.    
 
9.3  
Definition of Populations 
Our intent-to-treat population (modified ITT) will be defined as those subjects 
who complete a post-randomization assessment.   
 
9.4 
Interim Analyses and Stopping Rules 
There are no planned interim analyses.  Dr. Barber Garcia will assess adherence 
and retention.  If the treatment is deemed to be ineffective, unsafe, futile, or if there 
is evidence of poor study performance (e.g., slow accrual, high losses-to-follow-up, 
and poor quality control), a safety review may be warranted.  This action would 
occur in consultation with the study mentors (Zhu, Arnetz), the IMC, and NCCIH.  
Examples of findings that might trigger a safety review are the number of SAEs 
overall, the number of occurrences of a particular type of SAE, severe AEs/reactions, 
or increased frequency of events. Such findings are presented to the study statistician 
(Reeves) or to the IMC statistician to review the events by group to determine 
whether there are statistical as well as clinical concerns. The statistician reports his 

 
Neural Mechanisms of Treatment 
38 of 45 
Response Protocol, Version 6.0 
 
findings to a closed session of the IMC or to the Safety Officer and/or NCCIH. The 
findings are used to determine what steps will be taken. 
9.5 
Outcomes  
9.5.1 Primary Outcome   
Subjects will first complete localizer sequences for targeting of other 
series. A B0 field map (B = magnetic field) will be used to correct for 
distortion due to susceptibility artifacts. A high resolution T1 weighted 
anatomical volume will be obtained to provide a detailed view of brain 
anatomy.  Functional connectivity will be examined using the Blood 
Oxygenation Level Dependent (BOLD) effect. 
9.5.2 Secondary Outcomes   
Brain activation during the WL-SPT will be assessed by arterial spin 
labeling (ASL). In order to examine relationships between resting brain 
activity and other variables, cerebral blood flow (CBF) will be measured in a 
quantitative fashion via ASL, which is the optimal for assessing steady-state 
conditions. Nine series will be obtained (5-10 mins each): Pre-WL-SPT: 1 
MPRAGE; 2 resting ASLs; 2 resting BOLDs; post-WL-SPT: 2 ASLs; and 2 
BOLDs. 
9.6 
Data Analyses  
For fMRI analysis, image processing and data analysis will be accomplished by 
FSL software. Each subject’s functional images will be registered to their structural 
data using a six-parameter linear 3D transformation and then nonlinearly warped to 
standard space (MNI152). Analyses of both BOLD and ASL data will be 
accomplished via mixed effects ANOVAs. Data will be coded prior to analysis to 
conceal patient status to ensure blinding.    
Clusters of activation will be identified using a threshold of Z > 3.1 and statistical 
significance will be estimated according to Gaussian random field theory.  Functional 
connectivity analysis will be conducted (Aim 1) to identify changes in functional 
connectivity between the AMY-PFC in ADAPT completers vs. those in the waitlist 
condition. A seed to whole brain analytic approach will be used to identify any/all 
differences observed.  Pain-related brain activations are expected to diminish for 
those that complete ADAPT compared to the waitlist condition (Aim 2). For the 
exploratory aim, mechanisms associated with a positive treatment response 
(decreased pain intensity/ unpleasantness/ anxiety during WL-SPT) after ADAPT will 
be identified. Normalization of abnormal connectivity patterns are predicted to 
categorize changes in pain and anxiety. Specifically, decreases in brain activations 
and reductions in functional connectivity will be examined in relation to 
improvements in pain and anxiety post treatment using multiple (linear) regression.   
While all efforts will be made to minimize missing data through the use of 
electronic data capture and real-time adherence data collection, missing data is still 
inevitable in RCTs.  Thus, we will employ several strategies to handle missing data 
with specific attention on how to handle missing not-at-random.  Specifically, 

 
Neural Mechanisms of Treatment 
39 of 45 
Response Protocol, Version 6.0 
 
missing data will be handled via ML estimation with auxiliary correlate inclusion 
(e.g., Graham, 2003; Enders, 2010).  Missing not at random will be addressed with 
mixture MNAR methods (e.g., Gottfredson, Bauer, & Baldwin, 2014; Muthen, et al., 
2011; Sterba & Gottfredson, 2015). 
Given that other factors such as pubertal status and subjective pain levels could 
influence the outcome, these factors will be included in the analysis as control 
covariates.  Each participant’s exact age will be recorded at assessment allowing 
personnel to control for age as an additional covariate should the need become 
apparent during preliminary analyses.   
10. DATA COLLECTION AND QUALITY ASSURANCE 
10.1 Data Collection Forms  
Standardized, validated measures used in prior pediatric pain studies will be used 
(6.1 Schedule of Evaluations). These measures will be administered using the 
REDCap platform.  Participants and caregivers will be given the option to either 
complete baseline and post-assessment measures during their respective baseline/post 
assessment visit or before this visit using their own electronic device (to reduce the 
length of the in-person visit). A blinded post-baccalaureate research coordinator will 
serve as the outcome assessor and collect data at assessment visits.  Home practice 
during ADAPT will also be measured (online module completion).  Should a 
randomized participant prematurely discontinue participation in the study, study 
measures and endpoints will continue to be collected if possible.  Any concomitant 
interventions (i.e., medical and psychological) experienced by the participants (either 
allowed or prohibited) will also be assessed for and recorded at baseline and post 
assessments.  Participants will provide the reason and duration of concomitant 
interventions at the baseline and post assessment visits.   
To ensure confidentiality, identification numbers will be used on data collection 
forms in lieu of names. Regarding the use of online measures and web modules, 
material development will be conducted in accordance with MSU policies. Hardware 
for this study will be provided and maintained by MSU Informatics, which maintains 
a secure server for supporting projects that potentially contain protected health 
information (PHI) and are subsequently subject to compliance with federal and state 
regulations regarding data of this type. The data obtained from the web program will 
be stored on the server, which will be backed up regularly. 
 
10.2 Data Management  
All data will be identified with ID numbers exclusively and kept in locked files in 
a space in the Secchia Center or on a secure computer that is designated specifically 
for the purposes of this project. All de-identified data (with the exception of fMRI 
data) will be saved into REDCap, a password-protected database.  Data output will be 
stored on a network devoted solely to the research activities associated with MSU’s 
Biomedical Research Informatics Core (BRIC). In order to assure the accuracy of 
data entry, data will be verified in real-time by study staff via database-incorporated 
data entry checks. Electronic data stored on MSU’s network is backed up nightly. The 

 
Neural Mechanisms of Treatment 
40 of 45 
Response Protocol, Version 6.0 
 
server is maintained and all backups are conducted by the BRIC. The fMRI data will 
also be stored on a secure server, backed up nightly, and will only be accessible to 
study staff. 
10.3 Quality Assurance  
10.3.1 Training 
To ensure protocol integrity, staff training will include required human subjects 
training, GCP training, and study/intervention specific training.  Study staff training 
will vary based on roles (i.e., interventionists will receive specific training on 
conducting the intervention from the PI).   
10.3.2  Quality Control Committee  
N/A 
10.3.3 Metrics  
N/A 
10.3.4 Protocol Deviations.   
All deviations will be reported to the IRB for review.  They will also be recorded 
using a protocol deviation form documenting a brief description of the deviation, the 
number of participants who experienced a given deviation, and a summary of the 
action taken in response to the deviation or group of similar deviations.  All protocol 
deviations will also be documented in a protocol deviation log.   
10.3.5 Monitoring 
The study team will have quarterly meetings to monitor the progress of the study, 
the integrity of the treatment, discuss the need for any protocol refinements, and 
conduct regular safety monitoring checks of adverse events and unanticipated 
problems. 
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY  
11.1 Institutional Review Board (IRB) Review  
This protocol and the informed assent and consent documents and any subsequent 
modifications will be reviewed and approved by the MSU IRB.  
11.2 Informed Consent Forms 
A signed assent and consent form will be obtained from each participant and their 
legal guardian (e.g., person with power of attorney) before completing any study 
activities. The consent form will describe the purpose of the study, the procedures to 
be followed, and the risks and benefits of participation.  Consent forms will be IRB-
approved, and the subject is required to read and review the document or have the 
document read to him or her.  The designee will explain the research study to the 
subject and answer any questions that may arise.  The subject will sign the informed 
consent document prior to any study-related assessments or procedures.  Subjects will 
be given the opportunity to discuss the study with their surrogates or think about it 

 
Neural Mechanisms of Treatment 
41 of 45 
Response Protocol, Version 6.0 
 
prior to agreeing to participate.  They may withdraw consent at any time throughout 
the course of the study. A copy of the forms will be given to the legal guardian. 
All efforts will be made to ensure that youth and their families understand the 
study and the associated risks and benefits.  Participants will have opportunities to 
voice questions/concerns before formally providing consent/assent.  Non-English 
speakers or those with cognitive delays that would limit understanding of the 
consenting process will be excluded from participation in the study.  
11.3 Participant Confidentiality  
There is a minimal risk that the data collected for each participant may be viewed 
by individuals outside the research team.  To minimize risk to confidentiality, every 
effort will be made to ensure that research data are kept confidential and stored so 
that data cannot be accessed by individuals who are not part of the research team. 
Unique identification numbers will be assigned to participants, and all case report 
forms will be coded with this number rather than a name. A password-protected 
master list linking the identification number to participant names will be stored on a 
secure computer separate from the study data. Access to the master list will be limited 
to key study personnel. Upon study completion, all study materials and participants’ 
personal information will be destroyed, with the exception of recordings retained for 
training purposes. Locked filing space within the Secchia Center will be identified 
and used exclusively for the purposes of this study. 
All consent forms, contact information and identifying data will be stored either 
in a secure location within the Secchia Center or on a secure computer. The subject 
codebook will be stored separately in a password protected document.  Before they 
begin the study, participants and parents will be informed about the importance of 
confidentiality.. Regarding the use of online measures and web modules, material 
development will be conducted in accordance with MSU policies. Hardware for this 
study will be provided and maintained by MSU Informatics, which maintains a secure 
server for supporting projects that potentially contain protected health information 
(PHI) and are subsequently subject to compliance with federal and state regulations 
regarding data of this type. The data obtained from the web program will be stored on 
a secure server, which will be backed up regularly. 
11.4 Study Discontinuation  
The study may be discontinued at any time by the IRB, the NCCIH, or other 
government agencies as part of their duties to ensure that research participants are 
protected. 
12. COMMITTEES 
N/A 
13. PUBLICATION OF RESEARCH FINDINGS  
Any presentation, abstract, or manuscript will be made available for review by the sponsor and 
the NCCIH prior to submission. 

 
Neural Mechanisms of Treatment 
42 of 45 
Response Protocol, Version 6.0 
 
14. REFERENCES  
1. 
King S, Chambers CT, Huguet A, et al. The epidemiology of chronic pain in children and adolescents 
revisited: A systematic review. Pain. 2011;152(12):2729-2738. 
2. 
Korterink JJ, Diederen K, Benninga MA, Tabbers MM. Epidemiology of pediatric functional abdominal pain 
disorders: a meta-analysis. PLoS One. 2015;10(5):e0126982. 
3. 
Walker LS, Lipani TA, Greene JW, et al. Recurrent abdominal pain: symptom subtypes based on the Rome 
II criteria for pediatric functional gastrointestinal disorders. Journal of pediatric gastroenterology and 
nutrition. 2004;38(2):187-191. 
4. 
Caplan A, Walker L, Rasquin A. Validation of the pediatric Rome II criteria for functional gastrointestinal 
disorders using the questionnaire on pediatric gastrointestinal symptoms. Journal of pediatric 
gastroenterology and nutrition. 2005;41(3):305-316. 
5. 
Campo JV, Di Lorenzo C, Chiappetta L, et al. Adult outcomes of pediatric recurrent abdominal pain: do they 
just grow out of it? Pediatrics. 2001;108(1):E1-E1. 
6. 
Greco LA, Freeman KE, Dufton L. Overt and relational victimization among children with frequent 
abdominal pain: links to social skills, academic functioning, and health service use. J Pediatr Psychol. 
2007;32(3):319-329. 
7. 
Claar RL, Walker LS, Smith CA. Functional disability in adolescents and young adults with symptoms of 
irritable bowel syndrome: the role of academic, social, and athletic competence. Journal of Pediatric 
Psychology. 1999;24(3):271-280. 
8. 
Dorn LD, Campo JC, Thato S, et al. Psychological comorbidity and stress reactivity in children and 
adolescents with recurrent abdominal pain and anxiety disorders. J Am Acad Child Adolesc Psychiatry. 
2003;42(1):66-75. 
9. 
Campo JV, Bridge J, Ehmann M, et al. Recurrent abdominal pain, anxiety, and depression in primary care. 
JAMA Pediatr. 2004;113(4):817-824. 
10. 
Campo JV, Comer DM, Jansen-Mcwilliams L, Gardner W, Kelleher KJ. Recurrent pain, emotional distress, 
and health service use in childhood. The Journal of Pediatrics. 2002;141(1):76-83. 
11. 
Walker LS, Guite JW, Duke M, Barnard JA, Greene JW. Recurrent abdominal pain: A potential precursor of 
irritable bowel syndrome in adolescents and young adults. Journal of Pediatrics. 1998;132(6):1010-1015. 
12. 
Størdal K, Nygaard EA, Bentsen BS. Recurrent abdominal pain: A five-year follow-up study. Acta 
Pædiatrica. 2005;94(2):234-236. 
13. 
Dhroove G, Chogle A, Saps M. A Million-dollar Work-up for Abdominal Pain: Is It Worth It? J Pediatr 
Gastroenterol Nutr. 2010;51(5):579-583 510.1097/MPG.1090b1013e3181de0639. 
14. 
Horwitz BJ, Fisher RS. The irritable bowel syndrome. New England Journal of Medicine. 
2001;344(24):1846-1850. 
15. 
Walker LS, Dengler-Crish CM, Rippel S, Bruehl S. Functional abdominal pain in childhood and adolescence 
increases risk for chronic pain in adulthood. Pain. 2010;150(3):568-572. 
16. 
Dufton LM, Dunn MJ, Compas BE. Anxiety and somatic complaints in children with recurrent abdominal 
pain and anxiety disorders. journal Of Pediatric Psychology. 2009;34(2):176-186. 
17. 
APA. Diagnostic and statistical manual of mental disorders (5th ed). Arlington, VA: American Psychiatric 
Publishing; 2013. 
18. 
van der Veek SM, Derkx H, de Haan E, Benninga MA, Boer F. Abdominal Pain in Dutch Schoolchildren: 
Relations With Physical and Psychological Comorbid Complaints in Children and Their Parents. Journal Of 
Pediatric 
Gastroenterology 
And 
Nutrition. 
2010;51(4):481-487 
410.1097/MPG.1090b1013e3181d1051a1059. 
19. 
Ramchandani PG, Fazel M, Stein A, Wiles N, Hotopf M. The impact of recurrent abdominal pain: predictors 
of outcome in a large population cohort. Acta Pædiatrica. 2007;96(5):697-701. 
20. 
Cunningham NR, Cohen MB, Farrell MK, Mezoff AG, Lynch-Jordan A, Kashikar-Zuck S. Concordant 
parent-child reports of anxiety predict impairment in youth with functional abdominal pain. Journal of 
Pediatric Gastroenterology and Nutrition. 2014;60(3):312-317. 
21. 
Stanford EA, Chambers CT, Biesanz JC, Chen E. The frequency, trajectories and predictors of adolescent 
recurrent pain: A population-based approach. Pain. 2008;138(1):11-21. 
22. 
Walker LS, Sherman AL, Bruehl S, Garber J, Smith CA. Functional abdominal pain patient subtypes in 
childhood predict functional gastrointestinal disorders with chronic pain and psychiatric comorbidities in 
adolescence and adulthood. Pain. 2012;153(9):1798-1806. 

 
Neural Mechanisms of Treatment 
43 of 45 
Response Protocol, Version 6.0 
 
23. 
Cunningham NR, Jagpal A, Peugh J, et al. Using a simple risk categorization to predict outcomes in pediatric 
functional abdominal pain at 6 months Journal Of Pediatric Gastroenterology And Nutrition. 
2017;64(5):685-690. 
24. 
Di Lorenzo C, Colletti RB, Lehmann HP, et al. Chronic Abdominal Pain in Children: A Clinical Report of 
the American Academy of Pediatrics and the North American Society for Pediatric Gastroenterology, 
Hepatology and Nutrition: American Academy of Pediatrics Subcommittee on Chronic Abdominal Pain and 
NASPGHAN Committee on Abdominal Pain. J Pediatr Gastroenterol Nutr. 2005;40(3):245-248. 
25. 
Huertas-Ceballos AA, Logan S, Bennett C, Macarthur C. Psychosocial interventions for recurrent abdominal 
pain (RAP) and irritable bowel syndrome (IBS) in childhood. Cochrane Database of Systematic Reviews. 
2008(1). 
26. 
Palermo TM, Eccleston C, Lewandowski AS, Williams ACdC, Morley S. Randomized controlled trials of 
psychological therapies for management of chronic pain in children and adolescents: an updated meta-
analytic review. Pain. 2010;148(3):387-397. 
27. 
van der Veek SM, Derkx BH, Benninga MA, Boer F, de Haan E. Cognitive behavior therapy for pediatric 
functional abdominal pain: A randomized controlled trial. Pediatrics. 2013;132(5):e1163-e1172. 
28. 
Cunningham NR, Jagpal A, Tran ST, et al. Anxiety Adversely Impacts Response to Cognitive Behavioral 
Therapy in Children with Chronic Pain. The Journal of Pediatrics. 2016;171:227-233. 
29. 
Hudson JL, Rapee RM, Deveney C, Schniering CA, Lyneham HJ, Bovopoulos N. Cognitive-Behavioral 
Treatment Versus an Active Control for Children and Adolescents With Anxiety Disorders: A Randomized 
Trial. Journal of the American Academy of Child &amp; Adolescent Psychiatry. 2009;48(5):533-544. 
30. 
Lyneham HJ, Abbott MJ, Wignall A, Rapee RA. The Cool Kids Anxiety Treatment Program. In. Sydney: 
Macquarie University Anxiety Research Unit, Macquarie University2003. 
31. 
Ali A, Weiss TR, Dutton A, et al. Mindfulness-Based Stress Reduction for Adolescents with Functional 
Somatic Syndromes: A Pilot Cohort Study. J Pediatr. 2017. 
32. 
Kabat-Zinn J, Lipworth L, Burney R. The clinical use of mindfulness meditation for the self-regulation of 
chronic pain. Journal of behavioral medicine. 1985;8(2):163-190. 
33. 
Miller JJ, Fletcher K, Kabat-Zinn J. Three-year follow-up and clinical implications of a mindfulness 
meditation-based stress reduction intervention in the treatment of anxiety disorders. General hospital 
psychiatry. 1995;17(3):192-200. 
34. 
Hofmann SG, Sawyer AT, Witt AA, Oh D. The effect of mindfulness-based therapy on anxiety and 
depression: A meta-analytic review. Journal of consulting and clinical psychology. 2010;78(2):169. 
35. 
Zeidan F, Martucci KT, Kraft RA, Gordon NS, McHaffie JG, Coghill RC. Brain mechanisms supporting the 
modulation of pain by mindfulness meditation. The Journal of Neuroscience. 2011;31(14):5540-5548. 
36. 
Holzel BK, Hoge EA, Greve DN, et al. Neural mechanisms of symptom improvements in generalized anxiety 
disorder following mindfulness training. Neuroimage Clin. 2013;2:448-458. 
37. 
Zeidan F, Martucci KT, Kraft RA, McHaffie JG, Coghill RC. Neural correlates of mindfulness meditation-
related anxiety relief. Social cognitive and affective neuroscience. 2014;9(6):751-759. 
38. 
Kucyi A, Davis KD. The dynamic pain connectome. Trends in neurosciences. 2014. 
39. 
Tillisch K, Mayer EA, Labus JS. Quantitative meta-analysis identifies brain regions activated during rectal 
distension in irritable bowel syndrome. Gastroenterology. 2011;140(1):91-100. 
40. 
Derbyshire SW. Visceral afferent pathways and functional brain imaging. The Scientific World Journal. 
2003;3:1065-1080. 
41. 
Hubbard CS, Becerra L, Heinz N, et al. Abdominal Pain, the Adolescent and Altered Brain Structure and 
Function. PLoS ONE. 2016;11(5):e0156545. 
42. 
Bishop SJ. Neurocognitive mechanisms of anxiety: an integrative account. Trends in cognitive sciences. 
2007;11(7):307-316. 
43. 
Kim MJ, Whalen PJ. The structural integrity of an amygdala–prefrontal pathway predicts trait anxiety. The 
Journal of Neuroscience. 2009;29(37):11614-11618. 
44. 
Coombs III G, Loggia ML, Greve DN, Holt DJ. Amygdala perfusion is predicted by its functional 
connectivity with the ventromedial prefrontal cortex and negative affect. PloS one. 2014;9(5):e97466. 
45. 
Walker LS, Williams SE, Smith CA, et al. Validation of a symptom provocation test for laboratory studies 
of abdominal pain and discomfort in children and adolescents. Journal of pediatric psychology. 
2006;31(7):703-713. 
46. 
Lackner JM, Lou Coad M, Mertz HR, et al. Cognitive therapy for irritable bowel syndrome is associated with 
reduced limbic activity, GI symptoms, and anxiety. Behaviour Research and Therapy. 2006;44(5):621-638. 

 
Neural Mechanisms of Treatment 
44 of 45 
Response Protocol, Version 6.0 
 
47. 
Lowen MB, Mayer EA, Sjoberg M, et al. Effect of hypnotherapy and educational intervention on brain 
response to visceral stimulus in the irritable bowel syndrome. Aliment Pharmacol Ther. 2013;37(12):1184-
1197. 
48. 
Simons LE, Pielech M, Erpelding N, et al. The responsive amygdala: treatment-induced alterations in 
functional connectivity in pediatric complex regional pain syndrome. Pain. 2014;155(9):1727-1742. 
49. 
Broderick P. Learning to breathe. In: Oakland, CA: New Harbinger Publications; 2013. 
50. 
Cunningham NR, Nelson S, Jagpal A, et al. Development of the Aim to Decrease Anxiety and Pain Treatment 
for Pediatric Functional Abdominal Pain Disorders. Journal of pediatric gastroenterology and nutrition. 
2018;66(1):16-20. 
51. 
Birmaher B, Khetarpal S, Brent D, et al. The Screen for Child Anxiety Related Emotional Disorders 
(SCARED): Scale construction and psychometric characteristics. Journal of American Academy of Child 
Adolescent Psychiatry. 1997;36(4):545-553. 
52. 
Mental Health Screening and Assessment Tools for Primary Care. In. Addressing Mental Health Concerns 
in Primary Care. 1 ed: American Acadamey of Pediatrics; 2010. 
53. 
Mano KEJ, Evans JR, Tran ST, Khan KA, Weisman SJ, Hainsworth KR. The psychometric properties of the 
Screen for Child Anxiety Related Emotional Disorders in pediatric chronic pain. journal of Pediatric 
Psychology. 2012;37(9):999-1011. 
54. 
Birmaher B, Brent D, Chiappetta L, Bridge J, Monga S, Baugher M. Psychometric properties of the Screen 
for Anxiety Related Emotional Disorders (SCARED): A replication study. Journal of the American Academy 
of Child & Adolescent Psychiatry 1999;38(10):1230-1236. 
55. 
Kovacs M. Children's depression inventory: Manual. Multi-Health Systems; 1992. 
56. 
Walker LS, Greene JW. The functional disability inventory: measuring a neglected dimension of child health 
status. Journal of Pediatric Psychology. 1991;16(1):39-58. 
57. 
Kashikar-Zuck S, Flowers S, Claar R, et al. Clinical utility and validity of the Functional Disability Inventory 
among a multicenter sample of youth with chronic pain. Pain. 2011;152(7):1600-1607. 
58. 
McGrath PJ, Walco GA, Turk DC, et al. Core outcome domains and measures for pediatric acute and 
chronic/recurrent pain clinical trials: PedIMMPACT recommendations. The journal of pain : official journal 
of the American Pain Society. 2008;9(9):771-783. 
59. 
Bursch B, Tsao JC, Meldrum M, Zeltzer LK. Preliminary validation of a self-efficacy scale for child 
functioning despite chronic pain (child and parent versions). Pain. 2006;125(1):35-42. 
60. 
Stringaris A, Goodman R, Ferdinando S, et al. The Affective Reactivity Index: a concise irritability scale for 
clinical and research settings. Journal of Child Psychology and Psychiatry. 2012;53(11):1109-1117. 
61. 
Crombez G, Bijttebier P, Eccleston C, et al. The child version of the pain catastrophizing scale (PCS-C): a 
preliminary validation. Pain. 2003;104(3):639-646. 
62. 
Varni JW, Stucky BD, Thissen D, et al. PROMIS Pediatric Pain Interference Scale: an item response theory 
analysis of the pediatric pain item bank. The Journal of Pain. 2010;11(11):1109-1119. 
63. 
Petersen AC, Crockett L, Richards M, Boxer A. A self-report measure of pubertal status: Reliability, validity, 
and initial norms. Journal of Youth and Adolescence. 1988;17(2):117-133. 
64. 
Oldfield RC. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia. 
1971;9(1):97-113. 
65. 
Henry JD, Crawford JR. The short‐form version of the Depression Anxiety Stress Scales (DASS‐21): 
Construct validity and normative data in a large non‐clinical sample. British journal of clinical psychology. 
2005;44(2):227-239. 
66. 
Sullivan MJ, Bishop SR, Pivik J. The pain catastrophizing scale: development and validation. Psychological 
assessment. 1995;7(4):524. 
67. 
COVID-19 Exposure and Family Impact Survey (CEFIS). 2020. 
68. 
Bethell CD, Carle A, Hudziak J, et al. Methods to assess adverse childhood experiences of children and 
families: toward approaches to promote child well-being in policy and practice. Academic pediatrics. 
2017;17(7):S51-S69. 
69. 
Price DD, Bush FM, Long S, Harkins SW. A comparison of pain measurement characteristics of mechanical 
visual analogue and simple numerical rating scales. Pain. 1994;56(2):217-226. 
70. 
Kindler CH, Harms C, Amsler F, Ihde-Scholl T, Scheidegger D. The visual analog scale allows effective 
measurement of preoperative anxiety and detection of patients’ anesthetic concerns. Anesthesia & Analgesia. 
2000;90(3):706-712. 
71. 
Simons LE, Moulton EA, Linnman C, Carpino E, Becerra L, Borsook D. The human amygdala and pain: 
evidence from neuroimaging. Human brain mapping. 2014;35(2):527-538. 

 
Neural Mechanisms of Treatment 
45 of 45 
Response Protocol, Version 6.0