Functional Neuroimaging of Pain in Sickle Cell Disease Patients
Conditions: Sickle Cell Disease
Sponsor: University of Minnesota

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University of Minnesota 
Functional Neuroimaging of Pain in Sickle Cell Disease 
Study Protocol 
Principal Investigator 
Bin He, PhD 
Professor of Biomedical Engineering 
 
Oversight and Monitoring 
The proposed human study is part of a program grant, which was reviewed by NIH study section. The study we 
propose to do at the University of Minnesota only involves noninvasive EEG and functional MRI to quantify pain. 
The PI and Co-Investigators will monitor the safety of human subjects participating in the study. The research 
components only involve noninvasive EEG and functional MRI to quantify pain, which have been tested extensively 
in the PI’s lab and in the field. The study procedures and status will be reviewed regularly and if any potential issue 
be identified, the study will be stopped, and a meeting involving the PI and Co-Investigators be called to review the 
situation and identify plan to address the issue. The study will be resumed if the meeting of investigators addresses 
the issue satisfactorily. 
Overview of Study Design 
Sickle Cell Disease (SCD) is an autosomal recessive disorder caused by substitution of a valine residue for glutamic 
acid at position 6 (or Adenine to Thymidine transversion on codon 6) in the beta-globin gene, resulting in sickle 
hemoglobin (HbS). Under low oxygen conditions, HbS polymerizes to form rigid fibers and confers a sickle shape 
to the red blood cells (RBCs). Sickle RBCs cluster together, occluding blood vessels and impairing oxygen supply to 
the limbs and organs, resulting in inflammation, oxidative stress, ischemia, end-organ damage and acute painful 
episodes called ‘crises.’ Hypoxia/reperfusion injury, inflammation and organ damage perhaps activates peripheral 
nociceptors. 
SCD is associated with unpredictable recurrent acute pain episodes (‘crises’) and chronic pain that begins early in 
life. Opioid treatment remains a suboptimal approach due to side effects such as tolerance, addiction and altered 
renal clearance in SCD, resulting in morbidity and mortality. The lack of objective measures to quantify pain also 
contributes to inefficient analgesic therapy. 
Our goal is to develop and evaluate a novel quantitative EEG (qEEG) technology for quantification of pain and 
imaging of brain networks involved in pain generation and processing from noninvasive dense array EEG. We will 
also develop a novel multimodal neuroimaging technology integrating fMRI and EEG for imaging of brain networks 
involved in pain generation and processing. We will test the hypothesis that qEEG can provide objective 
quantification of induced and spontaneous pain. We will test the hypothesis that the proposed qEEG and fMRI/EEG 
multimodal neuroimaging methods will be able to delineate and image brain networks involved in chronic pain and 
acute pain in SCD patients. 
The proposed human study at the University of Minnesota involves only quantification of pain using noninvasive 
EEG and functional MRI. No therapy component is involved in the human studies at the University of Minnesota. 

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We will quantify and image induced pain and spontaneous pain. The induced pain study in healthy subjects has been 
already approved by the IRB (#1211M24481; PI: Bin He). 
Quantification and imaging of spontaneous pain in sickle-cell disease patients:  
We will directly investigate the pain severity assessment and brain pain imaging in SCD patients with 
spontaneous pain. Imaging spontaneous pain represents a challenge and the proposed study will be based on the 
novel techniques developed at the lab of Dr. Bin He.  
Experimental protocol: We will study SCD patients and healthy control subjects using qEEG and fMRI 
(and structure MRI) recordings in a 3T MRI system. The SCD patients with different pain severity levels controlled 
by medication (as part of clinical routine) will be studied. SCD patients with chronic pain will be monitored using 
dense array EEG and fMRI. During acute crisis SCD patients will stay in hospital for 5-7 days as clinical routine, 
receiving infusion IV narcotics. EEG monitoring and fMRI monitoring (if feasible depending on patients’ 
conditions) will be performed 30 min each to record acute pain due to crisis and chronic pain, when patients are 
under stable conditions. Within MRI scanner, the resting state recording will last for 6 minutes for fMRI recordings. 
The patients will be asked to have pain rating from score 0 to score 10 after each of the recording sessions. Control 
subjects will undergo 30 min EEG and fMRI recordings serving as baseline. 
Data analysis will be performed offline to quantify the pain and correlate to patients pain ratings, and to 
image functional networks associated with pain generation. Statistical analysis will include comparing patient results 
to that of healthy controls in order to detect abnormalities within EEG and fMRI recordings. Group analysis will be 
performed with multiple comparisons correction. Additionally imaging results will be compared to pain parameters 
reported by patients and their physicians to detect if imaging results have any correlation to pain experienced by 
patients. Correlations will be defined at a p-value of 0.05 after multiple comparisons corrrection. 
 
All subjects will be contacted for an introduction session for explaining of the study protocol, screening, 
and consenting. Subjects will be asked to give information on their neurologic diagnosis, the medications they are 
taking and any other health-related problems. The introduction session will last about 20 minutes.   
      
Subjects will be asked to participate in either A) induced pain study or B) sponstenous pain study.  
      
In study A, adult subjects with chronic pain or healthy subjects will be asked to sit quietly and comfortbaly, and 
recorded with EEG or lie down comfortably in a 3T MRI scanner recorded with fMRI. The session would last for 
about 1 hour.  
      
In study B, adult or pediatric (ages 5-18 yeards old) subjects will be asked to sit quietly and comfortbaly, and 
recorded with EEG or lie down comfortably in a 3T MRI scanner recorded with fMRI. The EEG alone session will 
last for about 1 hour; the fMRI session will also last for about 1.5 hours. Subjects will be asked to relax. For SCD 
subjects with crisis, only those under stable conditions will be recruited to participate in the study of EEG and fMRI. 
 
Piror to the fMRI session, subjects will be asked to complete addisional safetly screening form to ensure MRI safely. 
Subjects will be asked to pat down their body per CMRR safety guideline. Women subjects will be required to 
perform a pregnency test prior to each experimental session. The proposed human study at the University of 
Minnesota does not involve treatment. 
Subject Recruitment    
Only patients at or above 5 years old are included as patients at or above this age will be able to complete the 
required resting state task. Patients will be assessed to see if they are able to perform the fMRI portion of the 
experiment. If the patient cannot perform in the fMRI experiment, then only EEG data will be collected. 
 
Inclusion criteria: 
1. 5-64 years of age 
2. Patients with sickle cell disease at chronic stage or during crisis but under stable conditions 

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3. Healthy controls  
Exclusion criteria:  
1. Personal history of seizures or epilepsy 
2. Previous surgical procedure to the spinal cord or brain lesion 
3. Any metal objects or implantable devices, including but not limited to the following (dental metal is 
allowable): 
- 
Cardiac pacemaker 
- 
Implanted cardiac defibrillator 
- 
Carotid artery vascular clamp 
- 
Intravascular stents, filters, or coils 
- 
Aortic clip 
- 
Internal pacing wires 
- 
Vascular access port and/or catheter 
- 
Swan-Ganz catheter 
- 
Shunt (spinal or intraventricular) 
- 
Aneurysm clip(s) 
- 
Neurostimulator 
- 
Heart valve prosthesis 
- 
Any type of prosthesis (eye, penile, etc.) 
- 
Artificial limb or joint replacement 
- 
Bone growth/fusion stimulator 
- 
Bone/joint pin, screw, nail, wire, plate 
- 
Metal rods in bones 
- 
Harrington rods (spine) 
- 
Metal or wire mesh implants 
- 
Wire sutures or surgical staples 
- 
Insulin pump or infusion device 
- 
Any metal fragments (i.e. metal shop) 
- 
Any implant held in place by a magnet 
- 
Cochlear, otologic, or ear implant 
4. Previous severe (i.e. followed by loss of consciousness) head or brain trauma.  
5. Pregnancy 
6. Breathing or movement disorder 
7. Hearing aid use 
8. Hearing problems or ringing in the ears 
9. Metal in the brain/skull (e.g. splinters, fragments, clips, etc.) 
10. History of traumatic, tumoral, infectious, or metabolic lesion of the brain, even without history of seizure 
11. History of a fainting spell or syncope. 
12. Claustrophobia  
13. Non English Speakers 
14. Blind or deaf that will make communication or task completion difficult/impossible.  
15. Any other condition which would make the subject, in the opinion of the investigator, unsuitable for the 
study 
 
Risks and Benefits 
Risk of Collecting Personal Information: 
The primary risk of collecting personal information is breach of confidentiality of such personal information about 
the subject. 
 
Risks of MRI: 
The risks of MRI include the potential dislodging of any indwelling metals (stents, joint implants that are not 
titanium, wire sutures, aneurysm clips, shrapnel, etc.), disrupting indwelling medical devices (cardiac pacemakers, 

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medication pumps, heart valve replacements, etc.), the risk of metal projectiles (coins, keys, hairpins, oxygen 
cylinders, etc.) inadvertently presented during the MRI scan, and the unknown effects of MRI on the unborn fetus.  
The noise inside the magnet is loud and can mildly disturb subject’s hearing temporarily. Transient dizziness is 
sometimes reported by subjects upon removal from the magnet.  Strong claustrophobia is a contraindication. In 
EEG/fMRI study, there is a risk for electrode heating, but we will use MR compatible devices (Brain Product), 
which has special design for use in an MRI scanner to avoid electrode heating. 
 
Steps to Minimize Risks of Collecting Personal Information: 
Subjects will be asked for only personal information relevant to the inclusion and exclusion criteria of the study. 
Only the principal investigators, co-investigators, and research associates/assistants/technicians working on the 
project will have access to identifying information. Subjects will be assigned numbers that will be used during all 
data analysis. The file containing study ID numbers and identifying information for all subjects in the study will be 
encrypted on a computer in a locked room.  Subject names or other directly identifiable information will not appear 
on any reports, publications, or other disclosures of clinical study outcomes.  Any information that is included in 
published manuscripts (e.g. area of brain lesion location) will not be linked to any other information that would 
identify the subject. 
 
Steps to Minimize Risks of MRI: 
In the screening process, we will ask subjects if they have any medical conditions or implants and if they are taking 
any medications. This is important to know so that only those subjects who meet the inclusion and exclusion criteria 
are accepted into the study.  Subjects will also be screened for previous surgeries that might include noncompatible 
metal (nonferrous metals are compatible), indwelling medical devices, etc.  Those who report having devices or 
noncompatible metals will be excluded. All female subjects will undergo a pregnancy test before each session, and 
females who are pregnant will be excluded from the study.  Claustrophobia will be screened for in advance through 
interview. Subjects will wear earplugs and headphones during the MRI to protect against excessive noise. There is 
also a risk of heating or dislodgement of any metal objects.  Therefore, subjects will be asked to remove all jewelry 
and piercings and female subjects will be encouraged not to wear an underwire bra during the scanning session.  If 
the subject wears eyeglasses, they will take those off and will use non-metallic glasses matching their prescription, 
taken from a set of such glasses used by our laboratory for MRI studies.  
 
At the completion of the MRI session, we will manage the potential dizziness in subjects by having them remain 
seated for one or two minutes and then walk them to the waiting area carefully.  Subjects will not be dismissed until 
dizziness has subsided.  In our experience, recovery from light-headedness has never taken more than just a few 
minutes. 
 
If at any time during the MRI session, the subject experiences pain or discomfort, the testing will stop immediately. 
Furthermore, the researcher will observe the subject for any indications of further adverse events. Any adverse event 
will result in a temporary stop to the experiments while the activity is documented and further evaluated. 
 
Potential Benefits 
It is uncertain if there will be direct benefit to the subject for participation in the research, except for their knowledge 
that they are contributing to the establishment of an important noninvasive neuroimaging technology which may 
benefit other SCD patients in the future. The quantified pain information maybe helpful to the management of pain 
in the SCD patients. 
Informed Consent Process 
Consent will be discussed and obtained in an introductory session, before any tests have been scheduled. Subjects 
will be screened through an interview to ensure that they meet the necessary criteria.  Consent will occur before any 
test data are collected or any treatment is given. For SCD patients, there will be waiting period between when their 
physician recruit them to the study to the formal consent process. For healthy subjects the consenting process will 
occur in the introduction session of the initial visit. A graduate student research assistant will be mainly responsible 
for explaining the experiment protocol and answer subjects' concerns. Subjects must provide their own consent. If 

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they are unable to, they will not be eligible to participate in the study. For minors under 18 years old, their parents or 
guardian will also need to give consent. 
The prospective participant will be able to discontinue participation at any time.  This component has been included 
in the pre-screening tool, the informed consent and the initial discussion.  We are also asking those individuals who 
are contacted as potential participants to actively request more information therefore decreasing the likelihood of 
coercion.