Structure & Function of Dopaminergic Brain Networks Following Postnatally-Occurring Hypoxic Insults
Conditions: Perinatal Hypoxia, Dopamine, Neurobehavioral Manifestations
Sponsor: Case Western Reserve University

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[USE THIS BIOMEDICAL PROTOCOL TEMPLATE IF YOUR PROJECT INVOLVES ANY 
PHYSICAL CONTACT OR MEDICAL INTERVENTIONS WITH PARTICIPANTS]  
INSTRUCTIONS:
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When you write a protocol, keep an electronic copy. You will need to modify this copy 
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PROTOCOL TITLE:
Include the full protocol title.
Measuring Brain Activity of School Age Children.
PRINCIPAL INVESTIGATOR:
Name: Deanne Wilson-Costello 
Primary Department: Pediatrics
Telephone Number: 216-844-3387 
Email Address: Deanne.wilson-costello.uhhospitals.org
UH FACULTY ADVISOR:
If the principal investigator’s primary role at UH is resident, fellow or student, identify a faculty 
advisor.  N/A
Name 
Primary Department
Telephone Number 
Email Address
OTHER DEPARTMENTS INVOLVED IN THIS STUDY (IF APPLICABLE):
Case Western Reserve University School of Nursing
Case Western Reserve University School of Medicine
Department of Radiology, Case School of Medicine 
VERSION NUMBER:
Include the version number of this protocol if assigned by an outside entity.
N/A
DATE: 
Include the date of submission or revision.
03/13/2021
Objectives

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1. Describe the purpose, specific aims, or objectives.
2. State the hypotheses to be tested.   
Purpose: Our goal is to characterize structure and function of dopaminergic pathways and 
the cortical regions innervated by those pathways in post-hypoxic former preterm 
children. We hypothesize that dopaminergic projections, originating in the substantia 
nigra pars compacta (SNpc) and ventral tegmental area (VTA), projecting primarily to 
the striatum and prefrontal cortex (PFC) to modulate motor control and cognitive 
function, will be structurally and functionally impaired. Our primary study cohort is 
comprised of former preterm children born in 2004-2010 with birth gestational age 
between 22-28 weeks in whom we have characterized their postnatal hypoxic exposure 
continuously during their first eight weeks of life. To meet recruitment targets, we may 
additionally recruit additional former preterm children born between the ages of 9 and 17 
years old at consent, with birth gestational age between 22-30 weeks and birth weight 
appropriate for gestational age (AGA). For comparison, we plan to also recruit healthy 
control children based on eligibility criteria (between the ages of 9 and 17 years at time of 
consent; without diagnosis of autism, epilepsy, metallic implants, dental braces, or those 
who have been treated for a concussion), and who are within the age range of the eligible 
former preterm children at the time of consent.
Specific Aim 1: We will quantify and compare the structural integrity of dopaminergic 
circuits originating in the substantia nigra pars compacta (SNpc) and ventral tegmental 
area (VTA) that project to striatum, prefrontal cortex, and nucleus accumbens, in post-
hypoxic former preterm children versus healthy control children born at term within the 
age range of the eligible former preterm children. 
Specific Aim 2: We will quantify and compare functional activity during tasks that 
engage executive function within cortical brain regions of post-hypoxic former preterm 
children versus healthy control children born at term within the age range of the eligible 
former preterm children at the time of consent. Our emphasis will be upon the prefrontal 
cortex which receives projections from the SNpc and VTA.
Hypothesis 1: Post-hypoxic former preterm children will manifest significantly reduced 
white matter density within dopaminergic circuits originating from the SNpc and VTA 
when compared to healthy controls.
Hypothesis 2: Post-hypoxic former preterm children will exhibit reduced activity within 
cortical networks innervated by the SNpc and VTA when compared to healthy controls.
Background
1. Describe the relevant prior experience and gaps in current knowledge describing how it 
will add to existing knowledge. 
2. Describe any relevant preliminary data.  
Please add relevant references at the end of the protocol, not at the end of this section.
Hypoxic insults occurring during the perinatal period remain the leading cause of 
permanent brain impairment.1 Apparent cognitive and motor dysfunction, such as that 

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seen in cerebral palsy, will occur in 4-10% of those post-hypoxic newborns.2,3 Subtle 
impairment, such as that seen in disorders of minimal brain dysfunction will occur in > 3 
million post-hypoxic newborns.4,5 Collectively, hypoxia-induced morbidity and mortality 
afflicts 3% of all newborns, worldwide, and leads to substantial personal and 
socioeconomic burden.6
Specific neuropathology, elicited by subtle hypoxic insults that lead to cognitive 
dysfunction, is not well described in humans. Over 84% of preterm infants experience 
apnea of prematurity with accompanying intermittent hypoxia.7,8 Neuropathology, 
cognitive impairments, and motor impairments induced by severe hypoxic insults are 
well described9 and frequently lead to a clinical diagnosis of cerebral palsy.6,10 Cognitive 
and motor deficits are also associated with mild to moderate hypoxic insults,11 but the 
specific neuropathology is poorly defined. Mild to moderate hypoxic insults resulting 
from apnea of prematurity do not elicit the overt neuropathology observed following 
severe hypoxic events. As such, standard neuroimaging and diagnostic techniques,12 with 
the exception of positron emission tomography requiring infusion of radioactive 
ligands,13 have failed to identify major changes in brain structure or function. 
Nonetheless, disorders of minimal brain dysfunction and cognitive impairments do 
exist.14-16
To better characterize the behavioral and neurochemical morbidity induced by mild 
hypoxic insults, we developed a rodent model emulating this clinical scenario. Our rodent 
model recapitulates many cognitive and behavioral dysfunctions observed in preterm 
infants including impaired working memory, hypersomnolence, locomotor hyperactivity, 
and increased responsivity to novelty.17-19 Analyses of post-hypoxic rodent brains has 
revealed reduced levels of extracellular dopamine and increased protein expression of 
dopamine D1 receptors and vesicular monoamine transporter (VMAT2) within the 
caudate putamen nucleus.17,18 These findings suggest functional and structural deficits 
within dopaminergic circuits comprising mesotelencephalic pathways. 
Our goal is to characterize structure and function of dopaminergic pathways and the 
cortical regions innervated by those pathways in post-hypoxic former preterm children. 
This project’s scientific premise and specific aims are supported by findings from our 
rodent model and represent the next logical step of our research.
Inclusion and Exclusion Criteria
1. Describe how individuals will be screened for eligibility. 
For Study Group Children: Birth gestational age between 22-30 weeks and birth weight 
appropriate for gestational age (AGA). Healthy control children: Birth gestational age ≥ 
38 weeks gestation and birth weight appropriate for term gestation within the age range 
of the eligible former preterm children at the time of consent.
Our primary study group will first be recruited from a cohort of children, born between 
23-28 weeks gestation, with available oxygen saturation level data recorded continuously 
from the first day of life to 8 weeks postnatal age. Eligible and interested former preterm 

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children will be identified by site principal investigator Deanne Wilson-Costello, MD and 
co-investigator Juliann Di Fiore. These children are prematurely born survivors from 
Rainbow Babies & Children's Neonatal Intensive Care Unit, and have been followed 
since birth. Children in this cohort have already participated in research, and remain 
willing to participate in future projects. Eligibility from this group includes children born 
in 2004-2012, male or female, and able to provide assent. Exclusion criteria includes 
history of epilepsy, autism, or mental or physical impairment preventing valid 
administration of cognitive testing measures. Other exclusions include children who have 
contraindications to MRI such as cardiac pacemakers, intracranial aneurysm clips, 
metallic implants or external clips within 10 mm of the head; implanted metallic devices 
such as pumps or previously implanted neurostimulation devices; cochlear implants, 
defibrillators, pacing wires, body piercings that cannot be removed; metal filings such as 
shrapnel; dental braces; tattoos on the head and neck, or medical conditions 
contraindicated for MRI safety. Additionally, we will exclude children with a history of 
claustrophobia or who are currently pregnant or planning pregnancy. Dr. Wilson-Costello 
and/or Juliann Di Fiore will provide our research team with names/contact information of 
interested individuals. We will contact those individuals by telephone to describe the 
study and conduct a prescreening.
If recruitment targets for study group children cannot be achieved, we will engage the 
assistance of Dr. Wilson-Costello to recruit additional former preterm children between 
the ages of 9-17 with birth gestational age between 22-30 weeks and birth weight 
appropriate for gestational age (AGA). We will also expand recruitment with study 
notices in print and digital newsletters, community bulletin boards, flyers, and targeted 
emails using the TriNetX database.
We will approach a subset of 5 children if they are willing to be re-studied (i.e. volunteer 
a second time for the same study) to enable the team to establish reproducibility of study 
measures. 
PRESCREENING
The purpose of the prescreening telephone call will be to further explain the study to the 
parents, confirm their interest in taking part, and determine their child’s eligibility. We 
will introduce ourselves as research scientists from Rainbow Babies and Children’s 
Hospital, University Hospitals Cleveland Medical Center and Case Western Reserve 
University conducting a research study comparing the brains of children born at full term, 
with brains of children born prematurely. We will tell them we are looking at how certain 
parts of the brain look and how they work. We will tell the interested individual that we 
plan to take pictures of the brain using an MRI scanner. We will also record EEG, which 
measures brain waves, by having the child wear a stretchy cap on their head with gel 
placed into little holes in the cap. These same tests are often done in medical practice. 
During the MRI scan, we will ask the child to do a memory test. We will also ask 
children to play a timed board game during the EEG recording. While the child is being 
tested, we will ask parents to fill out questionnaires about the child’s health, behavior, 
and sleep.

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We will describe that an MRI involves using a strong magnet and radio waves to produce 
a picture of body parts. EEG involves recording electrical activity of the brain from the 
scalp. This research project will involve taking pictures of a person’s head combined with 
patterns of brain activity recorded on the surface of their head. This will help us gain a 
better understanding of the human brain. We will tell the parents/children that we expect 
to enroll at least 20 children for this study who were born prematurely and 10 children 
who were born at or near their due date. We will emphasize that participation in this 
study is voluntary.
If they continue to express interest in study participation, we will determine if they meet 
study inclusion criteria (e.g. we will ask them if the child is between 9 and 17 years old; 
how close to the due date the child was born; if the child would be able to play a board 
game and push a button during a memory game). Then we will determine if they have 
any exclusionary criteria including a history of epilepsy, autism, or previous history of 
concussion requiring medical treatment. We will also assess for any contraindications to 
MRI scans. We will ask them if they have a cardiac pacemaker, intracranial aneurysm 
clips; intravascular shunt; dental devices such as braces or dentures; metallic implants or 
external clips within 10 mm of the head; implanted metallic devices such as pumps or 
previously implanted neurostimulation devices; cochlear implants, defibrillators, pacing 
wires, body piercings that cannot be removed; metal filings such as shrapnel; tattoos on 
the head and neck; or a history of claustrophobia, or a current pregnancy (if female).
If they meet inclusion criteria and do not possess any exclusionary criteria, one of the 
certified research team members will schedule an appointment with the child/parent to 
obtain written informed assent and consent.
2. Describe the criteria that define who will be included in your final study sample.
 
Inclusion
1.
For Study Group Children: Birth gestational age between 22-30 weeks and birth 
weight appropriate for gestational age (AGA).
2.
For Healthy Control Children: Birth gestational age ≥ 38 weeks gestation and birth 
weight appropriate for term gestation within the age range of the eligible former 
preterm children.
3.
Ability of the child to provide assent, with the parent/legal guardian able to 
provide written informed consent for study procedures.
4.
Sensory and motor capability to complete study tasks (i.e. Grooved Pegboard test; 
verbal n-back memory test).
3. Describe the criteria that define who will be excluded in your final study sample.
Exclusion
1.
Mental Development index < 80 at 2-year follow-up for preterm cohort.
2.
Past history of concussion requiring medical treatment to avoid confounding of MRI 

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data.
3.
Current history of epilepsy to avoid confounding of EEG data.
4.
Current diagnosis of autism.
5.
Child who suffers from claustrophobia (per parent report).
6.
Child unable to participate in neuroimaging due to claustrophobia or medical 
contraindication to MRI including any implanted medical device, dental braces, surgical 
clips for aneurysms in the head, heart valve prostheses, electrodes or other metallic 
objects; pregnancy
7. Healthy control children who were treated in the Neonatal ICU during the newborn 
period for breathing difficulties.
8.
Healthy control children who were hospitalized for breathing problems in the first 3 
months of infancy.
9.
If the child is suffering from an acute illness, he or she will be temporarily deferred.
Number of Research Participants
1. Indicate the target number of research participants to be accrued locally. 
Our goal is to obtain 30 complete data sets (preferably Study group = 20; Healthy control 
= 10). Due to movement artifact in the MRI, some scan data may not be usable so we 
may need to enroll up to 35 participants. We may also conduct repeat studies on a subset 
of up to 5 children (~15%) to establish reproducibility of collected data. Only subjects 
who checked "yes I agree to be contacted..." on their first signed parent consent form will 
be approached by phone to ascertain interest in participating in the study a second time. 
Participants studied twice will be re-consented for the second data collection session.
2. If this is a multi-site study, indicate the total number of research participants to be 
accrued across all sites.
N/A
Vulnerable Populations
1. Indicate specifically if you will include each of the following special populations by 
checking the appropriate box: 
☐
Adults unable to consent
☒
Minors (infants, children, teenagers) 
☐
Wards of the state
☐
Foster Children
☐
Pregnant Women 
☐
Neonates
☐
Neonates of Uncertain Viability
☒
Employees of CWRU or UHHS
☐
Prisoners
☐
Illiterate Individuals
☒
Non-English Speaking
☐
University Students

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2. If the research involves individuals that are included in a vulnerable population, describe 
the additional safeguards included to protect the rights and welfare of the individuals for 
each population indicated.
We intend to recruit pediatric patients ages 9-17 who qualify as a vulnerable population 
because they are minors. These children will have a separate pediatric assent form along 
with a parental consent form. We will make sure all the child's questions are answered 
regarding the study. We will take the necessary time to explain all procedures and explain 
things in a more basic language to the children participating in this study, appropriate to 
their level.
It is possible that children/parents in the former preterm study cohort may not be fluent in 
the English language. Eligible study participants (children or their parent) who are not 
fluent in English will not be excluded. We will submit a translated version of the 
informed consent form to the IRB for approval prior to use. Only a UH-based certified 
professional translator who is fluent in both English and the child's/parent's language will 
conduct the informed consent. Other study related documents and procedures that need to 
be completed by the child or parent will be translated into the participant's native 
language.
We may encounter candidate study recruits whose parents are coincidentally employees 
of either Case Western Reserve University or University Hospitals. Although meeting 
criteria as a "vulnerable population" our recruitment procedures are not specifically 
targeting employees or students of University Hospitals/Case Western Reserve 
University. Nonetheless, all research participants, including potential employees/students 
of UH/CWRU, will have their records and study findings stored in de-identified formats 
and all efforts are made to maintain study participant anonymity.
3. If excluding pregnant women, illiterate or non-English speaking individuals, provide a 
scientific rationale for the exclusion.  Inconvenience or cost is not an acceptable 
rationale.
Child participants may not be pregnant because they will receive an MRI scan as part of 
participation and the effect of MRI on pregnancy and a fetus is not known. Pregnancy in 
the female parent of the child is permissible. 
Recruitment Methods
1. Describe the source of the research participants. 
Many subjects will come from the practice of a study investigator (i.e. Dr. Wilson-
Costello) and may be referred or recruited from other physicians’ practices. Subject 
recruitment will also occur by advertisement or flyers, particularly for recruitment of 
healthy control participants.

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2. Describe the methods that will be used to identify potential research participants.
The proposed study will involve participation of male and female children to achieve a 
total number of 30 complete data sets. All children to be studied will range in age 
between 9-17 years during the funding period. Study participants will include survivors 
of preterm birth, with birth gestations of 22-30 weeks and birth weights appropriate for 
gestational age. 
We intend to focus our recruitment on 20 children who were born preterm with birth 
gestational ages between 22-30 weeks, are survivors from Rainbow Babies & Children's 
Neonatal Intensive Care Unit, and have been followed since birth. The children invited 
for participation will be part of the maintained cohort for whom continuous oxygen 
saturation data were collected in their first 8 weeks of postnatal life. Co-Investigator 
Juliann Di Fiore maintains this research cohort. In the event that we cannot enroll 20 
children who have continuous oxygen saturation data from their neonatal hospital stay, 
Dr. Wilson-Costello will assist us to identify other preterm survivors who are similar to 
the study group population but may be between 9 and 17 years old and/or have birth 
gestations up to 30 weeks. We will also recruit for other preterm survivors via study 
flyers and advertisements.
In addition to children recruited from the existing preterm cohort, we aim to study 10 
children who were born at term, and were within the range of normal birth weights. 
Healthy control participants will be recruited using various strategies: (1) study flyers 
given to the parents of the prematurely born cohort children to pass along to parents of 
other children with ages similar to their own child. Interested parents will be asked to 
contact us if they wish to learn more about the study. This approach is currently and 
successfully used by our Co-Investigator Dr. Taylor in his research (Heverly-Fitt et al., 
2014);(2) the study flyers will be given to the parents of the prematurely born cohort 
children to pass along to parents of other children with ages similar to their own child; (3) 
study flyers will be posted in Primary Care Pediatric Clinics; (4) Study flyers will be 
distributed by professional colleagues/pediatric physicians to potential candidate 
children/families meeting study inclusion criteria; and (5) Study flyers will be posted in 
libraries, coffee shops, community/recreational centers, and local government and/or 
nonprofit organizations that provide services or are in communications with families. 
Study flyers will instruct interested parents of eligible children to contact us if they would 
be interested in learning more about the study.
Social media recruitment and virtual recruitment:
Facebook: We will digitally post study flyers on Facebook and post to community groups 
created to share knowledge within the Northeast Ohio area, groups specifically geared 
toward parents (with and without former pre-term children), with appropriate permission 
from the group’s administrator and/or organization. We will also allow individuals to 
‘share’ our study flyer on their personal pages. Individuals will be allowed to comment 

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on posts but study investigators will direct individuals to the contact information posted 
on the study flyer for more information.
NextDoor: NextDoor is a platform to communicate information throughout the 
community. Investigators will post the study flyer on the app/website, which provides 
contact information if families are interested in participating. Individuals will be allowed 
to comment on posts but study investigators will direct individuals to the contact 
information posted on the study flyer for more information.
Twitter: Study investigators will post their flyer on Twitter accounts operated by 
investigators and CWRU-owned and operated accounts. Individual Twitter users will be 
able to retweet and reply to investigators. Investigators and account owners will respond 
by directing families to our contact information on the flyer.
ResearchMatch.org: The study will be posted on ResearchMatch.org so that families 
searching for research studies can view our study title and contact information. 
Recruitment language to be used on ResearchMarch.org: Dr. Michael Decker and Dr. 
Elizabeth Damato at CWRU, and Deanne Wilson-Costello at Rainbow Babies and 
Children’s Hospital are looking for families to participate in a study on brain 
development. The study involves one 3-hour visit to the CWRU/University Hospitals 
campus where a research team will measure brain activity. First, children will lie quietly 
for about 30 minutes in the MRI scanner while playing a visual task-response game. 
After the MRI scan, brain activity will again be measured with EEG. This involves 
having the child wear a stretchy cap while playing the visual task response game and 
completing a pegboard puzzle. Parents will complete questionnaires about the child’s 
health history, behavior, and sleep. Both parents and children will be compensated for 
their time. The investigators are especially seeking children who were born prematurely 
(gestation 22-30 weeks) and also children who were born full term (gestation 38-41 
weeks). Children with epilepsy, autism, medical implants, dental braces, or those who 
have been treated for concussion are not eligible. Please call 216-368-2597 for more 
information.
The CWRU Daily: We plan to advertise our study on the CWRU Daily. The submission 
to the Case Daily is attached to this modification. Interested families are instructed to 
contact the study investigators.
TriNetX: Research personnel will work the with TriNetX personnel to identify families 
who meet eligibility requirements. Researchers will then use the approved email template 
to contact families as well as phone scripts for communication. We will call families a 
total of 3 times and leave a voicemail if they do not pick up our phone call. The original 
application to IRB requested a HIPAA waiver authorization and we will continue to 
utilize this authorization to work with the TriNetX team.
Heverly-Fitt, S., Wimsatt, M.A., Menzer, M.M., Rubin, K.H., Dennis, M., Taylor, H.G., 
Stancin, T., Gerhardt, C.A., Vannatta, K., Bigler, E.D., & Yeates, K.O. (2014). 

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Friendship quality and psychosocial outcomes among children with traumatic brain 
injury. Journal of the International Neuropsychological Society, 20(7), 684–693. 
doi:10.1017/S1355617714000393
3. Justify the feasibility of recruiting the required number of suitable research participants 
within the agreed recruitment period. For example, how many potential research 
participants do you have access to? 
Inclusion of the 20 children for the study cohort will be based upon the age range 
represented within the total cohort maintained by Co-Investigators Di Fiore and Wilson-
Costello. There are currently 42 children in the cohort available for recruitment.
4. Describe when, where, and how potential research participants will be recruited. 
Co-Investigator Julie Di Fiore and site principal investigator Dr. Wilson-Costello will 
identify former preterm children who meet study criteria. Dr. Wilson-Costello will 
contact the parent and determine if they are interested in learning more about the study. 
With parent permission, Investigators Dr. Damato, Dr. Decker or one of the study 
research assistants trained for consenting will contact the parent to further explain the 
study using the IRB-approved pre-screening script. If the parent/child remains interested 
after hearing of the study, Dr. Damato, Dr. Decker or one of the study research assistants 
trained for consenting will obtain informed consent.
Interested healthy control participants who respond to a study flyer will contact the 
investigators. We will further explain the study using the IRB-approved pre-screening 
script.
5. Describe materials that will be used to recruit research participants.
The flyer will indicate that we are conducting a study on brain activity in school age 
children and that we wish to enroll a broad representation of children. Parents would then 
be asked to contact us if they would be interested in taking part in the study. This strategy 
would allow us access to a large pool of potential controls who meet eligibility 
requirements. Using an IRB-approved telephone script, our research staff will then 
contact the parents of the child. The purpose of the telephone call will be to further 
explain the study to the parents, confirm their interest in taking part, and determine their 
child's eligibility. We are prepared to discuss any aspect of a child's participation at 
greater length, including research participant rights. Telephone numbers of the study PIs 
are provided to those asking for more or different information. 
The term-born healthy control participants are selected based on eligibility criteria 
(between 9 and 17 years old; without diagnosis of autism, epilepsy, metallic implants, 
dental braces, or those who’ve been treated for a concussion) and approximately matched 
to study children based on age. All healthy control candidate participants will have been 
of normal birth weight (> 2500 grams) and with gestational age > 37 weeks. 

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Additionally, we will exclude children from the healthy control group if they were treated 
in the neonatal ICU during their birth hospitalization for breathing problems or were 
hospitalized for breathing problems in the first 3 months of infancy. Children in special 
education programs will not be excluded as controls. Both groups of children are 
expected to be in generally good physical health, although we anticipate that the group of 
preterm-born children may have more chronic conditions (e.g. asthma) and more health-
related functional limitations than the term group.
Setting
1. Describe the sites or locations where your research team will conduct the research. 
2. Identify where your research team will identify and recruit potential research 
participants. 
3. Identify the physical location where research procedures will be performed. 
The research team will conduct the research from affiliated Case Western Reserve University 
departments of study investigators Dr. Damato-FPB Nursing; Dr. Decker-Physiology & 
Biophysics-Case SOM. Both have private offices where research materials can be kept in a 
locked cabinet behind locked doors. Identification and recruitment of potential research 
participants will take place in University Hospitals/Rainbow Babies & Children’s Hospitals, 
primarily in the Preterm Follow-Up clinic, and by telephone follow-up to interested research 
participants. Consented study participants (child and parent) will be asked to come to the 
Case Western Reserve University Magnetic Resonance (MR) Facility located within 
University Hospitals on 11100 Euclid Ave, Cleveland OH 44106 at a scheduled date/time to 
participate in the research study. 
Consent Process
Indicate whether you will be obtaining consent:
☒ Yes
☐ No
If yes describe:

Where the consent process will take place

Any waiting period available between informing the prospective subject and 
obtaining the consent

Any process to ensure ongoing consent

The role of the individuals listed in the application as being involved in the 
consent process

The time that will be devoted to the consent discussion

Steps that will be taken to minimize the possibility of coercion or undue influence

Steps that will be taken to ensure the research participants’ understanding
Following a telephone pre-screening process, the consent form will be presented privately 
in person or by telephone to the child and parent, based on parent’s preference. One of 
the study investigators (Dr. Damato or Dr. Decker) or one of the research staff certified to 

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obtain consent will be present during the presentation of the informed consent, the 
signing of the consent, and initiation of the research study. Study personnel will present 
the benefits, risks and alternatives to study participation. Subjects will be given a copy of 
the assent and consent forms explaining the procedure. The child/parent will be given 
adequate time to read the information and ask questions before they sign and date the 
form. A delay of at least 2 days will be allowed between the telephone screening process 
and the scheduled date to obtain written consent. The certified staff will allow adequate 
time for the child/parent to make an informed decision and to minimize the possibility of 
coercion or undue influence. Throughout the telephone pre-screening process and written 
informed consent process, we will repeatedly inform the parent/child that study 
participation is voluntary and confirm their interest in participating. The research team 
member obtaining consent will ask the parent/child to describe the study procedure in 
their own words to ensure understanding of the protocol. Prior to the scheduled MRI 
study date, one of the principal investigators or certified staff will contact the parent by 
phone to confirm continued consent for study participation. Copies of the assent and 
consent forms will be given to the person signing the document. The language used by 
those obtaining consent will be in English for those children/parents who are fluent in 
English; documents will be translated into the appropriate language for any interested 
families and a certified person proficient in the specific language will be used to translate 
during the consent process and protocol. We will use the child assent/parent consent form 
submitted with this application and the UH MRI safety screening form, which has also 
been submitted.
In rare instances, a parent may be unable to attend a consent visit or study visit (due to 
illness, location, etc.). Because of this, we will allow parents to sign consent forms while 
a study team member explains the consent process via phone. Our language to the parent 
is identified in a document called, “R21 Parental consent via telephone.” The parent will 
understand that they are giving permission for their child to be accompanied by a parent 
proxy with whom they have trusted to leave their child (prior to our study team’s 
involvement). In this instance, child assent will still happen in person and we will instruct 
the parent to ask the child the parent’s first and last name to confirm identity. Prior to 
consent, the study team will also ask the parent to provide us with the first and last name 
of the caregiver who is accompanying the child to the study visit. During consent and 
study day, we will ask caregiver to provide identification that bears the same name.
Waiver or Alteration of Consent Process or Documentation (consent will not be obtained, 
written consent will not be documented)
Indicate which part of the consent process you are requesting be waived or altered:
☐
I will obtain consent, but not participant’s signature
☒
I will obtain consent, but request a waiver for pre-screening purposes
☐
 I will obtain consent, but request a waiver of some of the elements of consent 
                      (e.g. use of deception)
☐
 I will not obtain consent, and I am requesting a full waiver of consent

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1. Give the rationale for the request of a waiver or alteration of the consent process or 
documentation. 
2. If you will obtain consent, but not document consent in writing (e.g. over the phone, 
verbally, electronic survey, etc.), please describe and provide a rationale. 
Describe how you will be documenting that a research participant has consented
Be sure to upload a consent script or information sheet with your study protocol
We are requesting a waiver of HIPAA authorization for the pre-screening process 
over the telephone. The waiver also includes pre-screening for eligible former 
preterm infants by accessing their information in the database maintained by Co-
Investigator Di Fiore and site investigator Dr. Wilson-Costello and obtaining their 
contact information to further describe the study and recruit participation.
The telephone pre-screening process requires that we access subject phone numbers 
and other potentially identifying information (e.g. names, knowledge of gestational 
birth history) in order to determine study eligibility. The waiver of signed consent 
will allow us to accurately identify those persons who are study eligible. For 
interested parents whose child has exclusionary criteria, the informed consent 
document would be the only document linking the interested parent/child with the 
study. All study eligibility data will be destroyed for any parent/child found not 
meeting study eligibility criteria. Study eligible parents who express an interest in 
participation will be asked to sign a written informed consent document and their 
child will sign a child assent document.
Using telephone pre-screening, we need to determine study eligibility of study 
cohort children, identified by Co-Investigator Di Fiore and site investigator Dr. 
Wilson-Costello, who agree to learn more about the study. We will also need to 
determine study eligibility of healthy cohort children who contact us in response to 
study flyers. If interest is affirmed after learning more about the study and the child 
meets study eligibility criteria, we will meet with the parent/child and obtain written 
parent consent and written child assent for participation.
This project will involve two groups: study participants and healthy controls. For 
both groups, we will speak to the parent first before approaching a child about the 
study. 
Study participants will primarily be selected from a cohort of families who have 
expressed interest in research study participation. Parents of children maintained in 
the cohort will be first identified by Co-Investigator Di Fiore and then contacted by 
Dr. Wilson-Costello by telephone and/or via postal mail and given an opportunity to 
indicate their willingness to be contacted to discuss possible participation in a 
research study. Using our HIPAA-compliant and IRB-approved pre-screening 
telephone script, our research staff will contact those parents who assented to be 
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criteria. Eligible families that express an interest in participation will be invited to 
participate. We are prepared to discuss any aspect of a child’s participation at 
greater length, including research participant rights. Telephone numbers of the 
study PIs are provided to those asking for more or different information. 
Healthy control children will be selected from those responding to study flyers. The 
flyer will indicate that we are conducting a study on brain activity in school age 
children and that we wish to enroll a broad representation of children. Potentially 
eligible children/parents would then be asked to contact us if they would be 
interested in taking part in the study. The purpose of the telephone call will be to 
further explain the study to the parents, confirm their interest in taking part, and 
determine their child’s eligibility. We are prepared to discuss any aspect of a child’s 
participation at greater length, including research participant rights. Telephone 
numbers of the study PIs are provided to those asking for more or different 
information. 
Participants approached for re-study will have indicated their willingness to be 
contacted for future studies on the initial signed parent consent form. Only parents 
who indicated on their first signed consent form will be approached by telephone. A 
separate telephone screening script for re-study participants is included in this 
addendum submission.
Only trained research personnel who have completed necessary certification for 
human subjects research will directly interact with children and parents involved in 
this study. Only parents who provide consent to be contacted for potential research 
participation are contacted by our research personnel. Following the telephone pre-
screening process, the consent form will be presented in person or by telephone to 
the child/parent. Written child assent and written informed consent from the parent 
is obtained. One of the key study investigators or one of the listed research team 
members who can obtain consent on this protocol will always be present during the 
signing of the consent and the initiation of the research study. We will present the 
benefits, risks and alternatives to study participation. Children/families will be 
given a copy of the consent form explaining the procedure. The child/family will be 
given adequate time to read the information and ask questions before they sign and 
date the assent/consent forms. We will allow adequate time for the child/family to 
make an informed decision and to minimize the possibility of coercion or undue 
influence. A copy will be given to the child/parent signing the documents. We will 
also provide every consented child/parent with a copy of the study flyer as an easy-
to-read information sheet about the study. The language of the informed consent is 
written at an 8th grade reading level and the language of the child assent is written 
at a 4th grade reading level. We will seek translation to another language as needed 
for eligible children/parents in the cohort study sample and in the healthy control 
sample. The top portion of the submitted MRI screening form documents the steps 
of our informed consent process.

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Our consent forms explain the nature of all procedures using lay terminology, and 
we stress that participation is voluntary. Our research assistants and Co-PIs are 
available to answer questions. One of the study investigators (Dr. Damato or Dr. 
Decker) is also available to answer questions about the study at other times. All 
activities are compliant with local IRB and HIPAA guidelines, such as destroying 
all pre-screening forms and obtaining verbal permission, as appropriate, for phone 
interviews. At the beginning of the study, and then periodically, any IRB, HIPAA 
or privacy requirements that may be in effect at that time also will be checked to 
assure that study procedures are compliant with current rules. With permission from 
the parent, the health care provider for consented eligible children are contacted to 
identify/clarify any exclusionary criteria.
Additional Considerations for Consent Process with Adults
Non English Speakers

If research participants who do not speak English will be enrolled, describe the 
process to ensure that the oral and written information provided to those research 
participants will be in that language during initial consent as well as throughout 
the study. Indicate the language that will be used by those obtaining consent. 

List the language(s) other than English that will be included.
Eligible study participants (children or their parent) who are not fluent in English will 
not be excluded. We will submit a translated version of the informed consent form to 
the IRB for approval prior to use. Only a UH-based certified professional translator 
who is fluent in both English and the child's/parent's language will conduct the 
informed consent. Other study related documents and procedures that need to be 
completed by the child or parent will be translated into the participant's native 
language. We will include any languages for which a UH-based certified professional 
translator is available.
Adults Unable to Consent

Describe the process to determine whether an individual is capable of consent.

List the individuals from whom permission will be obtained in order of priority 
(e.g. durable power of attorney for health care, court appointed guardian for 
health care decisions, spouse, and adult child). 
o
For research conducted outside of the state, provide information that 
describes which individuals are authorized under applicable law to 
consent on behalf of a prospective subject to their participation in the 
procedure(s) involved in the research.

Describe the process for assent of the research participants. Indicate whether:
o
Which subjects that are unable to consent will be required to give assent? 
If not all, explain why. 
o
Describe whether assent of the research participants will be documented 
and the process to document assent. 
N/A

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Research Participants Who Are Not Yet Adults (infants, children, teenagers)
1. Will parental permission be obtained from:
☒  One parent even if the other parent is alive, known, competent, reasonably 
available, and shares legal responsibility for the care and custody of the child or
☐  Both parents unless one parent is deceased, unknown, incompetent, or not 
reasonably available, or when only one parent has legal responsibility for the care 
and custody of the child
☐  Waiver of parental permission
2. Describe whether permission will be obtained from individuals other than parents, 
and if so, who will be allowed to provide permission. Describe the process used to 
determine these individuals’ authority to consent to each child’s participation in 
research. 
3. Indicate whether assent will be obtained from all, some, or none of the children. If 
assent will be obtained from some children, indicate which children will be required to 
assent. 
4. When assent of children is obtained describe how it will be documented.
Written child assent and parent consent (from one parent) will be obtained for all 
participants in this study. Permission will only be obtained from parents. The consent form 
will be presented in person or by telephone to the child/parent. Child participants will 
range in age from 9-17 years old; thus all child participants will sign a written assent form 
to document their willingness to participate in the study. Based on parent preference, 
consent forms may be mailed in advance to the parent prior to a mutually scheduled 
telephone call to conduct the consent process. The parent will sign the paper consent 
form(s) and return the signed documents to the investigative team in a provided stamped 
return envelope.
Sharing of Results with Research Participants
Describe whether results (study results or individual subject results such as results of 
investigational diagnostic tests, genetic tests, or incidental findings) will be shared with the 
research participants or others (e.g. the subject’s primary care physicians) and if so, describe 
how the results will be shared. 
☐  Results will not be shared with research participants
Research scans are not designed with the validity and vigor required for identification of 
any potential incidental findings. It is standard practice at other institutes, as well in all 
other ongoing studies within the Case Center for Imaging Research at UHCMC, that the 
IRB protocols and consent forms state that "no diagnostic review will be conducted." 
However, it is possible that abnormalities may be noted. Less than 3% of research MRI 
scans performed on healthy children will show clinically significant abnormalities (Gur et 
al., 2013). Abnormal waveforms on the EEG may be detected in approximately 2-3% of 
healthy children without neurological symptoms (Grant et al., 2016). If incidental health 
issues are noted, Dr. Wilson-Costello will discuss this with the parent and advise them to 

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seek further evaluation from the child's healthcare provider. Otherwise, research subjects 
will not be given the results of the tests. 
Grant AC, Chau L, Arya K, Schneider, M. Prevalence of epileptiform discharges in 
healthy 11- and 12-year-old children. Epilepsy & Behavior 2016; 62:53-56. 
Gur RE, Kaltman D, Melhem ER, Ruparel K, Prabhakaran K, Riley M, Yodh E, 
Hakonarson H, Satterthwaite T, Gur RC. Incidental findings in youths volunteering for 
brain MRI research. Am J Neuroradiol 2013; 10.3174/ajnr.A3525.
Study Design, Procedures and Timeline
1. Describe and explain the study design. 
2. Provide a description of all study-related research procedures being performed 
including procedures being performed to monitor research participants for safety or 
minimize risks. 
3. Describe:
☐  Procedures performed to lessen the probability or magnitude of risks
☐  List all drugs and devices used in the research and the purpose of their use and 
their regulatory approval status (more detailed information is requested in the 
section on Drugs and Devices at the end of this document.)
☐  The source records, including medical or educational records, which will be 
used to collect data about subjects
4. Describe when research procedures will take place and the duration of an individual 
subject’s participation in the study. Use of the descriptive table listing the study 
procedures that indicates the visit/week of the interventions below is encouraged. 
DESIGN & DESCRIPTION: The investigators will conduct an observational study 
comparing two groups of children to determine whether differences in birth events and 
oxygen levels during the newborn period lead to structural and functional impairment 
within the brain's dopaminergic pathways and the cortical regions innervated by those 
pathways. The dopaminergic system is involved in modulating motor control and 
cognitive function.
Our goal is to characterize structure and function of dopaminergic pathways and the 
cortical regions innervated by those pathways in post-hypoxic former preterm children. 
We will accomplish this through the use of neuroimaging analysis techniques, such as 
Pre-Screening
Visit 1
Visit 2
Visit 3
Six week Follow up
Estimated time requirement
Data Collection
X
Study Procedure 1
X
X
X
Study Procedure 2
X
X
Study Procedure 3
X
X
Phone Call Questionnaire
x

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diffusion tensor imaging with subtraction analyses and fMRI coupled with high-density 
electroencephalographic (EEG). We hypothesize that dopaminergic projections, 
originating in the substantia nigra pars compacta (SNpc) and ventral tegmental area 
(VTA), projecting primarily to the striatum and prefrontal cortex (PFC) to modulate 
motor control and cognitive function, will be structurally and functionally impaired. The 
primary sample for our proposed study is derived from a cohort of preterm infants 
admitted to Rainbow Babies & Children’s Hospital between 2004 and 2009 at a 
gestational age of 23 to 28 weeks. The purpose for developing the original cohort was to 
establish the effects of maintaining oxygen saturation levels between 85%-95% to 
decrease the development of retinopathy of prematurity. Oxygen saturation levels and 
desaturation events were recorded continuously from the first day of life to 8 weeks’ 
postnatal age. If recruitment targets for study group children cannot be achieved, we will 
engage the assistance of Co-Investigator Dr. Wilson-Costello to recruit additional former 
preterm children currently 9 to 17 years old with birth gestational age between 23-30 
weeks and birth weight appropriate for gestational age (AGA for comparison, we plan to 
recruit healthy control children within the age range of the eligible former preterm 
children. Our findings will provide new insight into the neural basis of cognitive 
dysfunction reported in many former preterm children who experienced mild to moderate 
hypoxic insults. 
APPROACH: Eligible and interested former preterm children will be identified by 
Deanne Wilson-Costello, MD and Juliann Di Fiore. These children are prematurely born 
survivors from Rainbow Babies & Children's Neonatal Intensive Care Unit, and have 
been followed since birth. Children in this cohort have already participated in research, 
and remain willing to participate in future projects. Dr. Wilson-Costello and/or Juliann Di 
Fiore will provide our research team with names/contact information of interested 
individuals. We will contact those individuals by telephone to describe the study and 
conduct a prescreening. 
Healthy control children will respond to study flyers. The study flyers will be (1) given to 
the parents of the prematurely born cohort children to pass along to parents of other 
children with ages similar to their own child; (2) posted in the Rainbow Primary Care 
Pediatric Clinics; (3) distributed by professional colleagues/pediatric physicians to 
potential candidate children/families meeting study inclusion criteria. Study flyers will 
instruct interested parents of eligible children to contact us if they would be interested in 
learning more about the study; and (4) posted in libraries, coffee shops, and 
community/recreational centers.
Following a telephone pre-screening process, the consent form will be presented in 
person to the child and parent. The principal investigator or one of the listed staff will be 
present during the presentation of the informed consent, the signing of the consent, and 
initiation of the research study. We will use the child assent/parent consent form 
submitted with this application and the UH MRI safety screening form, which has also 
been submitted. 

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In rare instances that parents or legal guardians cannot be present at the consent process 
or study visit, parents/legal guardians can be consented via telephone. Parents will also 
provide permission to the study team to allow the study team to contact the child first via 
phone to assess willingness to participate and subsequently provide permission, for their 
child to be assented in person (as usual) and come to the study visit with a trusted parent 
proxy. This will happen before child assent visit. At the day of the consent, we will ask 
child to bring a student ID or report card to verify their own identity.
No study procedures will take place before we receive the signed consent form from the 
parent.
If children come to either the consent process visit or the study visit (with their parent 
proxy who has been verbally approved by parent/guardian) and declines participation, the 
study team will cease all study related activities. We will then call the parent/guardian to 
inform them of the circumstances. 
The study team will confirm with parent/guardian before the consent phone call that child 
is under the supervision of a caregiver and ask for caregiver’s full name. The study team 
will verify the caregiver’s identity using state-issued ID or credit card bearing the same 
name given by parent at consent. During the study visit, the study personnel will have the 
caregiver present a photo ID before beginning any study-related procedures.
Compensation is given to the parent or parent proxy who completes the necessary 
questionnaires about child behavior or sleep.  We will inform the parent that this is our 
process in these rare and special circumstances.
Consented study participants (child and one parent) will be asked to come to the Case 
Western Reserve University Magnetic Resonance (MR) Facility located within 
University Hospitals on 11100 Euclid Ave, Cleveland OH 44106 at a scheduled 
date/time. A research staff member will contact participants by phone 1 and 3 days prior 
to the scheduled data collection visits to complete a COVID-19 screening form (see 
COVID-19 screening form).
The child should have washed their hair on the day of the study visit and not used any 
hair oils, conditioners, or hair products after shampoo. Data collection will involve 1 visit 
lasting approximately 2-3 hours in length. Participants who volunteer for re-study will 
have a second data collection visit lasting approximately 2-3 hours in length. 
Dr. Damato, Dr. Decker or a member of the research team will review the procedures to 
participants and confirm that written informed consent has been obtained. A research 
team member will assess the participant’s temperature using a no-touch infrared 
thermometer at the start of the study visit. We will supply clean disposable facemasks to 
participants for use during the study. Research staff will wear facemasks at all times 
during the study visit. Prior to the neuroimaging session, a magnetic resonance imaging 

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(MRI) screening will be repeated to ensure study eligibility for MR scanning and that it is 
safe for the child to take part in the study. 
A qualified physician or nurse practitioner will perform a focused neurological history 
and physical examination. All females will be asked to provide a urine specimen for 
pregnancy testing. If pregnancy test is positive, the child will be removed from the study 
due to exclusionary criteria. 
The child will be acclimated to the MRI/mock scanner and then be instructed on the 
verbal n-back memory task that will be administered during a portion of the MRI scan 
and during the EEG recording. 
Once positioned on the MRI scan table, an MRI scan is performed. We will provide 
earplugs or headphones that the child will be required to wear. A structural scan, DTI, 
and fMRI will be performed (total acquisition scan time = 30 minutes). During the fMRI, 
the child will perform the n-back memory task by pressing a button in response to 
alphabet letters presented on a screen in the scanner. 
While the MRI scan acquisition is occurring, one parent will complete questionnaire 
items regarding their child's typical behavior (estimated time 25-30 minutes). 
Following the MRI scan, a stretchy cap with holes in it will be placed over the top of the 
child’s head. Some gel will be put through the holes and some wires will be attached to 
the cap that will record brain activity across the scalp. Placement of the cap takes 
approximately 40 minutes including proper programming of the HD-EEG equipment. 
We will obtain 15 minutes of baseline EEG recording. During the baseline EEG 
recording, Dr. Damato, Dr. Decker or a member of the team will administer a 
neurobehavioral assessment, which will include the Grooved Pegboard test, where the 
child is timed while placing pegs into a board. Following completion of the EEG 
recording, child is assisted to remove gel from scalp and hair. 
Study incentive is provided for study completion ($50 gift card to child plus $50 gift card 
to parent or caregiver present). 
NOTE: A positive pregnancy test in girls under the age of 13 will be reported to the 
parent and to the child as well as to the Cuyahoga County Department of Children and 
Family Services (216-696-KIDS) as required by law. If the child is age 14 or older, we 
will report a positive pregnancy test to the child and will tell the parent about the 
pregnancy test results only if the parent asks for that information. We will also notify 
University Hospitals Social Work (216-844-8965) about any positive pregnancy tests so 
they can provide support to the child. If we become aware of abuse or neglect of a child 
in this study, we will notify the appropriate county social services agency as required by 
law (216-696-KIDS).

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Procedure
Responsible Party
Confirmation of signed informed child assent / 
parent consent & repeat MRI safety screen 
Dr. Damato or member of research team 
approved to obtain consent
Confirm that child has washed hair that day and 
not used any hair products after the shampoo
Research assistant
Perform brief neurologic history and physical 
exam 
Nurse Practitioner (Dr. Damato) or Physician (Dr. 
Wilson-Costello) 
Acclimate child to MRI / mock scanner 
Research assistant
Instruct child on verbal n-back memory task (5 
minutes)
Research assistant
Transfer child to MRI scanning room 
Dr. Flask or MR technician
MRI scan (structural, DTI, fMRI) performed. n-
back memory test is administered during fMRI 
scan (30 minutes)
Dr. Flask or MR technician
While child is in the MRI scanner, parent 
completes Child Behavior Checklist, Vanderbilt 
Assessment Scale, and Child Sleep Assessment 
(25-30 minutes).
Research assistant
Following MRI scan, apply HD-EEG head cap on 
child’s scalp, apply EEG gel, and program EEG 
acquisition software, check impedances (40 
minutes)
Research assistant
Obtain 15 minutes of baseline EEG recording
Research assistant
While EEG is being recorded, administer grooved 
pegboard task and n-back memory test (5 
minutes)
Research assistant
Following completion of EEG data collection, 
child is assisted to remove gel from scalp and hair
Research assistant
Study incentive payment is provided
Research technician/Dr. Damato/Dr. Decker
Radiation and Radioactive Substances
1. Does the research involve the use of radiation or radioactive substances?
☐  Yes     ☒  No – leave rest of the section blank
If yes, answer the following questions.
Please note that you must receive Radiation Safety Committee (RSC) prior to IRB 
submission.
2. Is the radiation use only for the purposes of the research study (e.g. over and above 
standard of care)
☐  Yes     ☐  No
3. Does the protocol use radionuclides?
☐  Yes     ☐  No
4. Provide justification for the additional risk associated with the research radiation use.

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ClinicalTrials.gov Information
Has this study been registered on ClinicalTrials.gov? 
☒  Yes. Provide the following: 
i. The ClinicalTrials.gov identifier:  NCT03407729
ii. Investigator/sponsor responsible for registering: Michael J. Decker, PhD
☐  No. Explain if there are plans to register or why registration is not required 
(i.e., the study is not NIH funded, registration is in process, or does not meet the 
definition of a clinical trial)
List of Data to be Collected
1. Indicate what identifiers you will collect
☒
Name
☒
Address
☒
Dates related to an individual (e.g., Date of admission, birth, surgery, etc.)
☒
Telephone number
☐
Fax number
☒
Email address
☐
Social security number
☐
Medical record number
☐
Health plan beneficiary number
☐
Account number
☐
Certificate/license number
☐
Any vehicle or other device serial
☐
Device identifiers or serial numbers
☐
Web URL
☐
Internet protocol (IP) address
☐
Finger or voice prints
☐
Photographic images
☐
Other: Any characteristic that would uniquely identify the individual
2. List all other data to be collected for the research study (e.g. laboratory values, physician 
notes, length of stay, etc.). 

Magnetic Resonance Imaging, specifically T1 structural scan, Diffusion Tensor 
Imaging (DTI), and functional Magnetic Resonance Imaging-Blood Oxygen 
Level Dependent (fMRI-BOLD)

High density electroencephalography (HD-EEG)

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
Neurobehavioral Assessments of child: Verbal n-back; Grooved Pegboard task 
Parent report of child behavior (parent-report): Child Behavior Checklist, 
Vanderbilt Assessment Test, Child’s Sleep Habits Questionnaire (for children 
ages 9-12), Pediatric Sleep Questionnaire (for children ages 9-17).

Urine collection (to determine pregnancy exclusion for female child participants)
Data Analysis Plan
1. Describe the data analysis plan, including any statistical procedures. Provide a power 
analysis if applicable.  
2. If applicable, describe the primary and secondary study endpoints including safety 
endpoints.  
Our intent in this exploratory cross-sectional two-arm pilot study is to develop sufficient 
Scientific Rigor to support a future study appropriately powered to account for our proposed 
primary outcome measures and co-variates. Our sample will include 20 prematurely born 
children who experienced hypoxic insults during postnatal life. To allow comparison to 
“normative” expectations, we will compare these 20 former preterm children with 10 healthy 
term-born controls without exposure to hypoxia and of similar age, sex, race distribution as 
the preterm group. Data from these 30 children will be used to develop appropriate sample 
sizes, using actual rather than predictive data, for future studies characterizing neural 
structure and function following postnatal hypoxic insults.
Specific structural and functional characteristics used in our analyses will include

apparent diffusion coefficients and fractional anisotropy generated from DTI data

fMRI-BOLD, measured during the pediatric verbal n-back, and HD-EEG 
sLORETA

neurobehavioral assessment results (grooved pegboard test, verbal n-back, Child 
Behavior Checklist, Vanderbilt Assessment test, Child’s Sleep Habits 
Questionnaire, Pediatric Sleep Questionnaire)
Covariates include 1) age, 2) sex, 3) race, 4) preterm vs. term birth, and 5) frequency of 
hypoxic insults (< 5000 versus ≥ 5000) during the first 8 weeks of life within the preterm 
group. The continuous outcome measure variables will be summarized using descriptive 
statistics (mean, standard deviation, median, interquartile range). Frequency analyses and 
stem-n-leaf graphs will characterize data distributions. Skewed continuous variables will be 
transformed to satisfy normality assumptions of hypothesis testing. Outcome measures for 
the two groups will be compared graphically using box plots. We will perform hypothesis 
tests for equality of data distribution for the two groups using t-tests or Wilcoxon sign rank 
test, as appropriate, with a significance level of 10%.
As we are interested in the differences of above mentioned outcome measures in two groups, 
we will focus on effect size estimation for the differences of our measures. To detect 
significant effect size, we will perform regression analysis on the outcomes of interest with 
the primary covariate of interest being group membership (preterm vs. term birth). In the 
regression analyses, we will control only for significant confounding effects of age, sex, race, 
and frequency of hypoxic insults. Using regression analyses, we will determine point 

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estimates, regression coefficients (beta), as well as 90% confidence interval of betas. The 
confidence intervals will be main estimated effect size or the differences in outcomes in two 
groups due to preterm and term birth.
Confidentiality of Specimens and Banking
☒ 
 I am not storing specimens in this research project – please leave the rest of this section 
blank
Describe:
☐  The source of the specimens      
☐  Where the specimens will be stored     
☐  How long the specimens will be stored     
☐  How the specimens will be labeled      
☐  How the specimens will be accessed      
☐  Who will have access to the specimens      
☐  When and how will the specimens be destroyed      
☐  How will the specimens be transported (Please note if transporting specimens, 
a Material Transfer Agreement (MTA) is required).     
Describe:
☐  The procedures to release specimens including:
i. The process to request a release     
ii. Approvals required for a release     
iii. Who can obtain specimens     
iv. The data to be provided with specimens, including if the data will be 
identifiable to others     
☐  For genomic data, please include an attestation of no master list and no attempt will 
be made to re-identify the specimens.     
Are you storing the specimen for future use for other research projects?
☐  
Yes
☐  
No
Confidentiality of Data
1. To maintain the confidentiality of the data:
☒
I will use a unique study identifier (not derived from the participants personal
            identifiers) to code individuals’ data  and I will store this ID log separate from 
            study data.
☐
Other (please explain)
2. How are you storing your electronic data?
☒
UH Redcap
☐
CWRU Redcap 

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☐
Secure Research Environment (SRE)
☐
CWRU Box
☐
OnCore
☒
UH Secure Network Drive
☐
CWRU Secure Network Drive
☐
Other - List storage method and provide justification:
3. ☒
I acknowledge that paper research data and documents will be stored in a double-
            locked secure environment in the following location: 
            Location: PI Michael Decker’s laboratory office; CWRU School of Medicine 
4. If sharing data, describe:  

The exact data elements that will be shared     

How data will be sent     
(Please note if sharing data, a Data Use Agreement (DUA) is required.
        N/A
HIPAA Authorization 
If you are going to be accessing PHI (Protected Health Information), indicate how HIPAA 
authorization will be obtained (check all that apply):
☒  
HIPAA authorization is in the consent form
☒  
Requesting a full or partial waiver of HIPAA for prescreening
☐  
Requesting a full or partial waiver of HIPAA
1. Describe why the study cannot be completed without the specified identifiable 
information. 
2. If the identifiable information will be used or disclosed by anyone other than the research 
team, please state who those individuals/entities are and provide justification for the 
disclosure. 
3. Describe how long identifiers will be kept for in relation to study length and data 
collection and analysis. 
The purpose of requesting identifiable information is to reduce research participant burden. 
We intend to first speak to potential research candidates by phone, at which time we will 
describe the study and establish their interest in participating. During the call, we will also 
establish the presence of inclusion criteria and any overt exclusionary criteria that may exist, 
before inviting the study candidate to meet in person with us to provide informed consent and 
obtain signatures. We appreciate that these steps increase the workload of the investigative 
team. However, they will reduce research participant burden by identifying non-eligible 
study participants before they take the time to meet with us in person for further evaluation of 
inclusion and exclusion criteria. We will destroy all pre-screening documents and records as 
soon as the child is determined either (1) study-ineligible or (2) parent has signed a written 
consent form and the child has signed a written assent form to participate or (3) child and/or 

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parent has opted to not participate in the study. No persons outside the research team will 
have access to identifiable information. Research data will be stored by the PI for 5 years 
after closure of the study.
☒  I assure that protected health information collected for purposes of this research study 
will not be reused or disclosed to any other person or entity, except as required by law, 
for authorized oversight of the research study, or for other research for which the use of 
disclosure of protected health information for which an authorization or opportunity to 
agree or object is not required by 45 CFR 164.512
Risks to Research Participants
1. List the reasonably foreseeable risks such as breach of confidentiality, discomforts, 
hazards, or inconveniences to the research participants related to their participation in 
the research. Include a description of the probability, magnitude, duration, and 
reversibility of the risks. Include the physical psychological, social, legal, and economic 
risks. 
2. If applicable, indicate which experimental procedures may have risks to the research 
participants that are currently unforeseeable. 
3. If applicable, indicate which procedures may have risks to an embryo or fetus should the 
research participant or their partner be or become pregnant. 
4. If applicable, describe the risks to others who are not research participants. 
5. Describe the availability of medical or psychological resources that research 
participants might need. 
Potential Breach of Confidentiality: Accessing of PHI involves the risk of potential breach of 
confidentiality. Participant's names will not be used in any written or oral report of the study. 
A number will be used to identify all information supplied. Participant identity will be known 
only to the study staff. 
Potential Time Burden: Participation may require the children to miss school and their 
parents to miss work, although we will preferentially schedule evening and weekend 
appointments. We will also schedule data collection during school holidays and summer 
vacation whenever possible. 
Telephone screening/In-person interviews of child/parents: The procedures used in 
evaluating children and families for the study are similar to those used in clinical follow-up 
of children. There may be some minimal risks associated with initial telephone screening. 
There are also minimal risks that the children or their caregivers will become anxious about 
the testing, or will experience some distress in being questioned about their personal lives. 
Neurobehavioral Assessments: Risks related to the neurobehavioral assessments, i.e. the 
pediatric verbal n-back, grooved pegboard task, parent-reported behavioral questionnaires, 
are minimal. These may include frustration with remembering the appearance of letters on a 
screen or the time burden of completing the tasks. 

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Electroencephalography (EEG): This non-invasive procedure is associated with minimal risk, 
or at the most, minor risk. Those include skin sensitivity to the gel or to the adhesive tape 
which is sometimes used to secure a recording electrode or wire.
Neuroimaging (MRI) 
Collision Hazard: The subject's participation in this study involves minimal risk. Because 
the MRI machine exposes the body to a very strong magnetic force, loose magnetic or 
metallic objects can fly into the magnet with great force if brought into the environment 
of the MRI scanner. The participant is asked to remove the following before entering the 
magnet room: hearing aids, beeper, cell phone, keys, eyeglasses, hair pins, barrettes, 
jewelry, body piercing jewelry, watch, safety pins, paperclips, money clip, credit cards, 
bank cards, magnetic strip cards, coins, pens, pocket knife, nail clipper, steel-toed 
boots/shoes, hair bands, eye shadow, and tools. We have established a security zone to 
prevent objects containing iron from coming into proximity of the magnet. To prevent the 
likelihood of wearable metallic substances in the scanning room, we will routinely ask 
subjects to change into a hospital gown or other suitable garment. Some persons should 
not participate in an MRI study and we will exclude these persons: people with metallic 
implants such as aneurysm clips or some types of prostheses (fake body parts), or with 
electronic implants such as cardiac pacemakers, intravascular shunts, stents, or filters; 
hearing aids, dental devices such as braces or dentures. 
Claustrophobia: The confining conditions of the MRI scanner can precipitate 
claustrophobia (feelings of being “closed in”) in some people. The radiology suite offers 
facilities that promote comfort and reduce anxiety. The mock scanner can assist in 
acclimating the child to the MR scanning procedure. If a child has feelings of 
claustrophobia during the study, the study will be terminated. 
Hearing: The MRI scanner produces tapping sounds during operation which may reach 
objectionable levels. To minimize any discomfort, subjects are provided with disposable 
earplugs or headphones. Children may discontinue their participation if the noise of the 
MRI scanner becomes too loud to tolerate. 
Radio Wave Exposure: There have been no ill effects reported from exposure to the 
magnetism or radio waves used for these studies, however that it is possible that harmful 
effects could be recognized in the future. The child will be able to communicate with the 
scanner staff using an intercom and/or signaling device. The staff will try to help the 
subject feel as comfortable as possible in the scanner. The subject can ask to stop the scan 
and be removed from the scanner at any time by using the intercom or signaling device.
Health/Sexual Activity: The effect of MRI on pregnancy and a fetus is not known. For that 
reason, if a female child is pregnant, or is planning to become pregnant, the child may not 
participate in this study. We will perform a urine pregnancy test on pubertal females and if the 
result is positive, we will inform the parent of the result and the child will be removed from 
study participation. We will also notify University Hospitals Social Work. The Cuyahoga County 

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Department of Children and Family Services will be notified of positive pregnancy test results 
for females under the age of 14 as required by law.
Provisions to Protect the Privacy Interests of Research Participants
Describe the steps that will be taken to protect research participants’ privacy interests.  
(consider issues such as physical space, proximity to other, and participant preferences) 
Subjects and their parent/ guardian will be given adequate time and space to sit down and 
comfortably and privately review the consent forms and screening forms. Consent forms 
presented in person will be reviewed and signed in a private room; data collection 
(grooved pegboard task, completion of questionnaires by parents) will be occur in a 
private room. Based on parent preference, consent forms may be mailed in advance to the 
parent prior to a mutually scheduled telephone call to conduct the consent process. The 
parent will sign the paper consent form(s) and return the signed documents to the 
investigative team in a provided stamped return envelope.
Subjects are provided with individual lockers in the MR scanning facility for storing their 
personal belongings during the scan. Subjects may use a locked room for changing their 
clothes and cleaning the gel off the scalp after the EEG. The scanner suite is secure and 
populated by the members of the research team and clinical staff only. 
Paper documents that can identify subjects will be kept in a locked cabinet in the faculty 
office of Dr. Michael Decker, Robbins Building, office E510. Only the Research 
Principal Investigators Drs. Elizabeth Damato and Michael Decker and the site principal 
investigator Dr. Wilson-Costello will have access to the locked file cabinet. Subject 
privacy during study procedures will be ensured by anonymizing the data through the use 
of a unique identifier number. These data will be stored on the UH REDCap system to 
ensure that the data is maintained behind institutional firewalls with access available only 
to Elizabeth Damato, Michael Decker, Deanne Wilson-Costello, and their certified staff 
associated with the study. 
Raw imaging data will be stored on the UH data only storage system using a unique 
identifier number. Imaging data using the unique identifier, as well as HD-EEG data, will 
be stored on REDCap, or a UH-approved encrypted flash drive, to be processed using 
specialized software with access available only to the primary investigator and certified 
staff. Results will be reported in an aggregate fashion with no individual identifying 
demographic information available.
Dr. Elizabeth Damato will be responsible for providing and documenting appropriate user 
access to the study database in REDCap and will prevent potential security concerns such 
as unauthorized access to data or malicious intent to destroy data and systems. Dr. Decker 
and Dr. Damato will oversee data audit software (REDCap) that is used to document user 
access, document data modification and backups. Dr. Decker and Dr. Damato will 
provide appropriate investigative team members with user accounts to enter data. Subject 
information and results will be stored by study ID numbers. REDCap software will be 

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used to de-identify PHI in the database. The paper data linking sheet holding identifiable 
information will be stored in the locked cabinet in faculty office of Dr. Michael Decker, 
Robbins Building, office E510. The linking sheet will be destroyed at the end of the 
study. Signed paper consent forms will be stored separately from the linking sheet in a 
different locked cabinet in Dr. Decker’s office. Only Dr. Damato, Dr. Decker and Dr. 
Wilson-Costello will have access to the locked cabinets. The data linking sheet is 
attached to this submission.
Potential Benefit to Research Participants
1. Describe the potential benefits that individual research participants may experience from 
taking part in the research. Include the probability, magnitude, and duration of the 
potential benefits. Indicate if there is no direct benefit. 
2. If no direct benefit, state the potential benefit to society or others. Do not list 
compensation. 
There is no direct benefit to the child by their participation in this research study. Information 
derived from this study may enable us to determine the underlying neuropathology causing 
the cognitive dysfunction that can occur following mild-moderate intermittent hypoxic 
insults in the postnatal period.
Withdrawal of Research Participants
1. Describe the anticipated circumstances under which research participants will be 
withdrawn from the research without their consent. 
2. Describe the procedures that will be followed when research participants withdraw or 
are withdrawn from the research, including partial withdrawal from procedures with 
continued data collection.  
A child participant would be removed from this study by the investigators if they cannot 
cooperate with study procedures or if previously undetected exclusionary criteria become 
evident during the data collection. These circumstances may include, but may not be limited 
to: (1) children who cannot cooperate with study procedures such as the ability to perform 
neurobehavioral tests; (2) if their hairstyle does not permit adequate EEG signal conduction 
(e.g. dreadlocks are a known problem); (3) if they meet exclusionary criteria such as 
claustrophobic behavior during the MRI scan or a positive pregnancy test. Data collection 
will occur in one visit; thus partial withdrawal with continued data collection does not apply 
to this protocol.
A subject’s participation in this research study is voluntary. Refusing to participate, 
withdrawing or being withdrawn by study staff will not alter their usual health care or 
involve any penalty or loss of benefits to which they are otherwise entitled. The images 
collected are for research purposes only and do not form part of the subject’s routine health 
care or offer interventions. The images are not a benefit of being in this research study. In the 
event new information becomes available that may affect the risks or benefits associated with 
this study or a subject's willingness to participate in it, they will be notified so that they can 
decide whether or not to continue participating.

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Alternatives to Participation
1. Please list other available clinical treatments. 
2. Please state if a subject could continue on standard of care therapy and what that might 
include. 
3. If not a clinical trial you may state that the alternative is not to participate. If there is a 
viable alternative you must list it in the consent. 
This is an observational study and clinical treatment is not provided. This study is being 
performed for research purposes only. The alternative to the study is simply not to 
participate.
Costs to Research Participants
☒  There are no costs to research participants or their insurance companies – please leave the 
rest of this section blank
1. If applicable, describe what costs the research participants will be responsible for 
because of participation in the research including but not limited to: transportation to 
study visits, parking for study visits, costs of procedures, lost, broken or stolen devices, 
costs of drugs or therapy, etc. 
2. You must clearly state if insurance will be charged and who will be responsible if 
insurance does not pay. 
3. List what research procedures and research interventions will be covered by this study. 
Research Participant Compensation
☐  There is no compensation for research participants – please leave rest of this section blank
 
1. Describe the schedule, payment method and payment total of any incentives or 
compensation that research participants will receive for participation in the research 
(e.g., gift cards or cash with amounts, t-shirts, devices, bags, swag, etc.)       
2. Describe the schedule, payment method and payment total of any reimbursements that 
research participants will receive for participation in research (e.g., parking, mileage, 
meals, etc.)     
As a token of appreciation of the time and effort made by the parent and child to participate 
in this study, we will compensate each child who completes the protocol with a $50 Amazon 
gift card. Each parent whose child completes the protocol and completes the parent 
questionnaires will also be compensated with a $50 gift card [note: only one parent per 
participating child is eligible]. In special circumstances that require a parent proxy to come 
with the child to the study visit, the study team, parent, and caregiver will make a decision as 
to who can best respond to the questionnaires about the child’s activities and behaviors. The 
parent or the caregiver who completes the questionnaire will be compensated $50. The total 
compensation for the child/parent unit is $100 value. If two children participate from the 
same family (e.g. one healthy child and one former preterm child OR two healthy OR two 
former preterm children), they will be eligible for $100 for each participating child/parent 

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unit. If a child/parent completes the protocol a second time, the child will receive a $50 
Amazon gift card and the parent will receive a $50 gift card for completing the re-study.
The $50 parent/caregiver incentive is also meant to cover expenses of parking during the 
time of data collection. Both the child and the parent/caregiver will receive their incentives 
on the day of the data collection visit.
Compensation for Research Related Injury
Describe who will pay for the costs of medical treatment and/or compensation in the event of a 
research related injury:
☐  
Funding agency is providing some/all payment for injury
☒  
Funding agency is providing no payment for injury
☐  
Not applicable
Provisions to Monitor the Data to Ensure the Safety of Research Participants
1. Describe the Data and Safety Monitoring Plan for the proposed study. Describe how 
often the data will be monitored for completeness, accuracy and adherence to the 
protocol.
2. Is there a formal Data and Safety Monitoring Board/Committee? If yes, provide 
information about the DSMB/C including the contact information of the committee 
member(s) (as applicable); whether it is independent from the study sponsor; how often it 
meets; the type of data that will be used; written reports, etc. 
Given the minimal risk of the procedures involved in the study the likelihood of adverse 
events is very low. Overall risk to participants should be similar to that of a clinical MRI 
scan. Collection of EEG data is non-invasive. The unblinded study coordinator will monitor 
records and debrief data collection personnel each week to detect adverse events. Data will 
be reviewed and monitored to ensure that its accuracy, completeness, and collection is in 
compliance with the protocol. All adverse events will be classified by severity and will be 
reported to the IRB in accordance with the rules regulating each severity class (expected vs. 
unexpected; serious vs. other; related vs. unrelated). With consultation of the physician 
involved in the project (Dr. Wilson-Costello), criteria for urgent medical referrals will also be 
established. Per NIH policy, we have developed a detailed Data and Safety Monitoring Plan, 
which has been approved by NINR/NIH. The approved 7-page document is attached. A 
DSMB has been assembled with 4 members outside the study team in addition to 3 members 
of the study team (Dr. Decker, Dr. Damato, and biostatistician Dr. Sattar). Data and 
procedures will be monitored weekly by the study team to ensure compliance with the 
protocol and integrity of the data. Quarterly written reports to outside DSMB members 
summarizing study progress and adverse events will be provided by Drs. Decker and 
Damato. The DSMB will be included in all formal procedures that report adverse events to 
the oversight University Hospital IRB and identify any need for premature termination of the 
protocol.

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DSMB members will include (1) Carolyn Landis, PhD: Licensed Clinical Psychologist & 
Professor of Pediatrics, Division of Developmental/Behavioral Pediatrics & Psychology, 
Rainbow Babies & Children's Hospital, Carolyn.Landis@uhhospitals.org. Dr. Landis will 
serve as DSMB chairperson; (2) Asim Shahid, MD: Assistant Professor of Pediatric 
Neurology/Staff Pediatric Epileptologist, Rainbow Babies & Children's Hospital, 
Asim.Shahid@uhhospitals.org; (3) Richard J. Martin, MD: Director, Neonatal Research 
Programs, UH Cleveland Medical Center, Professor of Pediatrics, CWRU School of 
Medicine, Richard.Martin@uhhospitals.org: (4) Ian Vannix, Lead Teaching Assistant, 
CWRU School of Medicine, Department of Physiology & Biophysics, isv@case.edu. Mr. 
Vannix will serve as the DSMB Executive Secretary. Dr. Wilson-Costello, UH-based site PI, 
will be invited to attend any meetings and be provided with interim written DSMB report 
updates.
Drugs or Devices
☒  There are no drugs or devices being utilized in this research project – please leave rest of this 
section blank
1. If the research involves drugs or device(s), describe your plans to store, handle, and 
administer those drugs or device(s) so that they will be used only on research 
participants and be used only by authorized investigators. 
2. How will the drug(s) be dispensed (i.e., indicate the pharmacy that will be used)?
3. If the drug is investigational (has an IND) or the device has an IDE or a claim of 
abbreviated IDE (non-significant risk device), identify the holder of the 
IND/IDE/Abbreviated IDE       
Additional Information
If you have any additional information regarding your study not covered in the template, please 
include it here.
Community-Based Participatory Research
☒  
This is not a community-based participatory research project – please leave rest of this 
section blank
If applicable, describe the involvement of the community in the design and conduct of the 
research. 
Note: Community based research is research that is conducted as an equal partnership between 
academic investigators and members of a community. In Community Based Participatory 
Research (CBPR) protects, the community participates fully in all aspects of the research 
process.  
International information

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☒  
This is not an international study – please leave rest of the section blank
☐  
We will be conducting this research at the following international sites:
1.
☐  
We are recruiting participants outside of the US from the following locations:
1.
☐  
We are sending data outside of the US to the following locations:
1.
☐  
We are receiving data from outside of the US from the following locations:
1.
MULTI-SITE RESEARCH (when UH or CWRU is the IRB of Record)
Does this project have multiple sites?
☐  
Yes
☒  
No
Non-Local Site Information for Multi-Site Studies
If this is a multi-site study where you are the lead investigator, list the following information for 
each relying site:
1. Name of site: 
2. PI of relying site: 
3. Name of IRB contact: 
4. Phone number of IRB contact: 
5. Email address of IRB contact: 
Non-Local Recruitment Methods for Multi-Site Studies
If this is a multi-site study and research participants will be recruited by methods not under the 
control of the local site (e.g. call centers, national advertisements) describe those methods. 
Local recruitment methods are described above. 
1. Describe when, where, and how potential research participants will be recruited. 
2. Describe the methods that will be used to identify potential research participants. 
3. Describe the materials that will be used to recruit research participants. 
Multi-Site Research Communication Plan (when you are the lead investigator)
If this is a multi-site study where you are the lead investigator, describe the processes to ensure 
communication among sites including:

All sites will have the most current version of the protocol, consent document, and 
HIPAA authorization     

All required approvals (initial, continuing review and modifications) have been obtained 
at each site (including approval by the site’s IRB of record)     

All modifications have been communicated to sites, and approved (including approval of 
the site’s IRB of record) before the modification is implemented     

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
All engaged participating sites will safeguard data, including secure transmission of 
data, as required by local information security policies     

All local site investigators conduct the study in accordance with applicable federal 
regulations and local laws     

All non-compliance with the study protocol or applicable requirements will be reported 
in accordance with local policy     
If this is a multi-site study where you are the lead investigator, describe the method for 
communicating to engaged participant sites: 

Problems     

Interim results     

The closure of the study     
References   
 
1. Rocha-Ferreira E, Hristova M. Plasticity in the neonatal brain following hypoxic-ischaemic 
injury. Neural Plast. 2016;2016:4901014. 
2. Boog G. [Cerebral palsy and perinatal asphyxia (I--diagnosis)]. Gynecol Obstet Fertil. 
2010;38(4):261-277. 
3. Volpe JJ, Kinney HC, Jensen FE, Rosenberg PA. The developing oligodendrocyte: key 
cellular target in brain injury in the premature infant. Int J Dev Neurosci. 2011;29(4):423-440. 
4. Towbin A. Organic causes of minimal brain dysfunction. Perinatal origin of minimal cerebral 
lesions. JAMA. 1971;217(9):1207-1214. 
5. Zhu T, Gan J, Huang J, Li Y, Qu Y, Mu D. Association between perinatal hypoxic-ischemic 
conditions and attention-deficit/hyperactivity disorder: A meta-analysis. J Child Neurol. 
2016;31(10):1235-1244. 
6. Kurinczuk JJ, White-Koning M, Badawi N. Epidemiology of neonatal encephalopathy and 
hypoxic-ischaemic encephalopathy. Early Hum Dev. 2010;86(6):329-338. 
7. Piermichele P, Picone S. Apnea of prematurity. Journal of Pediatric and Neonatal 
Individualized Medicine. 2013;2(2):1-7. 
8. Poets CF, Samuels MP, Southall DP. Epidemiology and pathophysiology of apnoea of 
prematurity. Biology of the Neonate. 1994;65(3-4):211-219. 
9. Huppi PS, Murphy B, Maier SE, Zientara GP, Inder TE, Barnes PD, Kikinis R, Jolesz FA, 
Volpe JJ. Microstructural brain development after perinatal cerebral white matter injury assessed 
by diffusion tensor magnetic resonance imaging. Pediatrics. 2001;107(3):455-460. 
10. Inder TE, Volpe JJ. Mechanisms of perinatal brain injury. Semin Neonatol. 2000;5(1):3-16. 

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11. Poets CF, Roberts RS, Schmidt B, Whyte RK, Asztalos EV, Bader D, Bairam A, 
Moddemann D, Peliowski A, Rabi Y, Solimano A, Nelson H & the Canadian Oxygen Trial 
Investigators. Association between intermittent hypoxemia or bradycardia and late death or 
disability in extremely preterm infants. JAMA. 2015;314(6):595-603. 
12. Azra Haider B, Bhutta ZA. Birth asphyxia in developing countries: current status and public 
health implications. Curr Probl Pediatr Adolesc Health Care. 2006;36(5):178-188. 
13. Phelps ME. PET: A biological imaging technique. Neurochem Res. 1991;16(9):929-940. 
14. Janvier A, Khairy M, Kokkotis A, Cormier C, Messmer D, Barrington KJ. Apnea is 
associated with neurodevelopmental impairment in very low birth weight infants. J Perinatol. 
2004;24(12):763-768. 
15. Perna R, Cooper D. Perinatal cyanosis: long-term cognitive sequelae and behavioral 
consequences. Appl Neuropsychol Child. 2012;1(1):48-52. 
16. Smith TF, Schmidt-Kastner R, McGeary JE, Kaczorowski JA, Knopik VS. Pre- and perinatal 
ischemia-hypoxia, the ischemia-hypoxia response pathway, and ADHD risk. Behav Genet. 
2016;46(3):467-477. 
17. Decker MJ, Hue GE, Caudle WM, Miller GW, Keating GL, Rye DB. Episodic neonatal 
hypoxia evokes executive dysfunction and regionally specific alterations in markers of dopamine 
signaling. Neuroscience. 2003;117(2):417-425.
18. Decker MJ, Jones KA, Solomon IG, Keating GL, Rye DB. Reduced extracellular dopamine 
and increased responsiveness to novelty: neurochemical and behavioral sequelae of intermittent 
hypoxia. Sleep. 2005;28(2):169-176. 
19. Hack M, Taylor HG, Schluchter M, Andreias L, Drotar D, Klein N. Behavioral outcomes of 
extremely low birth weight children at age 8 years. J Dev Behav Pediatr. 2009;30(2):122-130.
Please reference the Investigator Manual for local institutional requirements.