Supraspinal Processing of Sensory Aspects of Pain
Phase: NA
Conditions: Migraine in Children, Complex Regional Pain Syndromes, Musculoskeletal Pain, Functional Abdominal Pain Syndrome, Fibromyalgia
Sponsor: Children's Hospital Medical Center, Cincinnati

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SUPRASPINAL PROCESSING OF SENSORY ASPECTS OF PAIN
Principal Investigator: 
Robert C. Coghill, Ph.D., Professor of Pediatrics
Director, Pediatric Pain Research Center
Division of Behavioral Medicine and Clinical Psychology
Cincinnati Children’s Hospital Medical Center
Supported by: 
The National Institute of Neurological Disorders and Stroke (R01NS039426)

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Version Number
Version Date
Summary of Revisions Made
1
2
2/10/2023
-
Revisions to inclusion/exclusion criteria for healthy controls, 
pilots and patient populations focusing on concise language.
-
Revision to data sharing language to allow for PHI data transfer 
to related studies with similar data goals to relieve testing burden 
on participants (pg 23)
-
Surveys added to capture more sleep behavior and additional 
pain domains.(Pg 16)
-
Payment structures revised to reflect participant effort more 
appropriately and add in structure for pilot participants and 
alter payment for pilots pg 33

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1. PROJECT SUMMARY
Chronic pain affects approximately 20% of both adults and children in the US and is a source of 
substantial disability and health care costs.  Chronic pain can be challenging to diagnose due to 
the presence of poorly understood symptoms.  When diagnosed, current pharmacologic 
treatments for pain are remarkably ineffective, while effective non-pharmacologic treatments 
remain under-utilized.  These shortcomings in the diagnosis and treatment of pain arise from 
tremendous gaps in our knowledge about the basic central nervous system systems that 
process nociceptive information and instantiate an experience of pain. These gaps are further 
amplified in the case of pediatric chronic pain due to a lack of basic/translational research.  Our 
team of basic scientists and clinician scientists is uniquely positioned to perform human 
pediatric studies integrating functional neuroimaging with quantitative sensory testing and 
psychological assessments to delineate brain systems engaged during chronic pain.  We will 
examine four distinct chronic pain syndromes: migraine, complex regional pain syndrome, 
functional abdominal pain, and musculoskeletal pain.  We seek to 1) Identify shared and distinct 
brain systems engaged by different forms of pediatric chronic pain, 2) Determine if predictors of 
recovery differ across different chronic pain conditions, 3) Delineate brain systems associated 
with the spread of pain. To accomplish these aims, we will recruit 400 patients with chronic pain 
and 100 healthy participants (age range 10-17).  We will follow all participants longitudinally for 
1 year after initiation of treatment to assess the degree of recovery and spread of pain. This 
basic science investigation will provide a critical foundation of basic knowledge for future clinical 
trials of diagnostic markers for different forms of chronic pain and for the development of new 
treatments for chronic pain.  

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2. SPECIFIC AIMS
Chronic pain has a profound impact on children and adolescents.  Millions of adolescents are 
affected by migraine, complex regional pain syndrome, musculoskeletal pain, and functional 
abdominal pain.  In adolescents in the US, heath care costs associated with pain are estimated 
to be approximately $20 billion.(1) Youth with chronic pain have significant disability manifested 
by decreased school attendance, physical and social activities, and increased depression and 
anxiety.(2, 3) Current treatments for pediatric chronic pain are typically derived from adult care 
and are of limited efficacy,(4) leaving many children undertreated.(5) Despite the high 
prevalence and poor outcomes, pediatric chronic pain remains understudied and poorly 
understood.
Appropriate treatment for pediatric chronic pain is complicated by challenges with accurate 
diagnoses. Chronic pain presents in many forms with a plethora of symptoms and frequently is 
of unknown origin.  Given the ambiguity of the symptoms of many chronic pain disorders, 
clinicians face many challenges in accurately providing the patient with an appropriate diagnosis 
and subsequent treatment.(6, 7)  This diagnostic uncertainty is mirrored by the patient and is 
associated with increased pain intensity and significant disability.(8)
Delineation of brain systems engaged during chronic pain can provide insights critical for the 
better diagnosis and treatment of pain. For example, our data indicate that brain activation can 
be used to identify systems associated with successful therapy and can predict responsiveness 
to treatments prior to their initiation.(9) However, progress in this area is limited by the dearth of 
studies comparing brain systems across different chronic pain syndromes, a limitation arising 
from the treatment of different forms of chronic pain by different medical disciplines.   
Our team is uniquely breaking down barriers between different disciplines and performing fMRI, 
quantitative sensory testing (QST), and psychological assessments of pediatric patients with 
diverse primary chronic pain conditions. Building on these ongoing studies, we will conduct a 
prospective basic science investigation to directly compare brain systems associated with 
different forms of chronic pain in a sample of youth (ages 10-17) with chronic pain (100 with 
migraine, 100 with complex regional pain syndrome, 100 with musculoskeletal pain, 100 with 
functional abdominal pain) and 100 age/sex-matched healthy control participants. Functional 
MRI (BOLD and ASL), QST, and psychological data will be obtained to address these aims:
Aim 1: Identify shared and distinct brain systems engaged by different forms of pediatric 
chronic pain. Parallel recruitment and investigation of patients before initiation of treatment (i.e. 
baseline) with these diverse conditions is critical for systematically identifying the brain systems 
engaged uniquely by each chronic pain condition as well as for determining common brain 
systems that may span multiple conditions.  Accordingly, we will test the hypothesis that 
migraine, complex regional pain syndrome, functional abdominal pain, and musculoskeletal pain 
engage partially distinct brain systems. Identification of these systems will lead to a mechanistic 
foundation for better diagnoses of these complex conditions and will greatly add to our general 
understanding of pediatric chronic pain.  
Aim 2: Determine if predictors of recovery differ across different chronic pain conditions. 
We will longitudinally examine youth with chronic pain for 1 year to assess recovery trajectories 
following multidisciplinary (psychological, physical, and pharmacological) treatment to determine 
if different (or similar) multivariate predictors (neuroimaging, QST, and psychological 
assessments) of recovery are required for different chronic pain syndromes.  Different predictors 
would underscore the unique brain systems associated with each diagnosis, while similar 
predictors would point towards a more global brain system driving chronic pain. Development of 
trajectory predictors will have a significant impact on patient care as patients with markers for 
poor trajectories could be immediately directed to intensive inpatient rehabilitation instead of 

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having to unsuccessfully undergo months of outpatient therapy and suffer further entrenchment 
of their chronic pain. 
Aim 3: Delineate brain systems associated with the spatial distribution and spread of 
pain. The spread of pain is a particular problem with pediatric chronic pain.(10) Importantly, the 
prevalence of widespread pain increases progressively with age (11) indicating an urgent need 
to develop effective treatments for children so that they do not transition to adults with 
intractable chronic widespread pain. Using a combination of innovative, spatially-directed QST 
and comprehensive pain mapping across the body, together with neuroimaging, we will identify 
brain systems that are associated with the spatial spread of pain.  Longitudinal follow-up of 
patients will allow us to specifically examine patients who have increasing spread of pain to 
determine the brain systems that predict such adverse changes.

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3. SIGNIFICANCE
Chronic pain in adults and in youth remains a tremendous problem and is associated 
with tremendous societal costs. More than 20% (50.0 million) adults in the US have chronic 
pain, with 8.0% (19.6 million) of the total population having high-impact chronic pain.(12)  
Women, older adults and economically disadvantaged individuals have higher rates of both 
chronic pain as well as severe chronic pain.(12) Youth are impacted by chronic pain at similar, 
surprisingly high rates, with estimates ranging from 15-33% having chronic pain, and more than 
5% having severe chronic pain.(13, 14) In adults in the US, pain is associated with added health 
care costs of $261-300 billion(15), while in adolescents in the US, heath care costs associated 
with pain are estimated to be approximately $20 billion.(1) The costs of lost productivity are 
significant, with costs ranging more than $300 billion.  Similar to adults, youth with chronic pain 
have significant disability manifested by decreased school attendance, physical and social 
activities, and increased depression and anxiety.(2, 3) Despite high prevalence, pediatric 
chronic pain remains under-studied and poorly understood.
A unique challenge of pediatric chronic pain is that it occurs within the developing brain. 
The brain continues to mature through adolescence and into early adulthood. In particular, the 
prefrontal cortex is one of the last brain structures to mature.(16)  This region is critically 
important to the modulation of pain and is activated during multiple interventions for pain relief 
including expectations(17), meditation(18), cognitive behavioral therapy (CBT)(19), and 
placebo.(20) The presence of chronic pain during this critical phase of the development of pain 
modulatory structures may have dire implications for the patient, as pain exposure early in life 
can lead to long term increases in pain sensitivity. Consistent with this idea, youth with chronic 
pain frequently transition to adults with chronic pain despite the availability of state-of-the-art 
treatments.(21)
Appropriate treatment for chronic pain is complicated by challenges with accurate 
diagnoses. Chronic pain presents in many forms with a plethora of symptoms and frequently is 
of unknown origin.  Given the ambiguity of the symptoms of many chronic pain disorders, 
clinicians face many challenges in accurately providing the patient with an appropriate diagnosis 
and subsequent treatment.(6, 7)  This diagnostic uncertainty is mirrored by the patient and is 
associated with increased pain intensity and significant disability(8) and causes continued 
searches for what would be perceived as appropriate diagnoses.(22) Development of an 
improved understanding of the neurophysiological systems supporting symptoms of different 
types of chronic pain is critical for development of better diagnoses for chronic pain.
Spatial aspects of pain have long remained challenging to explain and can pose 
tremendous clinical problems. Spread of pain away from the initial locus can complicate 
diagnoses by obscuring the location of the underlying problem and by raising questions about 
the veracity of the patient’s report. Moreover, pain can spread outside of dermatomal 
boundaries in a fashion not adequately explained by the underlying neuroanatomy.(10, 23) 
However, the spread of chronic pain and sensory disturbances occurs with great frequency.  For 
example, the spread of pain during complex regional pain syndrome to multiple limbs occurs in 
a high proportion of patients.(23)  Patients with pain that radiates exhibit contralateral radiation 
most frequently, but significant proportions exhibit ipsilateral radiation.(23)  In addition, our Co-I 
Williams has determined that the spatial distribution of pain is associated with poor outcomes in 
pediatric patients following intensive therapy.(24) Despite the frequency and importance of this 
sensory dimension of chronic pain, remarkably little research has addressed spatial 
mechanisms of pain.
Pharmacologic therapies for chronic pain exhibit limited clinical efficacy. Despite the 
widespread use of pharmacologic therapies for chronic pain, they are effective for a remarkably 

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small number of patients.  A recent meta-analysis of clinical trials of drugs for neuropathic pain 
reveals that the 7.2 patients need to be treated in order to produce either a 30 or a 50% 
reduction in neuropathic pain of one patient.(25)  Our Co-I’s Powers and Hershey have recently 
shown that the most commonly used preventative drugs for pediatric migraine (amitriptyline and 
topiramate) are no more effective than placebo.(26) Consistent with this finding, a recent review 
of pharmacologic treatments for pediatric chronic pain reveals that there is limited evidence 
supporting the efficacy of pharmacologic therapy.(27)  Moreover, this limited efficacy of 
pharmacotherapy for chronic pain in both adults and children may, in part, result from the 
distribution of nociceptive processing across dozens of neurotransmitters and 
neuromodulators.(28)  Thus, targeting a single neurotransmitter system is not sufficient to 
adequately disrupt nociceptive processing when a myriad of other neurotransmitter systems are 
sufficient to maintain a state of chronic pain. Given this lack of efficacy of pharmacologic 
therapies, dramatically different systems-level approaches are needed to treat chronic pain.
Pain is processed 
in a highly 
distributed 
fashion.  I have 
recently developed 
a new overarching 
conceptual 
framework for 
understanding pain 
that provides the 
foundation for our 
future studies.(29) 
This framework, 
termed the 
Distributed 
Nociceptive System 
(DNS), integrates 
two neglected 
concepts - 
population 
coding(30) and 
distributed 
processing.(31-33) 
The DNS provides 
an integrated conceptual 
structure for understanding 
nociceptive mechanisms across 
the spinal cord and the brain. The central tenet of this framework is that the extraction and 
utilization of nociceptive information is a process that can be accomplished separately and 
largely independently by populations of neurons across multiple sites within the central nervous 
system.  As such, processing of nociceptive information can occur in a highly distributed 
fashion, yielding a system that is very resistant to disruption. The DNS provides a bridge 
between the basic neuroscience and clinical worlds by providing a mechanistic framework for 
developing an understanding of the perplexing symptoms of chronic pain. For example, altered 
receptive field tuning may result in enhanced recruitment of nociceptive neurons and spread of 
pain. Thus, examining systems supporting spatial tuning may provide important insights into 
how pain can spread and how this spread can be reversed. Moreover, the widely distributed 
Figure 1 Anatomic substrates supporting the distributed processing of nociceptive 
information. Note the extensive interconnectivity of the amygdala with the anterior cingulate 
cortex and insular cortex.
3b
3a
3a
3a
1
2
SI
SII
SPINAL CORD
POST.
INSULA
Dysgranular
Granular
AMYGDALA
Central
Nucleus
Lateral
Nucleus
Basal
Nucleus
Lateral
Basal
Nucleus
ACC
ANT.
INSULA
VPL
VPI
Po/SG
MD
PB
Nucleus

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brain systems that are involved in the construction of the pain experience may require 
distributed regulation to instantiate either positive or negative changes. Brain regions such as 
the amygdala have extensive connectivity with regions known to be involved in nociceptive 
processing and are ideally situated to regulate their activity (Fig. 1). Accordingly, our preliminary 
studies have focused heavily on the functional connectivity of the amygdala and its role in 
different forms of chronic pain. Our team of basic scientists and clinician-scientists is uniquely 
positioned to perform human studies that are firmly grounded in this mechanistic framework.  
4. STUDY DESIGN
Overview of experimental design and study flow: We will collect QST, fMRI, and psychological 
data from up to 500 youth, including 400 with chronic pain and 100 healthy controls in order to 
1) Identify shared and distinct brain systems engaged by different forms of pediatric chronic 
pain, 2) Determine if predictors of recovery differ across different chronic pain conditions, 3) 
Delineate brain systems associated with the spatial distribution and spread of pain. Pediatric 
chronic pain patients will be assessed (QST, fMRI, psychological assessment), ideally at 
initiation of treatment, (baseline) and will be followed longitudinally for a period of 1 year to track 
the trajectory of their recovery following multidisciplinary (pharmacological, psychological, 
physical) treatment, and the spatial distribution of their pain, as well as the emergence of new 
chronic pain conditions. Healthy youth will undergo the same assessments at analogous time 
points. Both traditional massive univariate as well as multimodal deep Ensemble learning 
methods will incorporate all modalities of assessment to classify chronic pain and to predict 
trajectory.  
Participants: A total of up to 500 participants (age 10-17 at the time of enrollment) will be 
recruited for combined QST, fMRI, and psychological assessments, with approximately 100 
having complex regional pain syndrome (CRPS), 100 with migraine, 100 with musculoskeletal 
(MSK) pain, and 100 with functional abdominal pain, and 100 age and sex matched healthy 
controls.  We anticipate that the sex distribution will be approximately 70% female, 30% male, 
with approximately 5% of participants having a gender identity as non-binary.  These 
participants will be MRI compatible (i.e., no claustrophobia, no metal/electronics that could 
increase risk and/or diminish image quality) and will meet inclusion criteria delineated in detail 
below. We are actively performing studies on all of these different patient populations (and 
healthy controls), and based on our current recruitment rates, we can readily meet these 
recruitment objectives. 
Pilot participants: An additional 20 participants (age 10-65) may be recruited to optimize 
selected study procedures. These participants would have no contraindications for the 
procedures that they experience.
Participant Timeline: Individuals with chronic pain will undergo (QST, MRI, psychological) 
assessments at baseline, ideally prior to initiation of multidisciplinary treatment. They will be 
followed with quarterly remote assessments and as well as with an in-person study visit (QST, 
psychological assessments) after one year to track the trajectory of their pain and to 
characterize emergence of spatial spread of their pain. 
5. PARTICIPANT SELECTION, RECRUITMENT, AND RETENTION PLAN 

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5.1 Eligibility Criteria
A total of 500 participants (+20 pilot participants) will be enrolled in this project, with all children 
undergoing MRI scans quantitative sensory testing. Patients evaluated at Cincinnati Children’s 
Hospital will be eligible for the study. Patients may have more than one chronic pain condition. 
All individuals regardless of gender, race, ethnicity and socioeconomic class will be considered 
potential study participants.  
Healthy Volunteers
  Inclusion Criteria:
1.
Male, Female, or Non-binary, age 10-17 years. 
2.
Good general health, no history/active chronic pain
3.
English speaking, able to complete interviews and questionnaires in English
4.
Parent or guardian (as applicable) and participant willing to comply with protocol, 
complete study assessments, and provide written informed consent.
5.
Access to the internet either by laptop, tablet, or phone (for REDCap Surveys)
  Exclusion Criteria:
1.
Pregnant females
2.
Morbid obesity or weight/size incompatible with MRI scanner
3.
History/active chronic pain
4.
Psychiatric medications
5.
Diagnosis of epilepsy, other neurological diseases, or medical condition (e.g. diabetes, 
cancer)
6.
MRI contraindications
7.
Orthodontic braces or other metallic implants which obscure or interfere with the MRI.
8.
Claustrophobia
9.
Skin conditions or past skin damage on the arms or legs in or near sites of sensory 
testing
10. Medications that may alter pain sensitivity or brain activity
Patients
  Inclusion Criteria:
1.
Patients will need a diagnosis of a chronic pain derived congruent with ICD-11 criteria 
[MG30.0; chronic primary pain - pain in 1 or more anatomic regions that persists for > 3 
months, is associated with significant distress or functional disability and cannot be 
better explained by another chronic pain condition (e.g., arthritis, lupus).(34)] related to 
headache (migraine, daily headache), abdominal (FAPD), localized MSK (single 
limb/joint, low back or chest pain), diffuse MSK (widespread MSK pain), or CRPS 
2.
If on medications, they need to be on stable doses of prescribed pain and/or psychiatric 
medications for 4 weeks before the baseline study visit.

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3.
Male or female, age 10 -17 (inclusive)
4.
English speaking, able to complete interviews and questionnaires in English
  Exclusion Criteria:
1.
Weight/size incompatible with MRI scanner
2.
Orthodontic braces, metallic or electronic implants, or other metal objects in the body 
which obscure or interfere with the MRI, or pose a risk from heating, movement, or 
malfunction in the MRI environment
3.
Claustrophobia
4.
Youth who are pregnant
5.
Any comorbid rheumatic disease, diagnosis of epilepsy, other neurological diseases, or 
medical condition (e.g. diabetes, cancer, IBD)
6.
Present psychiatric disease as defined by DSM IV (e.g. psychosis, bipolar disorder, 
major depression, generalized anxiety disorder), alcohol or drug dependence, or 
documented developmental delays or impairments (e.g., autism, cerebral palsy, ADHD, 
or mental retardation) that, in the opinion of the investigator, would interfere with 
adherence to study requirements or safe participation in the study
7.
Skin conditions or past skin damage on the arms or legs in or near sites of sensory 
testing
8.
Outside the age range (9 years old or younger; 18 years or older) at the time of consent
Pilot Volunteers
Inclusion Criteria:
6.
Male, Female, or Non-binary, age 10-65 years. 
7.
Good general health, no history/active chronic pain
8.
English speaking, able to complete interviews and questionnaires in English
9.
Parent or guardian (as applicable) and participant willing to comply with protocol, 
complete study assessments, and provide written informed consent.
10. Access to the internet either by laptop, tablet, or phone (for REDCap Surveys)
  Exclusion Criteria:
11. Pregnant females
12. Morbid obesity or weight/size incompatible with MRI scanner
13. History/active chronic pain
14. Psychiatric medications
15. Diagnosis of epilepsy, other neurological diseases, or medical condition (e.g. diabetes, 
cancer)
16. MRI contraindications
17. Orthodontic braces or other metallic implants which obscure or interfere with the MRI.
18. Claustrophobia

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19. Skin conditions or past skin damage on the arms or legs in or near sites of sensory 
testing
20. Medications that may alter pain sensitivity or brain activity
5.2 Recruitment
Healthy Volunteers
Healthy volunteers will be recruited through on-line advertisements, social media, paper 
advertisements, word of mouth, and e-mail.
Migraine Patients
Cincinnati Children’s Headache Center will be the primary source of recruitment of migraine 
patients.  About 2,000 children and adolescents per year are evaluated there. Our group with 
Co-I Hershey has successfully enrolled 3 to 5 participants per month in imaging and sensory 
testing studies consistently. 
Outpatient Chronic Pain Clinic
Patients with complex regional pain syndrome, musculoskeletal chronic pain conditions will be 
recruited from the Outpatient Chronic Pain Clinic. This clinic sees 300 patients per year and is a 
site of active recruitment for ongoing studies of complex regional pain syndrome and 
musculoskeletal pain in collaborations with Co-I Kenneth Goldschneider.
Functional Independence Restoration Program (FIRST)
Patients with complex regional pain syndrome, musculoskeletal pain, and multiple overlapping 
chronic pain conditions will also be recruited from the FIRST program. This inpatient program 
sees more than 50 patients per year and is the site of ongoing recruitment of CRPS patients 
and patients with widespread musculo-skeletal pain in collaborations with Co-I Sara Williams.  
Our recruitment rates have been extremely high (>90% for eligible patients) as research can be 
incorporated into patients’ daily schedule and barriers related to travel are non-existent.  
Gastroenterology Clinic
Patients with functional abdominal pain will be recruited from the Gastroenterology Clinic.  This 
clinic sees more than 100 functional abdominal pain patients per year and is the site of active 
ongoing studies in collaboration with Co-I Neha Santucci.
Other Forms of Recruitment
Patients and their families may hear about the study through clinicaltrials.gov or approved 
advertisements.  If they are not patients at CCHMC, CCHMC clinical personnel will evaluate 
their chart to ensure appropriate diagnoses and eligibility.
Recruitment and Retention Strategies Common to All Patients
Potential patients will be identified during an evaluation at one of clinics (mentioned above) at 
Cincinnati Children’s Hospital. The physician/nurse practitioner/psychologist who examines the 
child or adolescent will explicitly state that they will continue to receive the same high quality of 
care from them should they choose not to participate. If the family is interested in participating, 
informed consent and assent will be obtained. The physician, nurse practitioner, research 
coordinator, and/or a study PI will provide a full description of the study and answer any 
questions that the family may have. Approved procedures and forms of the Institutional Review 
Board will be utilized.  The purposes and the risks of the investigation and the procedures of the 
study will be explained. The families will be explicitly told that their medical care will not be 

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affected if they choose not to participate. No research screening or assessment procedure will 
occur until after written consent is obtained.
Identification of Eligibility
Patients and their caregivers who meet eligibility criteria will be informed of the study by their 
pain clinicians or study personnel at clinic appointments and could be provided a study brochure 
or flyer. Study brochures or flyers for all active clinical studies are typically posted on bulletin 
boards in the clinic, patient rooms, or waiting rooms. 
Screening
For each patient referred to the study, the study team will determine if the patient meets 
inclusion criteria by performing a chart review and administering a screening survey. The 
screening survey may include the Functional Disability Inventory, PEDSMidas, Visual Analog 
Scale (VAS) and Numeric Rating Scale (NRS) for pain ratings.
Retention Strategies
In an effort to retain each recruited patient, various methods could be employed such as 1) ride 
share service (as needed), 2) reminder calls, texts or emails, prior to each lab visit and follow-up 
clinical endpoint survey completion, 3) onsite childcare or a babysitting allowance for siblings, 
and 4) providing participants who reach the 1 year endpoint with a 3D print of their brain. 
Pre-screening of Clinical Patients
Patient charts via EPIC may be reviewed by research staff for inclusion. Patient history, 
demographics, clinic notes and clinical pain records may be reviewed to determine whether a 
patient meets initial inclusion/exclusion criteria. The information from the chart reviews can be 
used to generate an electronic list of potential study patients. A recruitment letter/message 
and/or email may be sent to the parent or guardian regarding the study. In addition, the study 
staff may also reach out to the family. If interested, adolescents and their families may be 
approached before/following their clinical visit or another convenient time.
MyChart Recruitment Communication
The research team must confirm that the patient’s family is potentially interested in research 
prior to contact, either through a clinician’s verbal or electronic acknowledgment or through the 
patient’s EPIC profile. Additionally, previous involvement in research would be considered as 
grounds for potential interest in future research opportunities. If interested, and potentially 
eligible as per the previously detailed pre-screening strategies, communication can be sent in 
the form of a MyChart message, a communication feature in the EPIC healthcare tracking 
system. 
Study personnel may wait in the various clinics and then approach patients in between provider 
visits to assess their interest in participating in research. The plan was to inform, consent and 
enroll participants in the study in-person. We also provide a virtual option. If the study personnel 
is made aware of a patient’s potential interest and eligibility in this study through EPIC, previous 
study involvement, or clinician communication, a coordinator would be able to reach out to the 
potential participant via MyChart. The ability to use MyChart as an additional method of 
communication will allow for more options of communication with the participant. This tends to 
be a preferred method of contact for families and is a more readily accessible communication 
channel as it's used to communicate with clinicians. Regardless of the method of initial contact 
(e.g. call, text, email, MyChart) study coordinator will primarily communicate with participant in 
the method they express is preferable.

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From the patient's perspective: approaching/soon after a visit in clinic, they would receive a 
MyChart message from a CRC with a brief summary of the study. We would explain that they 
were contacted because they are potentially eligible. If they’re interested in learning more and 
being screened, we will confirm contact info, and offer to discuss additional details over their 
preferred method of communication at their earliest convenience. 
Waiver of Consent for Screening
Ensuring the study is a good fit for the participant is an important aspect of the recruitment 
process and study goals. To this end, we request a waiver of consent for approaching potential 
participants through utilizing screening surveys and/or pain rating scales as a preliminary 
screening method. If the participant meets initial eligibility criteria they will be invited to enroll in 
the study after appropriate material review. Additionally, staff will be collecting and storing 
contact information such as name, phone number, and email from either chart review or 
physician referral to aid in recruitment efforts. All unused (ineligible) contact information will be 
deleted at the end of recruitment, maintained only to ensure potentially ineligible families are not 
repeatedly approached. 
5.3. Informed Consent
Process for Obtaining Consent: Informed consent will be obtained prior to conducting any study 
procedures—excluding waived pre-screening measures. A single informed consent form will be 
used. 
The study investigator or coordinator typically provides a detailed explanation of the study to a 
prospective patient. The study coordinator will provide the potential participant and his/her 
guardian a copy of the informed consent form and assent form to review. The staff member will 
review the document with the family, describing any study procedures and potential risks and 
benefits associated with participating in the study. A HIPAA form will be incorporated into the 
Informed Consent Form. The HIPAA form describes participant and data confidentiality 
associated with the study. After allowing adequate time for review, the participant and parents 
will have the opportunity to ask questions and receive answers. When all questions have been 
answered, the consent and assent will be signed and a signed copy provided to the participant 
and parents. This will all be conducted before any study measures and interventions are 
undertaken. 
A patient will be informed that he/she is not obligated to participate in the study. The informed 
consent process should ensure that there is no penalty for not participating in a research study 
and that treatment will not be compromised if patients do not participate or if they cease 
participation at any time. Adequate time will be allowed for the prospective participant to ask 
questions. 
The patient, their legal representative, and the investigator or person obtaining the consent must 
sign the informed consent. A copy of the signed form must be provided to the participant. The 
informed consent form is to be retained in the participant source binder, along with the 
completed informed consent process note documenting the consenting process.
If the participant is between the ages of 10-17 parental consent will be obtained during the 
consent process. If the participant is ≥18 the participant will sign consent without the need of 
parental consent.
eConsenting: Consent may take place by several methods: in-person paper consent, in-person 
electronic consent (using REDCap for the eConsent, detailed below) or over the phone and/or 
secure video line (via REDCap for eConsent, detailed below). No matter the consenting 

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process, study procedures will not occur prior to a fully executed consent form. A copy of the 
consent form will either be given to the participant in paper form or emailed to them via REDCap 
depending on how the consent is completed. In all cases, the consent process will be 
documented on the informed consent process note.
Staff will make sure that the eConsent database is updated as soon as possible after a new 
version of the paper consent is approved. Staff will also make sure paper consents are used to 
consent eligible participants in the event that the eConsent database is not updated prior to 
eligible participants being available for consent approach by a member of the study staff. For 
the reasons described, the eConsent will not be submitted to the IRB for approval.
Integrating Consent Electronically: The IRB approved consent document will be uploaded into 
the database instrument. The IRB approved consent will be modified to an electronic format that 
includes all the same elements found on the paper document (i.e. IRB number, approval dates, 
version number, etc.). The elements of the consent requiring a signature has been added as a 
generated field. The instrument includes fields to capture full name, signature, and date and 
time of the signature for the consenter, and witness and conditional text that states that all 
signatures are associated with the Participant ID# registered in the database. When completed, 
REDCap will generate a footer that contains the long date and time the document was 
submitted and “Confidential” listed in the header as an added precaution to preserve the 
research participants' confidentiality. REDCap's 'Auto-Archiver + eConsent Framework' will be 
used.  The 'Auto-Archiver + e-Consent Framework' survey option adds two things to the typical 
survey-taking process. 1) Before a participant completes the survey, an extra certification page 
is added to end of the survey that displays an in-line PDF copy of their survey responses in 
which they will be asked to confirm that all information in the document is correct. Once they 
confirm all is correct, the survey will then be marked as complete. The survey will not be 
considered complete until they fulfill the certification step. 2) Upon completion of the survey, a 
static copy of their responses in the form of a consent-specific PDF will be stored in the project's 
File Repository. The consent-specific PDF may have the values of the e-Consent Framework 
Options inserted at the bottom of each page in the PDF. These values (i.e., name, date of birth, 
etc.) are added to the PDF as extra documentation of the identity of the person who is 
consenting.
The HIPAA Consent is integrated into the consent form.
Signature Process: Participants—and legal guardians if the participant is underage—and 
witnesses/individual obtaining signature will type their first and last name into a text box, sign 
their name in the signature field with a stylus or finger and then click “Now” by the date field to 
automatically enter the date and time. A copy will be sent electronically to the participant. 
eConsenting Process: Participant presenting to clinic will be given an electronic tablet with the 
preloaded IRB approved and HIPAA documents for the study. Participants will be given time to 
read through the consent form(s) and then the study coordinator (or designee) will review the 
consent, and any study handouts with the participant.  Once the consenting process has been 
completed and all questions have been answered, the study and HIPPA consents will be signed 
and dated by the participant and witness and submitted via the REDCap database. Participants 
be sent an electronic copy of the ICF documents through their provided email and will receive 
documents. Signed and submitted documents will be available as a PDF in REDCap's File 
Repository.  A PDF of the eConsent document will be sent to CCHMC HIM per requirements.
Remote eConsenting Process: The remote econsent process will follow the same process 
outlined above with two minor differences. 1) Communication with participant will be not be in-
person. 2) Witness/Individual obtaining consent will enter their first and last name, signature, 
and time of signature in a separate instrument outside of the main consent form. This might lead 

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to a signature time difference between witness and participant (plus parent, if applicable). This 
separate instrument will additionally capture the REDCap/CCHMC username of the individual 
obtaining consent.
5.4 Withdrawal
Participant withdrawal from the study
This is not a treatment study and participants are free to withdraw at any time without 
consequences. The reason for withdrawal will be documented for all participants withdrawn from 
the study.
Investigator-initiated withdrawal criteria
Given that this is not a treatment study, there are several circumstances where the investigator 
may terminate the involvement of a participant.  
1.
Participants are unable to adequately communicate and understand the consent form 
and instructions given to them. 
2.
Participants decline further participation in the study.
3.
Participants are unable to keep the appointments.
4.
Participants fail to comply with experimental protocol or instructions. 
5.
Identification of brain, neurologic, or severe psychiatric abnormalities beyond those 
normally associated with chronic pain.
6.
Experimenter assesses that withdrawal from the study is in the participant’s best 
interest.
7.
Patients fail to adequately comply with or complete sufficient portions of their treatment.
8.
Healthy control participants are using opioid or other analgesic drugs or patients are 
using non-prescribed drugs (positive drug test).
5.5 Re-Consenting Patients Turning 18 
Participants may turn 18 after enrolling due to the longitudinal nature of the study. Participants 
that turn 18 during their involvement of the study will be invited to reconsent as legal adults. If 
the participant does not reconsent, the participant will be discontinued from remaining study 
procedures.
5.6 Option for Future Re-Contact of Participants
The dual principal investigators would like to maintain the option for future re-contact of study 
participants after completion by the participant or termination of the study. The purpose for re-
contact would be to invite participation in the conduct of related or ancillary studies with a sub-
population of study participants. An optional consent for re-contact will be included in the study 
informed consent and assent documents.

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6. STUDY PROCEDURES
6.1 Timeline of Procedures
Participants will be examined at in person baseline session(s), will complete quarterly remote 
surveys, and will return for a 1 year follow-up in person session. Parent(s)/Guardian(s) may also 
be asked to complete surveys.
Baseline Session(s): Participants will undergo symptom assessment, psychosocial 
characterization, quantitative sensory testing, and MRI. Questionnaires may be completed 
remotely while quantitative sensory testing and MRI will be in-person.  QST and MRI 
assessments may be on separate days to minimize participant burden. 
Quarterly Remote Surveys: Participants will undergo symptom assessment and psychosocial 
characterization at approximately 3, 6, and 9 months after their baseline visit.
1 Year Follow-up: Participants will undergo symptom assessment, psychosocial 
characterization, quantitative sensory testing. Questionnaires may be completed remotely while 
quantitative sensory testing will be in-person.  
6.2 Symptom Assessment
Ratings of pain: Patients will be instructed to provide ratings of pain intensity and 
unpleasantness at the beginning of each session and during quantitative sensory testing. To 
help them differentiate between pain intensity and unpleasantness, standardized instructions as 
described in Price (Price et al., 1983) will be used. Ratings of the spatial extent of pain may also 
be acquired.
Demographic and Health History: Parents will be asked to provide information related to their 
child’s demographic (e.g., age, biological sex, gender, date of birth; ethnicity/race), known 
medical or psychiatric diagnoses, and current medications and therapies. This information will 
determine final study eligibility. We will also collect information about the (a) parents' pain 
history, (b) the child’s sleep history, and (c) the child’s current residential address (city, state, zip 
code, and county).  The address will be used for geospatial coding neighborhood measures 
(e.g., deprivation index(35-37), poverty(38, 39), proximity to greenspace(40, 41)) related to 
socioeconomic status (SES).  After processing the address data for different geomarkers (e.g., 
deprivation index, greenspace), all HIPAA identifiers will be removed. As part of the health 
history, parents (or guardian) will be asked to complete a health care use assessment reflecting 
medical and other treatments for pain.
Puberty status (Pubertal Development Scale, PDS) and additional questions (i.e., medications) 
about their menstrual cycle (biological females) will be assessed.
Body map(42): Patients will be asked to indicate body parts that are affected by pain.
CCHMC Headache Questionnaire(43-45): Will be used to characterize the experience of 
migraines and headaches (e.g., frequency, intensity, quality, and location) based on ICHD3 
criteria.
Pediatric Migraine Disability Assessment (PedMIDAS)(46): Will be used to assess migraine 
related disability.  
CRPS diagnostic questionnaire: Will be used to assess the extent of CRPS symptoms 
according to the IASP diagnostic criteria. In addition, participants will be asked to describe any 
potential injury that was associated with the beginning of the symptoms. 

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Rome IV Diagnostic Questionnaire for the Pediatric Functional GI Disorders (47): Will be used 
to assess FAPDs, including irritable bowel syndrome (IBS), functional dyspepsia (FD), 
abdominal migraine, and functional abdominal pain - not otherwise specified (FAP-NOS).
Abdominal Pain Index (API) (48): Will be used to characterize frequency, duration, intensity, and 
other aspects of abdominal pain.
Pain Severity Assessment Tool (PSAT)(49): Will be used to characterize the presence of 
multiple sites of pain (based on several MSK sites) and the presence and severity of somatic 
symptoms. Subscales are generated for “Widespread Pain Index” (WPI) and “Symptom 
Severity” (SS), which are used to dichotomize the presence or absence of widespread MSK 
pain. Also, the subscales can be combined for a Total Symptom Severity Score.
Pediatric Pain Screening Tool (PPST): Will also be used to (1) discriminate between pain-free 
and chronic pain cases and (2) determine low- vs. high- (i.e., overlapping pain) risk groups.  
Additional screeners (e.g., temporomandibular disorders - 3Q/TMD(50)) may also be used.
6.3 Psychosocial Characteristics
Revised Adolescent Sleep and Wake Scale (rASWS, (51)): 10 item plus sleep duration items. 
ASWS will be used to assess participant’s sleep quality.
Child Fear of Pain Questionnaire  (FoPQ-Child, (52) ): FoPQ will be uses to assess participant’s 
behaviors towards pain.
Functional Disability Index (FDI,(53)): FDI will be used to assess a participant’s level of function 
with pain.
Pain Catastrophizing Scale (PCS-C, (54, 55)): PCS-C will be used to assess participant’s 
behavior towards pain.
Pain Stages of Change Questionnaire – Adolescent Short Form (PSOCQ13-A, (56, 57)): This 
survey will be used to assess how a participant copes with their pain.
PROMIS Measures(58):
Pediatric Anxiety: Will be used to assess anxiety.
Pediatric Depressive Symptoms: Will be used to assess depressive symptoms.
Pediatric Fatigue: Will be used to assess fatigue.
Pediatric Cognitive Function 7a: Will be used to assess cognitive functioning.
Pubertal Development Scale (PDS): The pubertal development scales PDS will determine a 
non-invasive account of pubertal development.
Pain Frequency, Severity, & Duration Scale (PFSD,(59)): Will be used to collect clinical pain 
history.
Children’s Somatic Symptoms Inventory (CSSI, (60)): Will capture levels of somatic complaints 
and sensory pain qualities.
PROMIS Pain Quality – Sensory(61): Will capture levels of somatic complaints and sensory 
pain qualities.
PROMIS Pain Interference(62): Will capture pain-related disability over the past week.
Tampa Scale of Kinesiophobia-11 (TSK-11, (63-65)) – Will capture fear of movement.

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Pediatric Daytime Sleepiness Scale (PDSS, (66-68)) – Will assess daytime sleepiness
Pre-Sleep Arousal Scale (PSAS, (69)) – Will assess pre-sleep arousal related to cognitive (e.g., 
racing thoughts, worry, and anxiety at bedtime) and somatic (e.g., tense muscles, cold 
extremities, or pounding heart before falling asleep) factors
Morningness/Eveningness Questionnaire (MEQ, (70)) – Will capture circadian phase preference 
(e.g., “chronotype”) related to morningness vs. eveningness
Adolescent Sleep Hygiene Scale (ASHS, (71)) – Will assess typical sleep habits
Adolescent Insomnia Questionnaire (AIQ, (72)) – Will capture behaviors and experiences 
related to insomnia
Life Orientation Test (YLOT, (73)) – Will assess dispositional optimism (e.g., positive 
expectations of the future).  
10-Item Positive and Negative Affect Schedule for Children (PANAS-C-SF) - Will be used to 
assess positive affect (i.e., joyful, cheerful, happy, lively, proud) in addition to negative affect 
(i.e., miserable, mad, afraid, scared, sad) over the past few weeks
Connor-Davidson Resilience Scale 10-item (CD-RISC-10, (74-76)) - Measures one’s ability to 
cope with stress and adversity.
Child PTSD Symptom Scale(77) (CPSS-V, (77)) - Participants are asked to identify the most 
distressing or traumatic event that bothers them and assess post-traumatic stress symptoms 
over the past month.
PROMIS Ped Family Relationships 8a, v1.0) – Will ask about relationships.
PROMIS Ped Peer Relationships 8a, v2.0 - Will ask about relationships.

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6.3.1 Timeline of Survey Administration (Table1 )
Survey Completion Timing**
Timing
(Approximate)
Data Collection Procedure
Base
(T1)
3m
(T2)
6m
(T3)
9m
(T4)
12m
(T5)
Pubertal Development Scale (PDS)





Menstrual Cycle (MC)





Functional Disability Inventory (FDI)





PROMIS Ped Anxiety





PROMIS Ped Depression





PROMIS Ped Fatigue





PROMIS Ped Cognitive Function





CHOIR Body Map





Primary
(In-person 
Preferred,
Remote for QHU)
Pain Symptom Assessment Tool (PSAT)





CCHMC Headache Questionnaire





Pediatric Migraine Disability Assessment 
(PedMidas)





ROME IV





Abdominal Pain Index (API)





3Q/TMD





Pediatric Pain Screening Tool (PPST)





Pain Frequency, Severity, & Duration Scale 
(PFSD)





PROMIS Pain Quality - Sensory





PROMIS Pain Interference





Pain Catastrophizing Scale – Child (PCS-C - 
Child)





Tampa Scale of Kinesiophobia-11 (TSK-11)





Revised Adolescent Sleep Wake Scale (rASWS)





Pediatric Daytime Sleepiness Scale (PDSS)





Pre-Sleep Arousal Scale (PSAS)





Adolescent Insomnia Questionnaire (AIQ)





Children's Somatic Symptoms Inventory (CSSI)





Fear of Pain Questionnaire (FOPQ – Child)





Pain Stages of Change Questionnaire (PSOCQ)





Child PTSD Symptom Scale for DSM-5





Supplemental
(Remote Preferred)
Positive & Negative Affect (PANAS)





Youth Life Orientation Test (YLOT)





Connor-Davidson Resilience Scale (CDRS-10)





Adolescent Sleep Hygiene Scale (ASHS)





Chronotype Questionnaire (MEQ)





PROMIS Ped Family Relationships





PROMIS Ped Peer Relationships





** Anticipated Survey Completion: Surveys or procedures conducted () and not conducted () at Screening (T0), 
Baseline Visits (T1) and Quarterly Visits at 3-, 6-, 9, and 12-months (T2-T5)

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6.3.2
Parent Surveys (Table 2)
Survey Completion Timing**
Timing
(Approximate)
Data Collection Procedure
Research
Domain*
Base
(T1)
3m
(T2)
6m
(T3)
9m
(T4)
12m
(T5)
Participant demographics
1





Health history form (Participant & Parent)
1





Health history form (Participant) - QHU
1





Pre-Visit
(Remote)
Health care cost diary (Participant)
1





Health care cost diary (Participant) - QHU
1





Fear of Pain Questionnaire (FOPQ – Parent)
5





Pain Catastrophizing Scale – Child (PCS-C, 
Parent)
5





QHU, Quarterly health update
** Anticipated Survey Completion: Surveys or procedures conducted () and not conducted () at Screening (T0), 
Baseline Visits (T1) and Quarterly Visits at 3-, 6-, 9, and 12-months (T2-T5)
6.4 Thermal Imaging
To better describe participants’ symptoms, temperature of their affected and unaffected body 
regions will be measured using an infrared camera. Changes in temperature in the affected limb 
is part of the diagnostic criteria for CRPS. Thermal imaging will provide valuable information on 
the symptoms exhibited by the participants, without any risk.
6.5 Quantitative Sensory Testing
Participants will first undergo psychophysical training in which they receive a standard set of 
heat and cold stimuli (up to 33 stimuli of 5 sec plateau duration) ranging from 0-49°C.  This 
procedure provides participants with experience using the rating scales, facilitates 
generalizability of results, and provides a measure of pain sensitivity that is independent from 
that obtained during the fMRI portions of the study.  Such training sessions also maximize 
reproducibility of pain ratings (78).  After completion of training, participants will undergo the 
following battery of sensory tests for the remainder of the psychophysical session.
Threshold Assessments:
Thermal thresholds: Innocuous warm, innocuous cool, cold pain, and heat pain thresholds (up 
to 6 presentations/modality) will be assessed using the method of limits.
Tactile Thresholds: Von Frey filaments with increasing thickness will be applied perpendicular to 
the participant’s skin with a very light pressure. The applied pressure will be enough to slightly 
buckle the filament. To avoid visual clueing, participants will keep their eyes closed for the 
whole duration of this task. Each filament will be applied up to 5 times at a given body site and 
threshold will be defined when participants are able to identify the touch in 80% of the trials.
Pressure Pain Threshold (PPTh): PPTh will be assessed with a hand-held algometer (Algomed, 
Medoc) across up to three repetitions of stimuli applied perpendicularly on testing site.  
Participants will be instructed to press a button and/or say “pain” at the first sensation of pain 
(PPTh).  
Spatial Tasks:
Conditioned Pain Modulation: Conditioned pain modulation (also known as diffuse noxious 
inhibitory control) will be activated by immersion of the hand in 0-10°C water and evaluated by 
examining the reduction in pain intensity ratings to a pressure pain threshold and noxious heat 

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stimulus (up to 49°C) applied to the trapezius and ventral forearm (respectively), as we have 
done recently (79).  
Spatial Summation of Pain: Spatial summation of pain will be assessed by placing two thermal 
stimuli (up to 49°C) on participants’ legs or other body regions, typically at a 10cm separation 
distance. Participants will be instructed to rate overall pain with one rating. Control stimuli (up to 
49°C+35°C, and up to 49°C alone) will allow the assessment of spatial summation.
Attentional Inhibition of Pain: During the spatial summation paradigm, participants will provide 
ratings during two attentional conditions: 1) Participants will be cued to rate overall pain with one 
rating. 2) Participants will be cued to divide their attention between both stimuli and instructed to 
rate pain from each stimulus separately. Control stimuli (up to 49°C+35°C, and up to 49°C 
alone) will allow the assessment of spatial summation and attentional inhibition of pain.
Graphesthesia: A graphesthesia task in which numbers between 0 and 9 will be drawn in a 
pseudo-randomized order on the participant’s skin using a rounded tip stylus-like device with 
very light pressure. The pressure will be enough to allow for a sensation of the stylus moving 
across the testing area. To avoid visual clueing, participants will keep their eyes closed for the 
whole duration of this task.
Two-point discrimination: One or two innocuous tactile stimuli will be delivered at various 
distances and the participant will report whether they perceive one or two points.  
Temporal Tasks
Offset Analgesia: Offset analgesia will be assessed using the three temperature method (up to 
49°C 5s, 50°C 5s, 49°C 20s) using continuous ratings of pain intensity, as we have done 
previously (80).  
Temporal Summation (TS): A standardized pinprick stimulator, up to 256 mN will be used for the 
assessment of TS.  VAS ratings of single pinprick stimulation will be compared with a series of 
10 repeated pinprick stimuli of the same force over the same area. The mean ratings of series 
divided by the mean pain ratings of single stimuli was calculated as the WUR.  We may also 
collect two additional ratings (e.g., 15 and 30 seconds after the 10 stimuli) of any remaining pain 
(e.g., after-sensations).  
6.6 Brain Imaging 
Total scanning time: Together with inter-scan intervals and time needed for positioning 
participants in the scanner, the proposed sequences (below) can be obtained in a 1-1.5 hour 
duration MRI scanning session. This duration has been used in the vast majority of our imaging 
studies since 1992 and we have found that participants can tolerate this duration with minimal 
difficulty. Participants are queried for possible discomfort at the end of every series. Participants 
can generally remain still during the 5-12 minutes acquisition series and can shift/reposition 
arms and legs between series if needed. 
Structural scan: A high-resolution T1-weighted sequence will be used for visualization of brain 
anatomy and for spatial normalization of functional imaging data. This sequence will last 
approximately 5 minutes. These data can be used for volumetric brain mapping of cortical and 
subcortical structures. T2 sequences and diffusion tensor imaging sequences may also be 
acquired to further characterize aspects of brain anatomy.  
Resting-state functional connectivity: Resting-state functional brain images will be acquired using 
conventional or multiband BOLD sequences. These sequences consist of rapidly-acquired series 
of brain images covering the whole brain. Each resting-state series acquisition will last up to 12 

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minutes. These images will be used to investigate functional connectivity between brain areas at 
rest. 
Cerebral Blood Flow (CBF): CBF will be measured in a fully quantitative fashion with arterial 
spin labeled (ASL) imaging (Luh et al., 1999). This technique, which is regularly used in our 
laboratory, allows investigation of steady-state brain activity, but has also been successfully 
used to study task related activity.  
Task-related activity: Functional brain images will be acquired using a BOLD sequence to similar 
to the one used for assessment of functional connectivity. ASL sequences may also be used for 
selected tasks. While these images are acquired, participants will undergo several sensory tasks. 
Multisensory task: The multisensory task will include visual (reversing/flashing checkerboard), 
auditory (tones) and sensorimotor (finger opposition) stimuli. Participants will be asked to focus 
on these stimuli while brain images are acquired. 
Spatial tuning task: The brain mechanisms regulating spatial tuning may be further delineated 
using our divided attention paradigm.(81) Two noxious thermal stimuli (≤48°C, 10s) will be 
delivered to participants’ legs at a 10cm separation distance.  Participants will provide ratings 
during two attentional conditions: 1) Participants will be cued to rate overall pain with one rating.  
2) Participants will be cued to divide their attention between both stimuli and instructed to rate 
pain from each stimulus separately.  Control stimuli (≤48°C+35°C, and ≤48°C alone) will allow 
the assessment of spatial summation and attentional inhibition of pain.
Graphesthesia Task: Spatial processing disruptions may be further probed with the 
graphesthesia task.  Numbers will be traced onto the legs of the participant and the participant 
will indicate which number was traced.  
6.7 Opting-out and Omission of Experimental Procedures
All experimental procedures are observational only and do not involve provision of any 
treatment. Accordingly, participants will be allowed to opt out of any experimental procedure 
without prejudice.  Similarly, time constraints or technical issues may result in omission of 
certain experimental procedures. Partial data sets will still have great utility given the lack of 
knowledge of pediatric pain.  Opted-out and omitted experimental procedures will be 
documented with a note to file, and as they are anticipated, will not be considered a deviation. 
6.8 Pregnancy
Adolescents who are pregnant or nursing may not participate. A urine pregnancy test may be 
conducted to confirm a lack of pregnancy if the participant is sexually active and not using 
appropriate birth control. Underage participants who test positive for pregnancy will have their 
parent/caregiver notified. Participants who become pregnant after the baseline session may 
remain enrolled.  
6.9. Drug/Substance Use
A urine sample will be collected from all participants to assess the usage of non-prescribed 
drugs/substances. Healthy participants with positive tests for opioids or other analgesics will be 
excluded. Patients using non-prescribed substances may also be excluded.  Underage 
participants who test positive for drugs/substances will have their parent/caregiver notified. 
7. DATA ANALYTIC PLAN
Behavioral data: Mplus(82) will be used to conduct all behavioral analyses to: 1) handle missing 
data via either maximum likelihood estimation or multiple imputation, with both allowing auxiliary 

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correlate variable inclusion(83, 84); an attrition analysis will be performed using SAS PROC MI 
to identify possible non-random attrition dependent variable values (MNAR). If dropout is 
systematic, Selection and Pattern Mixture Models, and their newer mixture versions, (85, 86) 
will be used to appropriately address MNAR attrition(83), 2) utilize several default parameter 
estimation algorithms (e.g., MLR, MLF, WLSMV) robust to Type-1 errors arising from non-
normal response data, and 3) to allow additional options (e.g., start values, Cholesky 
decomposition) in the unlikely event of parameter estimation non-convergence.
Neuroimaging Data: The FSL (FMRIB’s Software Library, Oxford, UK) software package will be 
used for the vast majority of image processing operations and statistical analyses. FSL analyses 
will be augmented by AFNI and/or CONN(87) and python scripts.
Spatial processing and transformation: T1-weighted images will be brain extracted and then 
non-linearly warped into standard anatomic space (MNI152). EPI images will be motion-
corrected, unwarped, and registered to the high resolution T1 structural image and then 
nonlinearly warped to standard space. To facilitate intersubject comparisons and to reduce the 
number of statistically independent comparisons, BOLD images will be smoothed with a 5 mm 
FWHM filter.
Processing of pCASL images into CBF images: A single fully quantified CBF volume 
(ml/100g/min.) will be calculated from each 4D series of PCASL images(88) following motion 
correction, tag-control subtraction, and assessment of T1 signal. CBF images will be 
transformed to standard space as described above. 
Statistical analysis of ASL data: CBF data from each individual will be motion corrected, and 
ratio normalized to minimize the impact of fluctuations in global signal. A first level fixed effects 
analysis will be executed within FEAT to identify within subject effects. A second level random 
effects analysis will be executed within FEAT to identify between group effects. Clusters of 
activation will be identified using a threshold of Z>3.1 and their statistical significance will be 
estimated according to Gaussian random field theory.(89)
BOLD / Connectivity analyses: The aCompCor approach will first be used to reduce variability 
due to physiological and scanner noise(90) using a processing pipeline integrating modules 
from FSL and AFNI. Denoised data will then be imported into FEAT. Time courses of activity will 
be extracted from seed regions. These seed regions will be objectively defined on the basis of 
each participant’s anatomy. Next, first level, fixed-effects analyses will be run for each BOLD 
series to identify voxels that have time courses that are significantly correlated with that of the 
seed or of the task. Second level analyses will examine effects across imaging series, but within 
subjects. Finally, third level random effects analyses will identify differences in functional 
connectivity according to groups. Clusters of activation will be identified using a threshold of 
Z>3.1 and their statistical significance will be estimated according to Gaussian random field 
theory.(89) Age and sex will be added as covariates.
Conjunction analyses: Conjunction analyses will be performed on both CBF and BOLD data in 
order to determine if activation (or connectivity) overlaps between chronic pain groups.(91) This 
analysis tests the null hypothesis of no overlap, and as such, is an optimal method to test for 
similar patterns (but not magnitudes) of activation or connectivity.  Statistical significance of 
overlapping clusters will be determined according to Gaussian Random Field theory.(89)
Structural analyses: T1-weighted structural data will be analyzed with FSL-VBM as we have 
done previously.(92) A regression analysis will be performed using a general linear model to 
examine the relationship between treatment type and grey matter differences across the whole 
brain. Age and sex will be added as covariates. Permutation-based nonparametric testing 
(10,000 permutations) will be used to evaluate this relationship in a voxel-wise fashion. 

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Threshold-free cluster enhancement will be utilized to define significant clusters. A familywise 
error corrected P value of P < .05 will be applied to correct for multiple comparisons and to 
identify clusters exhibiting a significant relationship between grey matter density and treatment 
type.  
Multi-task deep Ensemble learning model: We will design the novel multi-task deep Ensemble 
learning model to be a two-level ensemble model (Fig. 7), combining the predictive power of 
both state-of-the-art deep learning and traditional machine learning. We will 1) first build a 
diverse model library. The diversity plays a key role, and it is a necessary and sufficient 
condition in building a powerful stacking ensemble model.(93-95) Each input data type (i.e., 
features extracted from fMRI, QST, and psychological assessments) will be used to create a 
series of unique machine learning models. We will build a model library that will consist of a 
diverse set of multiple traditional models, including  SVM,(96) Artificial Neural Networks 
(ANN),(97) random forest (RF),(98) LR,(99) Ridge(100) and least absolute shrinkage and 
selection operator (LASSO).(101) Multiple models will be trained with different hyperparameter 
settings and training datasets. 2) We will then integrate the multiple machine learning classifiers 
from the model library using our multi-channel deep neural network (DNN) as a fusion 
model.(102, 103) The number of channels is designed based on the number of models in model 
library. Each input channel will contain several neural network blocks. The multiple input 
channels will be eventually fused into one output channel through a fusion block. Each block will 
consist of a fully connected layer, a batch normalization layer, and a dropout regularization 
layer. Followed by the fusion block, a softmax output layer will be used to predict chronic pain 
conditions (i.e., migraine, complex regional pain syndrome, musculoskeletal pain, functional 
abdominal pain, as well as heathy controls) and pain trajectory. We will perform nested k-fold 
cross-validation (i.e., training, validation, and testing dataset split method) to evaluate our model 
with multiple metrics, including multi-class accuracy, sensitivity, specificity, and area under the 
receiver operating characteristic curve (AUC). We will perform data augmentation on training 
data to prevent model overfitting using our prior method.(104) Hyperparameters of the model 
will be optimized based on validation data before testing on unseen test datasets. For feature 
ranking, we will apply a connection weights method(105) to identify the most discriminative 
features for each chronic pain condition or trajectory of recovery. The deep Ensemble learning 
model will be implemented using Python, scikit-learn, and Tensorflow package. Prior chronic 
pain studies(106) demonstrated that a robust deep learning model can be obtained using ~200 
samples. Thus, we expect that the sample size (500 subjects) in this work, combined with the 
data augmentation strategy, is sufficient for our deep learning model. During the data collection 
period, we will develop/optimize analysis pipelines with existing patient and control data. 
Power analysis and missing data: Power calculations were performed for neuroimaging data to 
ensure that we have an adequate sample size 1) to detect brain activity changes in hypothesis-
directed analyses and 2) to identify relevant brain mechanisms through deep Ensemble learning 
techniques. Power calculations for neuroimaging data are challenging since such calculations 
depend crucially on effect size as well as properties of the imaging data and statistical approach 
used to deal with the multiple comparisons of >20,000 voxels. We used the NeuroPower 
tool(107) to calculate statistical power and sample sizes based on our preliminary BOLD in 
youth with migraine. Based on between group comparisons of functional connectivity data 
between migraine patients and controls (preliminary data C.2.2), 36 participants (18 
participants/group) would be required for 80% power in between group comparisons. However, 
contrasts between patient groups would likely need greater numbers due to potentially more 
subtle differences. Consistent with this expectation, power calculations examining differences in 
functional connectivity of the amygdala between migraine and functional abdominal pain 
(preliminary data C.2.4) revealed that approximately 108 participants (54 participants/group) 
would be required to reliably detect differences between two chronic pain conditions. Both 

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power calculations were performed using z-transformed statistical images of the whole brain, a 
cluster-forming threshold of z>3.1 and p<0.05, isotropic smoothness of 5mm, and voxel sizes of 
2x2x2mm, 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. Power calculations for the deep 
Ensemble learning techniques are nearly impossible to develop given the nature of the 
analyses, however, analogous machine learning approaches with pain data required 109 
participants to develop a marker for a single group.(108) Accordingly, we estimate that 100 
participants/group would provide adequate power for both hypothesis-directed analyses and 
machine learning analyses. 
Plan for Robust and Unbiased Results: Our group has a history of producing highly reproducible 
imaging and psychophysical studies. Our original psychophysical finding of offset 
analgesia(109) has been replicated in more than 22 papers by laboratories across the world. 
Our original finding of anterior insular activation during pain(32)  has been replicated by 
hundreds of brain imaging studies.(110-113) Our imaging studies have been highly 
reproducible, in part, because we always use whole-brain searches rather than region of 
interest (ROI) analyses, consistent corrections for multiple comparisons using conservative 
cluster-forming thresholds, and random effects statistical models to increase generalizability and 
to diminish outlier effects. This highly-powered data set will be analyzed with a conservative, 
statistically rigorous approach designed to maximize reproducibility.(114) Towards this end, all 
analyses will be performed across the entire brain and both positive and negative relationships 
will be assessed and reported.(115, 116) These analyses will be controlled for multiple 
comparisons by cluster-based methods, such that family-wise error rates will be held to a 
p<0.05. Region of interest approaches will be avoided in order to minimize errors due to 
confirmation bias and “double-dipping.”(115, 116) Analyses will be conducted by individuals 
blinded to group assignment in order to further minimize biases.
8. DATA MANAGEMENT
An Electronic Data Capture (EDC) system that is designed to support reliable and secure entry 
of non-imaging data will be used for the study. Paper forms might be used for recording of pain 
ratings and may be used as backups for questionnaires in the event of computer malfunction 
during data acquisition.  
Data Entry: Data can be entered directly via a fully validated and 21 CFR Part 11 compliant, 
secure application and stored centrally. Data will be entered by subject study identification 
number; names will not be linked with participant data in the database. 
Data Validation and Monitoring: Real-time validations will be integrated into the data entry 
system. Inconsistent or questionable values can be flagged during entry, and reports can be 
automatically generated to the data entry client. These reports provide the information 
necessary to investigate any data entry errors or resolved questions regarding out-of-range or 
questionable values. 
Data Security and Integrity: All data changes are written to an audit trail. The audit trail identifies 
the data item by table, column and key field. The entry includes the user, date and time, as well 
as the old value and new value. Data are saved at regular intervals during data entry to prevent 
loss of information in the event of a disruption of the Internet connection. 
The following levels of security are employed to ensure privacy and integrity of the study data:

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1.
Access to the study data and protocol requires use of assigned user names and 
passwords.
2.
Individual roles and access levels are assigned by the study data manager. 
3.
Passwords are changed regularly. 
4.
Web-based entry uses secure socket layer data encryption.
9. DATA SHARING AND FUTURE USE
Data That Will Be Shared: Data sharing represents a critical dimension of the proposed 
research and is a requirement for publication in many journals and is required by NIH. The data 
will be quite complex with psychological, psychophysical, demographic information collected 
outside of the scanner, and multiple modalities of MRI information collected during scanning. 
Accordingly, this rich dataset can be utilized for many secondary analyses. All modalities of data 
will be shared, with raw data included. We will share identified data with other related studies at 
CCHMC for which participants have given consent that ask them to do the same procedures in 
order to decrease participant burden in scientifically appropriate situations.
Formatting of Data to Facilitate Sharing: As data is acquired, it will be named and placed into 
directory structures according to the BIDS standard (Brain Imaging Database Structure: 
http://bids.neuroimaging.io/). This standard accommodates all types of neuroimaging data to be 
acquired in the present proposal, and also allows for the inclusion of non-neuroimaging data 
such as psychological, psychophysical, and demographic information. Importantly, when data is 
in this format, it can be readily shared within OpenFMRI and other data warehouses.
Prior to sharing, all data will be de-identified in a HIPPA-compliant fashion. Data sets will be 
carefully reviewed to make sure that information such as age and sex cannot be used to gather 
additional information that could potentially identify individual subjects. For example, only year 
of birth, rather than date of birth, will be made available. All categorical demographic variables 
will be collapsed into categories large enough so that combinations of demographic categories 
for age, sex, area of residence, etc., will have 10 or more individuals in each cell. Neuroimaging 
data may be "de-faced" to further protect the privacy of participants. This data set will be 
accompanied by a data dictionary describing the content of each data set. 
Deposition into Open Databases for Distribution: Upon completion of the study (including 
primary and secondary analyses), the principal investigators will generate public use data sets 
for distribution. There are several potential data warehouses for distribution of this dataset: 
OpenfMRI, an NSF-funded project led by Russ Poldrack, OPEN PAIN, a NIH-funded project led 
by Vania Apkarian, COINS, led by Vince Calhoun, the Pain and Interoception Imaging Network 
(PAIN), led by Emeran Mayer. The final choice for deposition will be driven by the 
efficiency/accessibility of the database at the time of study completion. All of these databases 
support non-neuroimaging data (i.e. psychological questionnaire, pain ratings, migraine 
frequency, demographics, etc.) as well as neuroimaging data. 
Accessibility of the Data: Once deposited into an open database, data will be open to the 
greater scientific community according to the terms of the individual database. Data will then be 
fully available for secondary analyses, data mining, and to facilitate discovery by combining our 
data with that of other centers for large-scale analyses. We anticipate making the study data 
publicly available following the publication of the primary papers describing the results from the 
proposed specific, individual study (with a goal time line of within 12 months of the final data 
lock). 

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10. RISKS TO THE SUBJECTS
10.1 Human Subjects Involvement, Characteristics, and Design. 
Children will be recruited to undergo quantitative sensory testing and MRI scans in order to gain 
insights into central nervous system mechanisms supporting pain. 
10.2 Study Procedures, Materials, and Potential Risks.
At initial screening, participants will complete questionnaires to ensure eligibility.  At study visits, 
subjects (and their parent/primary caregiver, when appropriate) will provide information on 
demographics and complete standardized, psychometrically validated questionnaires and tests. 
Quantitative sensory testing will be conducted during the baseline and the followup visits.  
Magnetic resonance imaging of the brain will also be obtained during the baseline visit.  At each 
study visit, a review of adverse events will be conducted.  
10.3 Potential Risks. 
The risks associated with confidentiality are minimal because all data will be coded by subject 
number. Any potential risk associated with participation in this study related to potential side 
effects of the experimental task (i.e. sensory stimulation) and procedures (functional imaging 
and quantitative sensory testing) will be closely monitored in this study.  
Magnetic Resonance Imaging. 
While MRI involves the use of powerful magnetic fields and radiowaves, scanning does not 
expose subjects to any physical risks. 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 . 
MRI Incompatible Objects in/on the Participant: MRI incompatible objects in/on the body have 
the potential to move, heat, and/or malfunction. Participants with MRI incompatible objects 
within or on their body will be excluded from the study. Participants will be carefully screened 
before entry into the experiment and before entry into the scanner environment to minimize this 
risk.
Main Static Magnetic Field: The 3.0 Tesla static magnetic field strength of the MRI scanners to 
be used in this study is below the 8.0 Tesla limit recommended by the FDA guidelines for 
human research. The FDA has concluded that magnetic field below 8.0 Tesla does not by itself 
impose a risk to human participants. 
Specific Absorption Rate: The FDA guidelines for the specific radiofrequency absorption rate 
(SAR) are set by limiting the patient’s core temperature rise to less than 1 degree Celsius.  In 
the absence of core temperature monitoring equipment, the recommended FDA limits for the 
head are 3.2 W/kg, on average.  The MRI scanner system limits the SAR to 3.2 W/kg. In the 
event that this value is exceeded, the transmitter power supply is turned off automatically within 
3 to 5 seconds.  These measures ensure that the MRI scanner is well within the current FDA 
regulations on SAR.
Gradient Speed: The FDA suggested rate of change of magnetic field (dB/dt) is based only on 
avoiding discomfort to the participant. Peripheral nerve stimulation and other symptoms do not 
usually occur until dB/dt >20T/sec, and all sequences will be designed to avoid generation of 
such symptoms.
Acoustic Noise: The FDA deems risks from scanner noise significant when the peak unweighted 
sound pressure level exceeds 140 dB or when the A-weighted root mean square (rms) sound 

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pressure level is greater than 99 dBA with hearing protection in place.  Hearing protection will 
be accomplished with our MRI compatible A/V system headphones.  These specially designed 
headphones provide up to 30 dB of sound isolation from the MRI scanner, and will ensure that 
scanner noise levels do not pose any risk to hearing.  
Claustrophobia within the MRI Scanner: Healthy participants will be queried for claustrophobia 
and excluded. On occasion, a participant may be unaware of their claustrophobia until they are 
in the scanner. Since this is a basic research investigation, participants unable to tolerate the 
scan will simply be removed from the scanner. In addition, participants will be given a “panic” 
button to hold during the scans. In the event that a participant becomes uncomfortable, he or 
she can press the panic button to notify the operator of the need for immediate attention. 
Intercom contact will be opened immediately, and the participant can be removed from the 
scanner if needed. In addition, participants will be monitored visually and via microphone during 
the whole procedure to ensure that they are tolerating it.
Experimental Pain. 
The experimental pain procedures are widely used and safe procedures. We have specifically 
adapted them to be well-tolerated by children.  While generally safe, the experimental pain 
procedures confer some limited risks.  One risk common to all procedures is that the subject will 
experience pain or discomfort.  Specific risks of each procedure are discussed below. 
Thermal pain.  There is limited risk associated with the delivery of thermal pain. However, this 
task may produce transient reddening of the stimulated site. 
Cold Immersion. There is limited risk associated with the cold immersion procedure. 
Pressure Pain. There is limited risk associated with the pressure pain procedure.  However, this 
task may produce minor bruising or other transient trauma at the stimulation site in some 
subjects.  
Innocuous Sensory Stimulation 
Side effects or adverse events associated with the experimental tasks involving innocuous 
sensory stimulation are expected to be relatively minor. However, chronic pain patients may find 
normally innocuous tactile, visual, and auditory stimuli as painful or unpleasant.
Psychological Questionnaires 
Completion of psychosocial measures, aka questionnaires, may feel intrusive and 
uncomfortable to some persons. This might induce some mild psychological distress. If 
participants experience such feeling, they will be instructed to inform the experimenter. 
11. ADEQUACY OF PROTECTION AGAINST RISKS.
11.1 Informed Consent and Assent
Potential subjects will be identified during an evaluation at Cincinnati Children’s Hospital. In the 
case of patients, the physician/nurse practitioner/psychologist who examines the child or 
adolescent will explicitly state that they will continue to receive the same high quality of care 
from them should they choose not to participate. If the participant/family is interested in 
participating, informed consent from the adults and assent from the child will be both obtained. 
For both patients and healthy volunteers, the physician/nurse practitioner, research 
nurse/coordinator, and/or a study PI will provide a full description of the study and answer any 
questions that the family/participant may have. Approved procedures and forms of the 
Institutional Review Board will be utilized.  The purposes and the risks of the investigation and 

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the procedures of the study will be explained. The families/participants will be explicitly told that 
their medical care will not be affected if they choose not to participate. 
11.2 Protection Against Risk
Baseline evaluations will be conducted and exclusion criteria applied to ensure that subjects 
who are enrolled are not at known risk (e.g., metal orthodontia and fMRI). Open-ended 
questions about possible adverse health experiences will be employed in this study to 
prospectively assess potential risks among participants.  
Magnetic Resonance Imaging. The primary risk of MRI involves: 1) scanning in the presence of 
magnetic implants (or material) attached to the subject, and 2) claustrophobia. To minimize 
these risks, subjects will be screened prior to the imaging procedure.  In addition, subjects will 
be informed that they can discontinue the procedure at any time should they become 
uncomfortable. Subjects will be monitored visually and via microphone to ensure that they are 
tolerating the procedure. As the scanner is very loud, subjects’ hearing will be protected with 
noise-reducing headphones specifically designed for use in the MRI scanner.
Experimental Pain Procedure. Stimuli that have been used extensively by our laboratory and 
others’ laboratories do not produce tissue damage, burns, or frostbite.  Temperatures in this 
range are frequently encountered in daily life (snow, ice water bath, handwashing, dishwashing, 
etc.) and have been determined to not represent more than a minimal risk in other protocols at 
Cincinnati Children's Hospital.  While they produce pain, risk to the subject is minimal, because:  
(1) the pain is transient in nature, and generally subsides immediately after the procedure; (2) 
subjects are instructed that they may stop any procedure at any time with no adverse 
consequences; and (3) the level of pain experienced by subjects is below their tolerance level.  
Also, risks will be minimized by adhering to the exclusion criteria, and full discretion by the PI to 
exclude subjects for whom they feel there is excessive risk for participation.  Specific 
considerations will be used for the following assessments:
Thermal Pain: Combinations of stimulus temperatures, areas, and durations will never be 
sufficient to produce tissue damage.  For example, the temperature range that we routinely use 
with a 16x16mm probe would extend from 35°C-49°C.  All thermal stimuli will be delivered by 
devices that automatically shutdown in the event of malfunctions leading to temperatures 
sufficient to produce burns.  Furthermore, all participants will be conscious and will be free to 
terminate the stimulus at any time. To facilitate escape from stimulation, probes will never be 
strapped to the participant. Instead, probes will be either manually applied by the study staff, 
held in place by a spring-loaded device, or applied by having the participants passively rest their 
limb in contact with the probe. Thus, the participants will only have to move their body part away 
from the probe in order to escape the stimulus. 
Cold Immersion: While the cold water is perceived as unpleasant, there is minimal risk 
associated with this procedure. Subjects will immerse their foot to the ankle or hand up their 
wrist. Subjects will continue until the end of that trial or until they report intolerable pain. 
Subjects are told to remove their foot or hand anytime if it becomes intolerable. The maximum 
immersion time for any trial will be 90s with a minimum temperature of 0C for the foot and 
hand. 
Pressure Pain: Pressure will be delivered by a hand-held algometer (spring-controlled device 
delivering calibrated pressure via a flat 10mm diameter rubber tip) at an approximate rate of 
30pka/sec until reaching the first sensation of pain.  Subjects will continue until the end of that 
trial or until they report intolerable pain. Subjects are told to say ‘stop’ anytime it becomes 
intolerable.  The risks of bruising and lingering pain will be diminished by applying brief stimuli 
well below the subject’s tolerance level.  

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Innocuous Sensory Stimulation: The innocuous sensory stimuli are not delivered at an intensity 
with potential to damage the skin or elicit significant discomfort in healthy participants.  
However, chronic pain patients may perceive these stimuli as painful and/or unpleasant.  As in 
the case of the noxious sensory stimuli, all participants will be able to stop the procedure at any 
time.  
Psychological Questionnaires: If participants experience psychological discomfort during 
completion of psychological questionnaires, they will be able to skip any/all items of the 
questionnaires. 
11.3 Adverse Event Reporting. 
All participants will be monitored for safety during the study. Adverse Events will be reported 
from Visit 1 until the final endpoint.  Beginning at Visit 1, each visit will include a review of any 
adverse events solicited by use of standard open ended question. AEs include new events not 
present prior to initiation of study procedures or events that were present prior to study 
procedures but have increased in severity.  AEs will be recorded and monitored using an AE 
case report form that will record AEs by body system, preferred term, severity and relationship 
to the study, actions that were taken, and current status of the participant.  Study staff will notify 
the PI immediately of any serious adverse events or any adverse events that are suspected to 
be related to the study. 
11.4 Incidental Findings 
The imaging protocol used in this study includes only the minimum MR scanning needed to 
execute the tasks and paradigms for the research project. Board-certified radiologists at 
CCHMC have determined that the limited anatomical images generated are not adequate to 
diagnose or to rule out pathology. No report will be generated or supplied to the 
participant/parents/legal guardians of the participants. However, all scans performed for this 
project will be reviewed for gross abnormalities by a board-certified or board-eligible radiologist 
through the PACS system. Although no diagnosis will be made, in the event that abnormal 
findings are identified, the PI will be informed and will assume responsibility for notifying the 
parents/legal guardians of the participants. 
We will collect contact information for the physician of each participant on the first visit.  In the 
case that abnormal findings are identified, the participant’s physician will be contacted by the PI, 
or a designee of the PI and the findings reported.  A report generated by the radiologist will be 
made available to the physician if requested. 
There is a small chance that psychological assessments and other procedures may reveal that 
participants are at high risk for clinically significant psychological/psychiatric issues.  If clinically 
significant findings are detected, participant/parents will be notified and referred for 
psychological/psychiatric evaluation.  In the event that research personnel become aware of 
suicidal ideation on the part of any study participant, the following steps will be taken: (1) 
immediate referral to a licensed clinical psychologist associated with the study, (2) professional 
and confidential assessment of suicide risk and resources available, (3) immediate notification 
of parent or legal guardian (if applicable), and (4) referral for appropriate services. It is important 
to note that data entry and evaluation of psychological questionnaires may be completed days 
or weeks after patient visits, but that these procedures will still be followed upon identification of 
suicidal ideation.
For clinically significant findings of neuroimaging, the participants/parents/legal guardians of the 
participants 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 

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for conditions that are benign.  However, the presumption is that detection of a potentially 
clinically significant finding will prove to be beneficial.
11.5 Confidentiality
Investigators will take all reasonable measures to protect the confidentiality of participants and 
their families, including the following:
Attribution of an ID number to each participant: Each participant is assigned a Participant 
Identification Number (PID). All interview and research data are stripped of identifiers and 
labeled with the study number. The enrollment log with participant identifiers will be maintained 
in a secured, locked location available only to the study staff. The participant’s name and any 
other identifying information will not appear in any presentation or publication resulting from 
these studies. In addition, findings from these studies will be reported in an aggregate manner. 
Disclosure of the participants’ answers outside the research could not reasonably be thought to 
place the subjects at risk of criminal or civil liability or be damaging to the subjects' financial 
standing, employability, or reputation.
Securing Files: All participant records, including consent forms, will be maintained in a filing 
cabinet in the locked office of the PI or designees, and will be accessible only to the principal 
investigator and designees. Computer data files (without subject identifiers) will be stored on 
computer servers with secure passwords or encrypted electronic storage devices. 
Deposition of Data into a Repository: Information from all testing, including MRI data, will be 
placed into a central data repository that can be accessed by other researchers. Data and 
samples will be de-identified before submission to any central repository.
12. DATA SAFETY AND MONITORING PLAN 
We recognize the need for careful safety, performance, and data monitoring plans to ensure the 
well-being of the children and adults in this study as well as the scientific integrity of the project. 
Under the guidance of the study statistician, the research team will generate data and assist the 
PI in preparing regular safety, performance and data monitoring reports.
Safety Monitoring: Since this study involves no increase over minimal risk, we are proposing 
that the PI will provide regular oversight of patient safety. At each quarterly monitoring interval, 
the PI will review adverse events for significance and relationship to the study as well as 
reasons for losses for follow up.  Safety data reports, which will include overall summaries and 
summaries by experimental group will be reviewed in a blinded fashion to ensure confidentiality 
of subjects. Suspected serious adverse events will be directly and immediately reported to the 
PI and physicians overseeing this study (Kenneth Goldschneider, Andrew Hershey, Neha 
Santucci).  If a serious adverse event is reported, the PI may review the data in an unblinded 
manner. Any adverse events related to the study procedures will be reported to Cincinnati 
Children’s Hospital Medical Center’s Institutional Review Board.  
Performance Monitoring: The PI in conjunction with members of the study team will meet 
regularly to evaluate the progress of the study, including accrual and retention, performance, 
protocol adherence, and other factors that can affect study outcome.  
Data Monitoring: The study biostatistician or other study team members will provide routine data 
monitoring reports including assessments of data quality, data completeness, and timeliness of 
data entry.  These metrics will be used by the study team to evaluate the progress of the study. 
Stopping Rules:  If an unanticipated serious adverse event occurs as a direct result of 
participation in the study occurs, subject accrual will discontinue until the Institutional Review 

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Board (IRB) has reviewed the information and the subject has received adequate care.  Subject 
recruitment will commence again only after the IRB has given the principal investigator the 
permission to continue.  If during the course of the study new information becomes available 
about the safety of any procedure, the PI will review the evidence to make a decision about 
discontinuing the study. 
13. POTENTIAL BENEFITS OF THE PROPOSED RESEARCH TO RESEARCH 
PARTICIPANTS AND OTHERS. 
There is expected to be no direct benefit to the participants of the proposed research as it is 
designed to examine basic mechanisms of pain. However, the knowledge gained will be crucial 
for developing a better understanding of pain mechanisms and can provide a foundation for the 
development of new diagnoses and treatments for pain.  The risks associated with this study 
are no more than minimal.  
14. IMPORTANCE OF THE KNOWLEDGE TO BE GAINED. 
The knowledge gained in this study has the potential to provide translational evidence about 
pain mechanisms in children.  As such, it can provide a foundation for the development of new 
diagnostic and treatment procedures.  The risks associated with this study are no more than 
minimal, and thus, are reasonable in relation to the importance of the knowledge that may 
result.  
15. COST OF PARTICIPATION
There are no costs associated with study participation.
16. REIMBURSEMENT FOR STUDIES 
Participants will typically receive up to $410 as payment for their participation. Pilot participants 
will typically receive up to $150 as payment for their participation. Funds will be placed on the 
ClinCard after completion of every session.  If sessions are repeated due to technical failure or 
other factors (i.e. MRI scanner ceases to function), participants will receive additional 
compensation in line with the regular payment schedule. 
Participants will receive payment according to the following schedule:
Baseline visit: Sub-total: $225
This amount includes a payment of $50 for the completion of the questionnaires, $75 for 
quantitative sensory testing, and $100 for the MRI scan. 
Online sessions: Sub-total: $60
During each of the three online sessions, children will receive $20 for the completion of the 
questionnaires. 
One-year follow-up: Sub-total: $125
This amount includes a payment of $50 for the completion of the questionnaires, $75 for 
quantitative sensory testing

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In addition, at the completion of the 1 year follow-up session, participants will receive a 3-D print 
of their brain using their baseline MRI scan. If a baseline scan is not available, children will have 
the option to choose from two other proportional 3-D print objects.
Pilot participants will receive payment according to the following schedule:
Baseline visit: $150
This amount includes a payment of $25 for the completion of the questionnaires, $50 for the 
quantitative sensory testing, and $75 for the MRI scan.
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