Brain Mechanisms of Attention and Pain in Youth With Functional Abdominal Pain Disorders
Conditions: Functional Abdominal Pain Syndrome
Sponsor: Michigan State University

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Title: Brain Mechanisms of Attention and Pain in Youth with Functional Abdominal Pain 
Disorders  
 
 
Principal Investigator:  
Natoshia Cunningham, PhD 
 
 
 
 
 
Assistant Professor of Pediatrics 
 
 
 
 
Division of Behavioral Medicine and Clinical Psychology 
 
 
Co-Investigators: 
 
Susmita Kashikar-Zuck, PhD 
 
 
 
 
Professor of Pediatrics 
 
 
 
 
Division of Behavioral Medicine and Clinical Psychology 
 
 
 
 
 
 
 
 
 
Lee Denson, M.D. 
 
 
 
 
Professor of Pediatrics  
 
 
 
 
Division of Gastroenterology, Hepatology, & Nutrition  
 
Michael Farrell, M.D. 
 
 
 
 
Professor of Pediatrics 
Division of Gastroenterology, Hepatology, & Nutrition 
 
Robert Coghill, PhD 
Professor of Pediatrics  
Division of Anesthesia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents: 
 
1. Abstract 
 
 
 
 
 
 
 
 
2 
2. Purpose of Study 
 
 
 
 
 
 
 
2 
2.A. Specific Aims 
 
 
 
 
 
 
 
3 
3. Background 
 
 
 
 
 
 
 
 
3 
4. Duration 
 
 
 
 
 
 
 
 
4 
5. Potential Benefits 
 
 
 
 
 
 
 
5 
6. Potential Risks, Discomforts, and Inconveniences 
 
 
 
5 
7. Risk/Benefit Analysis  
 
 
 
 
 
 
6 
8. Data and Safety Monitoring Plan 
 
 
 
 
 
6 
8.A. Safety Events 
 
 
 
 
 
  
 
6 
8.B. Data Management   
 
 
 
 
 
             6 
9. Methods 
 
 
 
 
 
 
 
 
6 
9.A. Study Design 
 
 
 
 
 
 
 
6 
9.B. Participants 
 
 
 
 
 
 
 
7 
9.C. Procedure  
 
 
 
 
 
 
 
8 
9.C.1. Recruitment and Screening 
 
 
 
 
8 
9.C.2. Assessments 
 
 
 
 
 
 
8 
9.C.3. Payment  
 
 
 
 
 
 
9 
9.D. Measures  
 
 
 
 
 
 
 
9 
9.E. Data Analysis 
 
 
 
 
 
 
             10 
9.F. Sample Size 
 
 
 
 
 
 
 
10 
10. Security 
 
 
 
 
 
 
 
 
10 
11. Protection of Children  
 
 
 
 
 
 
11 
 
12. References 
 
 
 
 
 
 
 
 
11 
 
 
 
 
1. Abstract: The goal of the current project is to enhance understanding of the neural 
mechanisms associated with the pain experience in youth with functional abdominal pain 
disorders (FAPD), which is the most common and debilitating presentation of FAPD.  This study 
will examine the neural mechanisms associated with pain induction and diminished attentional 
regulation during pain in FAPD.  Findings from pilot studies indicate that increased anxiety in 
FAPD is associated with higher pain-related impairment, and that anxiety may adversely impact 
response to a cognitive behavioral intervention for pain.  While pain outcomes improve when 
anxiety is also addressed in treatment for FAPD, a sizable portion fail to respond to currently 
available interventions.  Further, the PI found that induced pain in FAPD is associated with 
changes in regional brain activity and functional connectivity between brain regions that are 
implicated in chronic pain.  It is crucial to better understand the neural mechanisms which may 
place youth with FAPD at risk for poorer outcomes in order to ultimately develop more effective 
treatments.  In this study, neural mechanisms of response to a pain symptom provocation task in 
youth with FAPD will be compared to healthy controls.  The impact of anxiety levels will also be 
explored.  This study will also examine neural mechanisms associated with disrupted attentional 
regulation during pain induction in youth with FAPD.   
 
2. Purpose of Study: The objectives of this study are to identify neural mechanisms of increased 
pain in pediatric FAPD and examine mechanisms of disrupted attention in the presence of 
induced pain.  The overarching goal is to determine whether youth with FAPD process pain 
differently than healthy youth and to identify the brain areas involved.   
 

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2.A. Specific Aims:  
Aim 1.  Identify neural mechanisms during pain induction using the water load symptom 
provocation task (WL-SPT) in youth with FAPD vs HC.  H1a. Brain regions associated with 
attentional, affective, and visceral afferent processing will show greater activations after the WL-
SPT in youth with FAPD vs HC.  H1b. AMY-PFC functional connectivity will be enhanced 
following WL-SPT in the FAPD group vs HC. H1c.  Increased brain activity and functional 
connectivity will correspond to higher pain in FAPD. 
Aim 2.  Examine how diminished attention regulation impacts the WL-SPT response in FAPD.  
Regional brain activations after the WL-SPT (H2a) and functional connectivity between AMY-
PFC (H2b) will be enhanced during a cognitive task, which will be related to higher pain ratings 
and response time (H2c).  
 
3. Background 
Functional abdominal pain disorders (FAPD) are a set of common pediatric chronic pain 
conditions associated with significant disability and substantial medical costs.  FAPD is 
characterized by abdominal pain or discomfort which occurs at least for 2 months or longer in the 
absence of an identifiable organic cause (1).  FAPD is present in 14% of youth in primary care 
(2), and accounts for nearly 50% of GI visits (3, 4).  FAPD is associated with increased functional 
disability (5, 6), anxiety (7-9), and depression (10) that may persist (11, 12).  Early and effective 
intervention is critical for preventing long-term problems; however, many (~40%) fail to respond 
to currently available evidence-based treatments such as cognitive behavioral therapy (CBT) (13).   
 
Clinical anxiety is highly prevalent in FAPD and is predictive of poor outcomes.  A large 
portion of youth with FAPD meet criteria for anxiety disorders (8, 10, 14).  Anxiety exacerbates 
the severity of FAPD, predicts persistent pain and disability, and corresponds to poorer treatment 
outcomes (15-20).  The PI (see Preliminary Findings) found that anxiety attenuates response to 
CBT for pain in youth with chronic pain, including FAPD (21).  Although anxiety plays a key 
role in predicting poor FAPD outcomes, a mechanistic understanding how youth with FAPD may 
be cognitively impacted by their pain (22) is required to refine and modify improve upon current 
treatments.    
 
Neural mechanisms of FAPD are poorly understood.  Despite efforts to identify aspects of the 
brain-gut axis responsible for the development and maintenance of FAPD, results are inconsistent 
(23).  Neuroimaging studies focusing on the IBS subgroup suggest common areas of activation in 
response to pain include regions associated with visceral afferent processing, such as the 
thalamus, insula (INS), anterior midcingulate cortex (aMCC) (24) and the primary and secondary 
sensory cortices (S1 & S2) (25).  Brain regions associated with affective processes and emotional 
arousal, including the amygdala (AMY) and the pregenual anterior cingulate cortex (pgACC), are 
activated by pain induction (rectal distention) in patients with IBS, but not in healthy controls 
(24). In a recent study of pediatric IBS, structural abnormalities were found in regions implicated 
in attention regulation (e.g., prefrontal cortex (PFC), posterior cingulate (PCC), INS, and S1 
(26)). Further, functional abnormalities were found between the PFC-PCC; however, pain 
induction was not performed.  Unfortunately, the broader FAPD group (3, 4) has not yet been 
explored in neuroimaging research.  While anxiety impacts the severity of FAPD (9, 20, 27, 28), 
the rates of anxiety during pain induction has not been consistently studied in fMRI research.   
 
Diminished attention regulation may contribute to amplified pain levels in youth with 
FAPD.  Pain has a unique attention demanding quality, and pain and attention can influence one 
another (29).  Diminished attention regulation (i.e., increased attention to pain) may characterize 
children with chronic pain and persistent disability.  Increased attention towards pain increases 
pain perception (30).  A review (23) suggests multiple pain processing regions (i.e., ACC, SI, 

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INS), can be modulated by areas associated with attention (e.g., PFC) in FAPD (31-37).  Further, 
poorer performance on a challenging cognitive task in the presence of pain is considered 
characteristic of chronic pain conditions (38) such as FAPD.  This pain-attentive group has 1) 
more gray matter in pain/salience regions (anterior INS, aMCC, supplementary motor area, 
orbitofrontal cortex, thalamus, caudate), and 2) greater functional connectivity in sensorimotor 
and salience resting-state networks (38), which may account for increased impairment. 
 
Anxiety-facilitated disruptions in attention regulation may categorize youth with FAPD at 
greatest risk for poorer outcomes, though associated neural mechanisms have not yet been 
studied.  Clearly, anxiety has adverse effects on attention and cognitive performance (39), and 
attention to pain may be due to appraisal of pain as a source of threat (40, 41).  Brain regions 
associated with anxiety and attention may amplify bottom-up nociceptive input and create an 
intrusive pain experience.  Targeting both attention and anxiety may disrupt the pain experience.  
Indeed, research suggests children who focus on their abdominal pain report higher levels of pain 
and anxiety (42, 43).  However, these studies relied on subjective reports, which are biased. 
Interestingly, brain imaging studies based on healthy adults (44-47) identified a pain network 
within the brain which may capture areas associated with attention and anxiety (23).  
Understanding the effects of diminished attention regulation on FAPD in youth with varying 
levels of anxiety may lead to novel treatments (29) by identifying new targets to enhance existing  
by identifying new targets to enhance existing approaches.  Since FAPD pain can vary, functional 
connectivity analysis (BOLD) may shed insights into patterns of brain regions activated during 
transient pain (29, 48-50) whereas ASL provides understanding of brain activation during stable 
pain. 
 
Current treatments are ineffective.  Pharmacologic treatments (i.e., antispasmodic agents, low 
dose anti-depressants) have limited support (51).  Although CBT is helpful for some (52), ~40% 
fail to respond (13). Moreover, youth with chronic pain and high levels of anxiety have a limited 
response to CBT (21).  It is plausible that CBT fails in many patients with FAPD because the 
attentional demands from the pain interferes with the ability to learn and benefit from CBT 
strategies to cope with pain (53), such as relaxation and changing negative thoughts.  Therefore, 
targeting the disrupted attentional processes in treatment through mindfulness meditation or 
attention bias modification training may enhance the effects of other CBT components.  
Therefore, targeting the disrupted attentional processes in treatment training may enhance the 
effects of CBT.  It is important to examine disrupted attention regulation and other 
neuromechanistic factors impacting pain (54, 55) to ultimately develop and test interventions to 
enhance outcomes (PI’s future research). 
 
4. Duration: Six months will be allotted to develop the cognitive task and complete preliminary 
data collection. We anticipate actively enrolling study participants for the remaining 1.5 years.  
Physicians will identify potentially eligible youth and introduce the study, and study staff will 
then assess eligibility during an initial screening after the medical visit.  
fMRI visit:  Participants will complete one study visit (~2 hours) where they will report 
on baseline symptoms (~15 minutes).  The research staff member will complete the following 
items with the child (~15 minutes): measures of pain intensity/unpleasantness/anxiety (via the 
Visual Analog Scale), information on child abdominal pain symptoms (child and caregiver). 
Next, participants will participate in an fMRI scan (~100 minutes). This will include pain 
intensity and unpleasantness ratings/state anxiety, a cognitive task, and a symptom provocation 
task to induce abdominal discomfort during an fMRI scan. The total time required to complete the 
study visit is approximately 2 hours. Participants will enter the MRI (total scan time ~1 hour and 
40 minutes) and perform a cognitive task to enhance attention to pain.  Following study 
completion, we estimate 6 months for data analysis.  

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5. Potential Benefits: There are no direct benefits expected.  For the fMRI portion of the study, 
any structural brain abnormalities identified will be examined by a radiologist and the 
information will be provided to the child’s primary care physician in addition to informing the 
primary caregiver of the participant in the unlikely event of the detection of an abnormality.  
However, the scans will be of limited diagnostic value, and should not be considered a benefit. 
 
6. Potential Risks, Discomforts, and Inconveniences:  
a) Emotional Distress.  Self-report measures about symptoms and psychological functioning 
typically does not result in distress; however, staff will check in periodically to assess distress. 
 
b) Time Commitment and Fatigue.  The neuroimaging study visit will require approximately a 
two hour time commitment which may cause slight discomfort or inconvenience.  In addition, 
participants will be removed from the scanner half-way through the data collection process (after 
~45 minutes) to complete the water loading task (WL-SPT) prior to resuming the fMRI data 
collection.  Research staff will regularly check in to assess patient comfort and fatigue. 
 
c) Confidentiality.  There is a small risk data may be viewed by those outside the study team. 
 
d) fMRI related Risks.  fMRI does not pose any known risk to the participants.  There are no 
known risks from exposure to the magnetic fields and radio waves used in the fMRI data 
collection procedure.  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.  In addition, although we will screen participants for claustrophobia, 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.  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, they may feel sleepy/bored. 
 
e) The water loading symptom provocation task (WL-SPT) is a non-invasive and validated 
procedure for induction of gastroenterological discomfort in youth with FAPD.  We have 
successfully pilot tested the feasibility of this task in 17 youth with FAPD undergoing 
neuroimaging with no adverse events.  Moreover, the WL-SPT procedure was previously 
validated by Walker and colleagues (2006).  Children are, by design, likely to experience 
abdominal discomfort during the procedure, which produces symptoms similar to but less intense 
than those naturally experienced by children with FAPD.  As noted by the authors of the 
validation study, “This level of discomfort was acceptable to children and their parents” (Walker 
et al., 2006, p. 710).  It will be explained to families in the consent/assent process that 
participation is completely voluntary and that they may drop out of the study at any time, for any 
reason, which will in no way compromise 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 study vomited following water 
ingestion.  “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 potential concern could be for the 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 

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value (up to 1.5 L).  Further, allowing a specific time frame (up to 15 minutes) creates conditions 
which make water toxicity impossible. Study staff will be on hand to check in on participants and 
ensure the participant stops drinking water after a complete sensation of fullness is attained.  A GI 
study physician (Dr. Farrell or Denson) will be on call in the event of any questions/concerns.  In 
addition, participants will be instructed that they are free to terminate the task at any time. 
 
7. Risk/Benefit Analysis: The risk/benefit ratio is favorable for this study and adverse events are 
not anticipated. The risk is minimal because all interventions can be terminated immediately.  
 
8. Data and Safety Monitoring Plan: This project involves functional imaging with a symptom 
provocation task.  We recognize the need to provide a plan to ensure scientific integrity and 
safeguard the well-being of participants. Adverse events will be carefully monitored and 
documented. During the study visit, adverse events (whether or not they are thought to be study-
related) will be monitored and documented in several ways.  The PI and the study team will 
maintain an individual log to record increases in pain (beyond what is expected from the WLSPT) 
or mood-related problems during the study.  In the event of a suspected adverse event, the PI will 
consult with study team members including study physicians and Dr. Kashikar-Zuck, a licensed 
clinical psychologist.  The PI will also report any significant study-related or unanticipated 
adverse events to the Institutional Review Board.  Given that this study is using evidence-based 
protocols, it is felt that monitoring at the level of the PI, her research team, with oversight from 
the IRB and study sponsor is sufficient. 
 
8.A. Safety Events: We anticipate no adverse safety events (e.g. extreme pain). Vomiting, while 
unlikely, is an expected safety event.  This study involves no increase over minimal risk, so a 
Data Safety Monitoring Board will not be created for this study. Any adverse events related to the 
study procedures will be reported to Cincinnati Children’s Hospital Medical Center’s Institutional 
Review Board. There are no adverse effects identified to date from undergoing functional 
imaging studies with MRI. Potential risks from MRI are addressed in the guidelines for the 
operation of clinical MR systems by the FDA in 2014.  No sedation will be used during the MRI.    
 
8.B. Data Management:  All data will be identified with ID numbers exclusively and kept in 
locked files in a space in Dr. Cunningham’s research laboratory that is designated specifically for 
the purposes of this project.  All deidentified data (with the exception of fMRI data that will be 
stored on a separate, secure server) will be entered into a Redcap database on a network devoted 
solely to the research activities of BMCP.  Electronic data stored on CCHMC’s network is backed 
up nightly.  The server is maintained and all backups are conducted by the Division of 
Information Services.  Access to data and participant identities will be limited to Dr. Cunningham 
and key study personnel (e.g., mentoring team, research coordinator, fellow).  The fMRI data will 
also be stored on a secure server, backed up nightly, which will only be accessible to study staff. 
 
9. Methods: 
9.A. Study Design:  Youth with FAPD and healthy controls will be recruited (see recruitment 
sections and participant inclusion/exclusion criteria below) 
Pilot testing phase: To determine initial feasibility, up to 5 HC and 5 youth with FAPD 
who otherwise would not meet the broader fMRI safety criteria (e.g., agoraphobia, braces) will be 
recruited. For these participants, the cognitive task with and without WL-SPT will be conducted 
outside of the scanner.  Measures of pain intensity, pain unpleasantness, and state anxiety will be 
obtained throughout.  We will compare differences in RT in youth with and without FAPD after 
the WL-SPT.  The total time of this visit is expected to be 1.5 hours. 
Active study phase: At the neuroimaging visit, all children will receive an fMRI scan, 
where they will complete some preliminary scans and then a cognitive task, and then be removed 

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from the scanner to complete a water loading symptom provocation task (WL-SPT), a non-
invasive validated procedure in pediatric FAPD populations to induce abdominal sensations 
similar to those experienced during an FAPD episode (see Walker et al., 2006).  After the WL-
SPT task, they will resume the fMRI scan and will complete additional scans including the 
cognitive task they completed earlier to assess for diminished attentional regulation.  Measures of 
pain intensity, pain unpleasantness, and state anxiety will be obtained throughout.  The duration 
of the brain imaging visit is two hours, with the majority of that time spent in the scanner. 
 
9.B. Participants:  A total of 10 youth with be recruited to pilot test the procedures outside of the 
scanner (up to 5 HC and up to 5 with FAPD).  Then, for the active part of the study, a total of 50 
participants will be recruited (25 with FAPD and 25 HC).  Children with FAPD will be recruited 
based on the presence of an FAPD diagnosis (see inclusion/exclusion criteria below). Healthy 
controls (HC) will not have an FAPD diagnosis.  
 
Inclusion Criteria: 
a. Children (boys and girls) between 11-16 years of age and their parent/primary caregiver. 
b. Meets criteria for one of two study groups: 
• 
FAPD: based on physician diagnosis of FAPD confirmed by a validated Rome 
IV measure.  
• 
HC: based on a rule out of an FAPD diagnosis (using the Rome IV measure).  
 
We will recruit approximately 50% of HCs with and without clinical levels of anxiety (e.g,. 
SCARED cut-off score greater than or equal to 25) to match the anxiety levels anticipated in the 
FAPD group. 
 
 
c. Sufficient English language ability necessary to complete study measures and protocol 
 
Exclusion Criteria  
a. Children with significant medical condition(s) with an identifiable organic cause 
including those that may account for abdominal pain symptoms (e.g., Inflammatory 
Bowel Diseases such as Ulcerative Colitis and Crohn’s Disease).  Rationale: Children 
with a significant medical condition may impact the study results.  Further, youth with 
organic conditions that include abdominal pain may not meet criteria for FAPD even if 
they present with similar symptoms. 
b. Children with a documented developmental delay, autism spectrum disorder, a previously 
diagnosed thought disorder (i.e., psychosis), or bipolar disorder will be excluded. 
Rationale: These comorbidities may confound the study aims by impacting the dependent 
measures. 
c. Significant visual, hearing, or speech impairment.  Rationale: Children will be excluded 
if they are not able to see the testing stimuli, hear the test examiner, or respond verbally 
to the test examiner, even with the help of corrective or assistive devices (e.g., glasses, 
hearing aids). 
d. Organic brain injury.  Rationale: Children must not have a history of epilepsy, a head 
trauma associated with a loss of consciousness, or any other organic disorder since these 
conditions could possibly affect brain function and cognition and interfere with study 
results. 
e. *Other exclusionary criteria specific to the fMRI component of the study: 
a. Participants with an implant such as a cochlear implant device, a pacemaker or 
neurostimulator containing electrical circuitry or generating magnetic signals will 
be excluded.  Participants must also not have any significant ferrous material in 
their body that could pose the potential for harm in the fMRI environment or 

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cause signal suppression of key regions (i.e. orthodontia).  Rationale: Implant 
devices can malfunction and/or be damaged.  Strong magnetic fields in the fMRI 
environment can cause some metallic objects to move and/or heat, and therefore 
pose a safety risk.  All children will be screened prior to participation using a 
standardized questionnaire in the fMRI component of the study to ensure that the 
fMRI magnetic fields will not pose any risk to their safety. 
b. Female participants who report current/suspected pregnancy will be excluded.  
Rationale: There is minimal yet potential fetal risk due to electromagnetic 
radiation from the MRI.  Female participants who self-report that they may be 
pregnant will be excluded from the study. 
c. Participants with evidence of claustrophobia will be excluded.  Rationale: Such 
participants may experience extreme distress when entering the fMRI scanner. 
Claustrophobia will be assessed using a validated module of the Anxiety 
Disorders Interview Schedule as part of the initial screening process.  Youth will 
be excluded from participating if they report excessive fear of enclosures. 
*Note that these exclusionary criteria do not apply to those recruited for the study’s pilot portion. 
 
 
 
9.C. Procedure:  
9.C.1. Recruitment and Screening:  Eligible participants with FAPD will be identified for the 
study from new or existing participants seen at the outpatient pediatric GI clinics. We request a 
waiver of HIPPA authorization for preparatory research to identify potential participants based on 
inclusion/exclusion criteria.  We are also requesting a waiver of documentation of consent for the 
screening process.  Participants will be assured that their usual medical care will not be affected 
based upon whether or not they choose to participate.  HCs will be enrolled using a multi-pronged 
recruitment approach potentially including flyers placed in the community and around CCHMC, 
a CCHMC database of healthy individuals willing to participate in research, and online 
advertisements (e.g., CCHMC email blasts).  HC who express interest will be contacted by 
research staff via telephone.  Research staff will describe the study, answer questions, and 
complete a brief (IRB approved) phone screening with the caregiver and child to assess for 
FAPD, anxiety, and MRI eligibility.  If potentially eligible, HC will be invited to complete a 
neuroimaging visit where they will be formally consented by research staff and complete the 
formal study measures. 
For both youth with FAPD and those that are HC, written consent from the primary 
caregiver and written assent from the child will be obtained.  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 CCHMC will be provided.  Following informed consent and child 
assent, the following screening measures will be completed with the child by a member of the 
research staff: a measure of FAPD symptoms/diagnosis, clinical anxiety, and questions regarding 
fMRI eligibility.  This process takes ~10 minutes.  Study staff will complete the ROME IV FAPD 
diagnostic checklist with the participant’s gastroenterology provider to ensure that the child meets 
FAPD criteria.  Some patients will have already completed the SCARED at their medical visit as 
a part of clinical practice.  For those patients, SCARED data will be obtained through EPIC.  The 
participants and families will answer questions to ensure the child can safely enter the scanner 
and undergo fMRI and study procedures.  Screening may take place after the clinic visit.  If youth 
are determined to be eligible, they will be invited to participate in an fMRI visit.   
 
9.C.2. Assessments: Qualifying participants and their respective caregivers will be scheduled to 
complete an in-person neuroimaging visit. Next, participants will enter the MRI and perform a 

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cognitive task to enhance attention to pain. Performance is measured by reaction time. This task 
was previously used in brain imaging studies of healthy adults to understand the effects of pain 
induction, and captures a “pain-attentive” group (i.e., reaction times >100 ms) (38) thought to 
categorize chronic pain conditions such as FAPD. This task involves judgements on groups of 
digits to indicate 1) the most frequently listed digit ignoring the value, and 2) the largest digit 
ignoring the frequency. Similar tasks were used in a pain study of healthy adults (50), and with 
healthy children (without pain) with evidence of brain activations in expected areas (56). 
Imaging protocol. Brain images will be acquired via a 2015 model Philips 3T Ingenia 
MRI system using a 32-channel head coil. Pain intensity/unpleasantness and state anxiety ratings 
will be acquired after each sequence.  Imaging will occur using block design, and will include 
sequences obtained at rest, and in the presence/absence of the cognitive task (with and without 
water loading).  The pilot testing phase will allow for refinement of a neuroimaging protocol for 
the active study. 
 
9.C.3. Payment:  Families will receive payment for this study in the form of a reloadable debit 
card (ClinCard).  A handout will be given to families that will explain how to use the 
card.  Because families are being paid for their participation, CCHMC is required by the Internal 
Revenue Service (IRS) to collect and use the participant’s social security number (SSN) or 
taxpayer identification number (TIN) to track the amount of money that they are pain.  Families 
will need to complete a Federal W-9 form for this income tax reporting.  This form requires the 
participant’s Social Security number.  This form will be given to the CCHMC business office.  It 
will not be kept as part of the participant’s study chart.  Subjects will receive a $25 incentive for 
their screening visit.  Participants recruited to participate in the pilot testing phase (no MRI) will 
be compensated $50. We will reimburse families and participants who are recruited as part of the 
active research project for the visit that includes the MRI an additional $100. 
 
9.D. Measures: Standardized, psychometrically validated instruments used in prior pediatric pain 
studies will be used.  These measures will be administered using the REDCap data capture 
platform.   
Screening:  
FAPD questionnaire (57) . Measure to confirm diagnosis of FAPD based on Rome IV diagnostic 
criteria. 
Screen for Child Anxiety Related Disorders (SCARED) (58, 59). A 41-item measure of anxiety 
over the past 3 months for children ages ≥8 (60). Scores ≥25 = clinical anxiety cut-off. The 
SCARED was validated in pediatric pain (61), and >50% of children with FAPD experience 
clinical anxiety, which is related to higher pain/disability (9).  If this measure is not obtained 
clinically, it will be administered as part of the research protocol. 
MRI Safety and Screening.  Research staff to determine if patient can safely complete fMRI 
protocol. 
Numeric Rating Scale (NRS) (62) for pain.  Average, highest, and lowest pain levels in the past 
week will also be assessed.   
Functional Disability Inventory (FDI) (63).  15-item measure of physical/daily function in last 
few days.  This measure has been validated in pediatric chronic pain (64) and used in pediatric 
FAPD samples (9,24). 
  
Note.  For patients with FAPD, some measures (SCARED, FDI, NRS) may be available as 
part of the participants clinical screening.  If so, they will be obtained from the EMR. 
 
Measures administered during fMRI visit:  

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Pain History. Family socio-demographic factors (e.g., age, parent employment), and child pain 
information (e.g., duration, location, medication) will be obtained (available as covariates). 
Pain Intensity/Unpleasantness via the Visual Analog Scale (VAS)  (65, 66). Scale with the words 
“no pain intensity/unpleasantness” and “worst pain intensity/unpleasantness”, validated for 
children ≥8 years. Large effects after the WL-SPT have been observed (67). 
State Anxiety (VAS) (68). 0-10 self-report of how anxious the child is feeling in the moment. 
Fullness Rating Scale (67). Youth will be asked to indicate how full they felt after water ingestion 
by selecting from images representing different levels of fullness, from empty to full.  
Pain Catastrophizing Scale for Children (69). A valid measure of maladaptive beliefs about pain 
and feelings experienced when in pain. 
 
9.E.  Data Analysis:  For the fMRI data, image processing and data analysis will be 
accomplished using FSL (70).  Each subject’s functional images will be registered to their 
structural data using a six-parameter linear 3-D transformation and then nonlinearly warped to 
standard space (MNI152) (71-73). The aCompCor approach will be used to preprocess BOLD 
data for functional connectivity and psychophysiological interaction analyses (74). This process 
minimizes the impact of global signal changes as well as signal changes induced by movement 
and other sources of noise. Analyses of data will be accomplished via mixed effects ANOVAs.  
Pain-related activation will be identified in images by comparing pre vs. post water loading data 
within subjects. These findings will then be contrasted across FAPD and HC groups. Multiple 
regression analyses will be used to examine if the changes in brain regions are related to the pain 
intensity/unpleasantness/anxiety.  Next, changes in pain-related brain activation and functional 
connectivity during the cognitive task following the WL-SPT will be examined.  There will also 
be a wealth of data available for exploratory analysis. Such analyses may include examining 
resting state FAPD data vs. HC data and exploring groups by anxiety level. 
 
9.F. Sample Size:  Analyses were powered to address pain intensity/unpleasantness differences 
measured during the pilot WL-SPT study (67).  A Monte Carlo simulation was performed to 
obtain a power estimate for the analyses under the following assumptions: 1) equivalent sample 
sizes for the two groups, 2) covariates (age, gender, ethnicity, SES, baseline pain) will explain 
(R2 = 0.35) 35% of the variance, and 3) an effect size difference between FAPD and HC of d = 
0.73 is observed.  Monte Carlo simulation results showed power >0.80 to detect a d = 0.55 
difference if 20 per group (total N = 40) are available for analysis after proper handling of 
missing data.  Additional power calculations using 
http://neuropowertools.org/neuropower/neuropowerinput were conducted based on neuroimaging 
data available from Dr. Coghill (mentor). For between group changes, data comparing youth with 
chronic pain (migraine) to healthy controls was utilized. Based on these data showing moderate to 
large effect size differences, a total of 35 subjects are required for power of .8 and p <0.05.  Thus, 
a total sample size of at least 40 (which assumes 20% of data will be lost due to motion and other 
artifacts) ensures adequate power to observe at least moderate effects.  Furthermore, 10-15 per 
group is sufficient to detect differences in child (75, 76) and adult (77) fMRI studies. 
 
10. Security:  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. All project staff will be required to take the Collaborative 
Institutional Training Initiative (CITI) course on research responsible conduct.  Research 
personnel will be informed of the study aims and procedures, with particular attention given to 
the importance of confidentiality.  Unique identification numbers will be assigned to participants, 
and all data forms will be coded with this number rather than a name.  A master list linking the 
identification number to participant names will be locked in a file cabinet in Dr. Cunningham’s 

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office 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.  Locked filing space within Dr. Cunningham’s research laboratory will be identified 
and used exclusively for study purposes. CCHMC IRB approval will be obtained for this study 
prior to participant recruitment and data collection, and the IRB will be immediately informed of 
any adverse events that occur across the duration of the proposed study.  In addition to the 
licensed clinical (Dr. Zuck) and medical (Drs. Farrell and Denson) providers, Dr. Cunningham 
herself is a licensed clinical psychologist and has a wealth of experience in conducting research 
involving vulnerable populations (e.g., children) and sensitive topics (e.g., anxiety). 
 
11. Protection of Children:  The sample will consist of children ages 11-16, and their parent, 
because the study is tailored for the age-group of children most affected by FAPD and 
representative of the patients seen in our clinics.  The study team will obtain assent from child 
participants and consent from caregivers.  The study will be explained in developmentally 
appropriate language.  The PI, a licensed clinical psychologist, has considerable experience 
working with youth ages 11-16 through a wide array of research and clinical experiences with 
pediatric samples throughout her training, including the pilot studies for this current application.  
The study team has extensive clinical and research experience with this population as well.  The 
PI will directly oversee the process of screening patients, running participants, and maintaining 
data.  Thus, the PI will be able to assure protection from risk, confidentiality, and assessment of 
psychological functioning. 
 
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