Brain Characteristics Noted Prior to and Following Treatment of Deformational Plagiocephaly With a Helmet
Conditions: Nonsynostotic Plagiocephaly
Sponsor: Boston Children's Hospital

Title: Brain Characteristics Noted Prior to and Following Treatment of 
Deformational Plagiocephaly with a Helmet 
 
NCT: 02392195 
 
Date: Last modified 5/29/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Title: Brain Characteristics Noted Prior to and Following Treatment of 
Deformational Plagiocephaly with a Helmet 
 
Abstract 
 
A dramatic increase in the number of infants diagnosed with Deformational 
Plagiocephaly (DP) has been observed worldwide since institution of the American 
Academy of Pediatrics’ Back to Sleep Program.1-5 According to one published report, the 
incidence of DP ranges between 3-48%6; this translates into120,000-2 million 
infants/year who develop DP in the United States alone. Some healthcare providers 
believe that DP is a purely cosmetic condition. This mindset undermines the importance 
of prevention and correction.  In New Zealand, a recent study demonstrated that 39% of 
children without corrective action had persistent DP at age 3 to 4 years.7 Additionally, 
several studies have demonstrated associations between impaired social interactions, 
developmental problems and DP.8-13 Thus some researchers now believe that there may 
be a spectrum of untoward outcomes from brain remodeling resulting from DP 14, 15. 
Recent technological advances now allow the detection of diminutive changes in brain 
structure. In this multidisciplinary descriptive pilot study we will use brain MRI (Magnetic 
Resonance Imaging) and a cerebral tissue oxygenation monitor, namely Frequency 
Domain Near Infrared and Diffuse Correlation Spectroscopy (FDNIRS/DCS) to describe 
if differences in brain structure and characteristics exist in infants with significant DP 
before and after correction of the deformational defect.  This study will enable 
investigators to seek preliminary evidence that brain development is influenced by the 
shape of the cranial vault, and that changes in brain structure and characteristics occur 
with helmet therapy.  Additionally this study will help to determine the need for a larger 
investigation of this phenomenon that would further establish an association between DP 
and developmental delay. 
 
Team and Resource Description 
 
Study Team 
This study will advance the science on DP by utilizing new and innovative non-sedated 
MRI Imaging procedures (available at Children’s Hospital Waltham) to detect problems 
with infant brain development.  Each of the investigators for this study has a clinical 
practice at BCH and views patient care through a different lens (Neuroradiology, 
Nursing, Neurosurgery, and Plastic Surgery). It is through our unique perspectives that 
we have collectively identified a gap in knowledge that needs to be filled and have 
formed a multidisciplinary cohesive team to do so.   
 
Dr. Michele DeGrazia: This Primary Investigator has experience caring for sick and 
premature infants with DP.  She also serves as the PI on two studies investigating a new 
positioning device called the cranial cup in effort to prevent/correct positional head 
shape deformity in a population of Neonatal Intensive Care patients.  Dr. DeGrazia’s role 
will be to oversee study operations, including identifying and consenting potential study 
subjects. 
 
Dr. Ellen Grant: This Co-Primary Investigator is an accomplished researcher.  She 
currently has a number of ongoing investigations examining infants with brain injury of 
various etiologies using a variety of new technologies including advanced, non-sedated 
MRI and FDNIR/DCS.  

 
Dr. Mark Proctor,Dr. Alexander Allori, and Dr. Carolyn Rogers: These Co-investigators 
are accomplished surgeons with firsthand knowledge and experience treating infants 
with DP and both have published multiple manuscripts on the subject of cranial 
malformations. They will responsible for identifying and consenting potential study 
subjects. 
 
Dr. Nadine Gaab: Dr. Gaab is an assistant professor of pediatrics at Harvard University 
who currently conducts research on developmental cognitive neuroscience within the 
division of Developmental Medicine at Boston Children’s Hospital. Dr. Gaab is 
experienced with conducting non-sedate MRIs and neurobehavioral assessments on 
young patients and will assist the research team with the effective implementation of 
these procedures. 
 
Dr. Maria Franceschini: Dr. Franceschini is an associate professor of radiology at 
Harvard Medical School and a developer of the FDNIRS/DCS technology. She is a co-
investigator and consultant on use of the FDNIRS/DCS technology in this study.  
 
Dr. Kimberlee Gauvreau: This Co-investigator will provide biostatistical support. 
 
Hillary Kuzdeba: Project Manager, will assist with overseeing study operations. 
 
Courtney Porter: Research Coordinator, will assist in facilitating the study by guiding 
parents through the study trajectory.   
 
Introduction 
 
A dramatic increase in the number of infants diagnosed with DP (Deformational 
Plagiocephaly) has been observed worldwide since the institution of the American 
Academy of Pediatrics’ Back to Sleep Program.1, 16 It is estimated that the Neurosurgery 
and Plastic Surgery departments at Children’s Hospital Boston (BCH) care for a 
minimum 2500 infants per year with positional DP. At present, because DP is considered 
a purely cosmetic condition, there are limited preventative and corrective resources 
available to parents and healthcare providers. Additionally, because it is believed to be a 
benign condition some infants with milder forms of DP may not be recommended for 
treatment. However, several recent studies have demonstrated associations between 
developmental problems and DP, leading some to question whether DP causes both 
skull and brain deformation. 8-13 The purpose of this multidisciplinary descriptive pilot 
study will be to use brain MRI and a cerebral tissue oxygenation monitor called 
Frequency Domain Near Infrared and Diffuse Correlation Spectroscopy (FDNIRS/DCS) 
to describe if differences in brain structure and characteristics exist in infants with 
significant DP before and after correction of the deformational defect, and to seek 
preliminary evidence that might link DP with developmental delays.  
 
Background and Significance 
 
Incidence 
The rate of Sudden Infant Death Syndrome has significantly declined since 
implementation of the American Academy of Pediatrics, Back to Sleep Program in 1992 
by recommending that infants sleep in the supine position. However with this change in 
infant sleep position the incidence of DP has dramatically increased 3, 16. The incidence 

of DP ranges between 3-48% (120,000-2 million) for all infants.6 Infants with DP have 
irregular or misshapen heads. DP develops as the infant’s thin soft skull conforms to the 
flattened bedding upon which the infant is placed.7 Issues such as prematurity, lack of 
full bone mineralization, neurological deficits, preferential head position (torticollis), 
sedation, paralysis and limited tummy time increase the risk for DP. 5, 8, 17, 18 While it is 
reported that some milder forms of DP resolve spontaneously, a recent study 
demonstrates that 39% of children without corrective action had persistent positional 
head shape deformity at age 3 to 4 years.7 
 
Deformational Plagiocephaly in Full Term, Healthy Infants 
Brachycephaly is one form of DP.  Brachycephaly is reported to result from the infant’s 
head resting on a firm mattress or other solid surface when in the supine position.  
Common in term infants, this deformation is characterized by occipital flattening 
(unilateral or bilateral), ear misalignment, frontal bossing, and facial asymmetry.19 This 
form of DP has become more prevalent since initiation of the Back to Sleep campaign by 
the American Academy of Pediatrics (AAP) and other guiding agencies during the 
1990’s.5, 6, 19, 20  The Back to Sleep campaign recommends parents place their infants 
supine to sleep and this change in sleep position has resulted in a dramatic decline in 
Sudden Infant Death Syndrome.1   
 
Plagiocephaly is another common form of DP associated with the supine sleeping 
position and the Back to Sleep campaign.20, 21  Plagiocephaly usually results from the 
head being positioned in the same direction repeatedly and may or may not be related to 
congenital muscular torticollis.5, 22  With this type of head shape deformity there is 
asymmetry of the head shape (one side of the occiput is flattened), and ear 
misalignment can be present.  
Dolichocephaly is a narrow, elongated head shape.  This deformation develops when 
the infant is frequently placed in the prone or sidelying-position and is commonly seen in 
the premature infant population and rarely observed in full term infants.18, 23  The actual 
incidence of dolichocephlay is not known, though infants that are sick or recuperating 
from illness, and spend more time in their beds in the prone position, are more 
vulnerable to developing this type of positional head shape deformity.23 
Social Impact of Deformational Plagiocephaly 
The literature is replete with documents to support the claim that the undesirable head 
shape and facial features associated with DP can lead to problems with parent infant 
attachment and social isolation as the child grows.8-11 This is because parents of infants 
with positional head shape deformities find their infant to be less attractive. In fact, 
parents are so concerned about DP that a recent search of the Internet revealed a 
number support groups for parents, allowing them to share their concerns and obtain 
information about this common problem.24-27  
 
Neurodevelopmental Impact of Deformational Plagiocephaly 
The cranial vault is made up of several plates of bone that are separated by sutures. The 
bone plates allow protection for the brain while the sutures allow for expansion and 
growth of the brain. Brain growth is rapid during the first three years of life.  During 
normal growth it is believed that cells in the dura mater, a lining of the brain respond to 
brain expansion and influence bone growth.28 However, it is not known to what extent 
brain development is impacted when this normal process of brain expansion and bone 
growth is disrupted.  

 
Much of the work with respect to cranial structure, brain development and developmental 
delay has involved infants with craniosynostosis.29 Craniosynostosis is a severe 
condition that results in inadequate brain growth from premature fusion of one or more 
sutures of the skull, and requires surgical intervention to prevent long-term untoward 
neurodevelopment outcomes.23  
 
More recently though, some investigators are hypothesizing that DP may cause 
developmental problems in infants from the abnormal formation of the brain due to 
impaired expansion and compression from the deformed skull. This hypothesis, 
developed in response to numerous anecdotal and published reports linking DP (an 
unintended consequence of the Back to Sleep Program to prevent Sudden Infant Death 
Syndrome) to gross/fine motor delays, problem solving difficulties, communication 
deficits, vision/hearing problems and delayed developmental milestones, and has 
resulted in a broader examination of this phenomenon 7, 20, 21, 30-33, beyond the aesthetics.  
 
In review of the literature, one study of 287 infants with DP, 36% of parents reported that 
their child had one or more developmental delays such as gross motor delays, problem 
solving difficulties, and personal-social problems.7 Similarly, another study comparing 
toddlers with and without DP showed that toddlers with DP scored lower than 
demographically similar, but unaffected peers using the Bayley Scales of Infant 
Development III.34 Additionally, in 2002, Balan et al demonstrated depressed cortical 
sound processing, indicative of dysfunction in auditory processing, in a sample of infants 
with posterior DP when compared to infants without DP.12 Furthermore, Siatkowski et al 
in 2005, studying the visual fields of 40 infants with DP found that 35% had constriction 
of one or both hemifields by at least 20 degrees, suggesting that DP may affect visual 
field development.  However Siatkowski also reported that there was no correlation 
between laterality of the constriction, to laterality of the asymmetry.35 
 
With these mounting concerns over the associations between DP and untoward 
outcomes, healthcare providers now question the long held belief that DP is a purely 
cosmetic condition. Some now hypothesize that there may be a spectrum of untoward 
outcomes that result from brain remodeling and this may depend upon the extent to 
which the skull is misshapen.14, 15 Thus investigators are now reevaluating whether or 
not DP is linked to neurodevelopmental problems.13  
 
Technological Advances 
Magnetic Resonance Imaging (MRI). MRI offers a safe alternative to other radiologic 
imaging techniques.   This is because MRI uses a strong magnet instead of radiation to 
make images of the body’s interior.  The clarity and detail of the pictures from the MRI 
studies allow for the examination of the human body structures and functions. Therefore 
in recent years, MRI has become the tool of choice for examining the newborn and infant 
brain and in this study an MRI of the brain will permit the examination of brain volume, 
myelination and perfusion.  Furthermore newly discovered methods for obtaining 
sedation free MRI’s will be employed by the investigators.    
 
In newborns and infants, MRI is routinely used in the diagnosis and monitoring of 
conditions such as hypoxic-ischemic injury, brain occupying lesions or neoplasms, 
stroke, encephalopathy, and white matter injury in preterm infants.36-47 The typical MRI 
scan in neonates and infants takes approximately 30-45 minutes. In preparation for the 
MRI study infants are generally fed, wrapped snuggly, then earmuffs are placed over 

their ears to protect them from the tapping sound of the scanner. Some infants also 
require light sedation to ensure they remain still during the imaging procedure.36 
 
The 3 T field strength is reported to be optimal for MRI’s of the neonatal and infant brain. 
A typical MRI sequence may include a volumetric T1-weighted sequence, T2- weighted 
axial sequence, a susceptibility-weighted image or an axial diffusion sequence with a 
calculated apparent diffusion coefficient map, and at least 1-2 MR spectroscopy (MRS) 
samples.36 Also MRA and MRV may be obtained to look at both the arterial and venous 
structures respectively. 
 
MRI has been used extensively to diagnose and predict outcomes for infants with 
hypoxic ischemic encephalopathy and white matter injury of preterm infants.  In hypoxic 
ischemic encephalopathy an array of changes to the brain are observed with MRI and 
vary according to the timing of the exam. In simple terms, beginning 2-3 days following 
the injury, T1-weighted images provide information on signal abnormalities or change in 
the thalamus, putamen, globus pallidi and cortex, while T2-weighted images 
demonstrate changes to the thalami and basal ganglia after 7 days.  In contrast, 
diffusion weight images are beneficial in examining the neonatal brain for hypoxic injury 
in the first few days following the injury and will typically show reduced diffusion in the 
ventrolateral thalmi. MRS is often added to measure lactate, a by-product of tissue 
injury. In preterm infants MRI is most frequently used to look for white matter injury 
associated with intraventricular hemorrhage.  In this condition high signal intensities are 
observed on T1-weighted images and hypointense signals are noted on T2 weighted 
images in the posterior ventricular white matter and frontal white matter.36 Many studies 
have linked MRI findings of thalamic and white matter injuries to severe cognitive and 
motor disabilities supporting the use of MRI for the routine examination of infants with 
suspected brain injury.36, 39, 40, 48  
 
In addition to diagnosing and monitoring conditions such as hypoxic ischemic 
encephalopathy and white matter injury investigators are now beginning to use MRI to 
identify relationships to detect brain remodeling. In 2007 Mewes et al, found significant 
differences in skull shape and brain parenchyma between 20 term and 24 preterm 
infants. In addition they also found that premature infants exhibited a specific type of 
non-synostotic DP called dolichocephaly that influenced both subcortical and cortical 
brain morphology. From these findings, Mewes hypothesized that brain displacement 
seen on MRI was the result of mechanical forces from the abnormal cranial structure in 
the cohort of premature infants with dolichocephaly.49 
 
In the past, nearly all infants undergoing MRI required sedation and or analgesia, 
however recent advances in MRI now allow for these studies to be performed without 
sedation. 50-53 At BCH, there are two quality improvement programs are underway, the 
Try Without Program designed for children aged 4-6 years and Feed and Wrap Program 
for infants aged 0-3 months.  Both programs have noted promising results.  The Try 
Without Program boasts a success rate of 89.5% (unpublished data) as of May 2010 
and the Feed and Wrap Program has been in place for many years with regular reported 
successes. Moreover, it is with these new programs in mind that researchers are now 
reconsidering MRI as feasible tool for exploring conditions once thought too risky due to 
the need for sedation.  
 
Frequency Domain Near Infrared and Diffuse Correlation Spectroscopy (FDNIRS/DCS). 
Near-Infrared Spectroscopy is an inexpensive bedside tool for evaluating oxy and deoxy-

hemaglobin levels in the brain and can provide important information about brain 
health.54 There are many NIRS technologies available for use in pediatric population and 
these technologies have been extensively examined in the literature.  However, for this 
investigation we have selected to use the FDNIR/DCS system for the purposes of 
examining cerebral oxygen consumption.  
 
At BCH, bedside FDNIR/DCS has been found to be a reliable measure of cerebral blood 
flow (CBFi) and neuronal cerebral oxygen consumption (rCMRO2) when compared to 
cerebral hemoglobin saturation (SO2) measures obtained by the more commonly used 
continuous wave (CW) NIRS systems. For instance in one prior study at MGH, 
quantitative FDNIRS instrumentation was used to measure neonates with hypoxic 
ischemic injury and the relative cerebral metabolic rate of oxygen consumption 
(rCMRO2) was significantly increased in brain‐injured infants compared to healthy GA 
and age matched neonates, whereas SO2 showed no significant change. 54 Furthermore 
regional increases in rCMRO2 were observed during development, while rSO2 showed 
no significant change.55  
 
Additionally, in in one prior study at CHH using the combined FDNIRS/DCS system, 
significant decreases in CBFi and rCMRO2 were observed in term infants undergoing 
hypothermia therapy for clinical hypoxic ischemic brain injury, whereas SO2 showed no 
significant change. Furthermore, in a study of premature infants at BWH, FDNIRS/DCS 
was found to offer a safe and quantitative bedside technique to assess hemodynamic 
and metabolic parameters, facilitating individual follow‐up and inter‐subject 
comparison.56 Moreover, in premature infants, SO2 was insensitive to post-menstrual 
age (PMA), correlating better with hemoglobin concentration in the blood, though CBFi 
and rCMRO2 correlated better with PMA. In summary, this work at Harvard hospitals 
suggests that SO2 is less sensitive to injury, metabolic suppression with hypothermia, 
and increasing metabolic demand with development, while rCMRO2 shows significant 
changes and thus has great potential as a biomarker of brain injury and development.  
Therefore it is for these reasons that we have selected FDNIRS/DCS system as the tool 
of choice for measuring cerebral oxygen consumption, a marker of brain health, in this 
investigation.  
 
 
Purpose Statement 
 
Some researchers and healthcare providers are concerned that DP may be more 
problematic than once thought.  Concurrently, technological advances now allow 
researchers to detect diminutive changes in brain structure. In this multidisciplinary 
descriptive pilot study we will use brain MRI and a cerebral tissue oxygenation monitor to 
describe if a difference in brain structure and characteristics exist in infants with 
significant DP before and after correction of the abnormality. Knowledge generated from 
this study will enable investigators to seek preliminary evidence that brain development 
is influenced by the shape of the cranial vault, and that changes in brain structure and 
characteristics occur with helmet therapy.  Additionally this study will help to determine 
the need for a larger investigation of this phenomenon that would further establish an 
association between DP and developmental delay. 
  
 
 
 

Specific Aims   
 
1. Specific Aim: To describe if differences in brain volume/structure exist by Brain MRI in a 
sample of infants prior to and following treatment of significant DP with helmet therapy. 
 
2. Specific Aim: To describe if differences in myelination of axonal pathways exist by Brain 
MRI in a sample of infants prior to and following treatment of significant DP with helmet 
therapy. 
 
3. Specific Aim: To describe if differences in myelination of axonal pathways exist by Brain 
MRI in a sample of infants with significant DP compared to infants with similar 
characteristics but less severe or no DP. 
 
4. Specific Aim: To describe if differences in perfusion of cerebral structures exist by brain 
MRI in a sample of infants prior to and following treatment of significant DP with helmet 
therapy.  
 
5. Specific Aim: To describe if differences in cerebral oxygen consumption by Frequency 
Domain Near Infrared and Diffuse Correlation Spectroscopy (FDNIRS/DCS) exist in a 
sample of infants prior to and following correction of significant positional head shape 
deformity 
 
6. Specific Aim: To describe the cognitive ability in five areas of neurobehavioral 
development in a sample of infants with DP prior to and following helmet treatment using 
the Mullen Early Scales of Learning (MSEL).  
 
Research Design and Methods 
 
Design: This is a descriptive pilot study. 
 
Setting: Infant participants meeting inclusion and exclusion criteria will be enrolled 
through the outpatient plagiocephaly clinics (Neurosurgery and Plastic Surgery clinics) at 
Boston Children’s Hospital, Boston Children’s Hospital Waltham and Boston Children’s 
Physicians South (Weymouth) 
 
Table 1. 
Inclusion Criteria 
Exclusion Criteria 
- DP requiring helmet therapy  
-Term gestation at birth (37 weeks or 
greater) 
-Less than/or equal to 8 months of age 
-No history of major health problem such 
as birth injury, genetic disorder, intracranial 
hemorrhage, hydrocephalus, neurologic 
abnormality 
-No history of implantable metal device or 
internal/external orthotic device 
- DP not requiring helmet therapy 
-Premature gestation at birth (less than 37 
weeks gestation). 
-Greater than 8 months of age 
-History of major health problem such as 
birth injury genetic disorder, intracranial 
hemorrhage, hydrocephalus, neurologic 
abnormality 
-History of implantable metal device or 
internal/external orthotic device 
–Infants not completing prescribed 
treatment for correction with a helmet 

 
Primary Study Sample: We believe that a sample size of 10 subjects meeting the 
inclusion and exclusion criteria in Table 1., will provide enough information to determine 
the need for a larger investigation of this phenomenon. To ensure the desired sample 
size of 10 subjects, a convenience sample of 10-15 infants (that includes 5 additional 
patients for attrition) with DP, recommended for treatment with helmet therapy, will be 
recruited into this study.  
 
Comparison Sample: In Aim 2 we will retrospectively identify a sample of infants with 
similar characteristics (gender, age and race/ethnicity), with a less severe form of DP, or 
no DP to serve as comparisons.  
 
Staff Education:  All research staff will be Citiprogram trained.  Also, research staff 
involved in recruiting, consenting and data collection procedures will receive training by 
the study PI.   
 
Human Subjects: Prior to initiation of study procedures IRB approval will be obtained.  
The risk of a serious adverse event is unlikely in this study; however there are other 
inconveniences and risk to participation to be considered as follows: 
 
Inconvenience: If recruited at Boston Children’s Hospital Waltham or Boston Children’s 
Physicians South (Weymouth), study subjects and their parents may be asked to go to 
Boston Children’s Hospital on two separate occasions to complete the cerebral tissue 
oxygenation monitoring. Parents will be given the option to decline this testing. 
 
All study subjects and parents will be asked to return to BCH Waltham on two separate 
occasions to have testing that is not part of the routine management for DP with helmet 
therapy.  Parents will not be compensated for their time, the cost of transportation or 
parking during these visits, and the visits will last approximately 2 ½ hours. In the event 
that the study team is unable to obtain measures during the scheduled visits due to time 
limitations, parents will be given the option to schedule additional appointments to 
complete the measures. There will be no obligation to attend these appointments. 
 
Risk with Brain MRI:  MRI is considered a safe FDA approved procedure with no 
inherent risk to the study subjects; however significant injury can occur to individuals 
with implantable or external metal devices that undergo MRIs. Therefore, all MRIs will be 
performed by, appropriately credentialed, BCH personnel. All study subjects will be 
thoroughly screened to be sure they have no implantable or external metal devices upon 
enrollment, during consent and prior to each MRI study. Additionally, parents of all study 
subjects will be asked to change their infant into (hospital or own) attire that is free of 
metal prior to each MRI study.  Furthermore since the Brain MRI requires that the infant 
remain still for approximately ½ hour, anecdotal evidence suggests there is a 50% 
chance that a Brain MRI will not be able to be obtained on the first attempt necessitating 
the need for a repeat visit. 
 
Risk with FDNIRS/DCS: The use of American National Standards Institute (ANSI) and 
Food and Drug Administration (FDA) approved light levels does not involve any known 
risk. The laser light used to make the measurements has very low power and is 
considered to present minimal risk–that is, no more risk than the subject would 
encounter in everyday life. The light intensity used with this device is many times less 

then the amount of near infrared light the subject would receive during an outdoor walk 
on a sunny day. 
 
The optical probe requires close contact with the skin. It doesn't cause pain or distress. It 
may cause some minor skin irritation, but this effect is no greater than that encountered 
from clinical EEG monitoring probes. 
 
 
Enrollment Procedures: Trained clinical and research staff will screen infants for study 
eligibility, including MRI eligibility, prior to arrival for their clinic appointments at Boston 
Children’s Hospital, Boston Children’s Hospital Waltham, or Boston Children’s 
Physicians South (Weymouth). A recruitment flier will be handed out by clinic 
administrative staff to families coming in for possible posterior deformation. The flier will 
provide parents with the opportunity to be aware of the study before being approached 
by an investigator. The clinical staff will ask parents of the prospective participants who 
meet eligibility criteria if they are interested in hearing about a research study. Parents 
who agree to hear about the study will be approached by one of the investigators for 
consent.  The investigator will describe the study in detail and answer any questions.  
The investigator will also confirm MRI eligibility. Parents of infants who meet study 
criteria, and who agree to have their infant participate will be asked to sign a 
consent/HIPPA form. Parents will be provided with a study activity checklist to use as a 
reference as they progress through the study trajectory. Parents will also be asked to fill 
out a short demographic survey (ex: infant age, race, known medical conditions) and 
provide their contact information for follow-up later in the study. 
 
If parents do not want to enroll at the time of their clinic visit but are still interested in 
possibly participating, the consent team will provide them with a copy of the consent 
form for them to take home and review, along with the study team member’s contact 
information if the family would like to contact them to enroll or ask questions. In these 
instances where the family would like some time to make a decision, the consent team 
will ask the parents if they would be willing to have the team contact them by phone a 
few days after the clinic visit to check in and learn of their decision to participate.  The 
study team will attempt to contact a family to learn of their decision a maximum of 3 
times after the in-person clinic visit. If the team is unable to get in touch with the family 
after 3 attempts, they will stop trying to contact the family.  If parents do not want to be 
contacted and indicate this to the team, there will be no more contact attempts. 
 
Study Procedures: The treatment of significant cranial asymmetry, with cranial remolding 
orthosis typically commences as early as possible, usually around 3-6 months of age. 
Treatment involves a lightweight, plastic and foam orthosis made from a 3-D scan of the 
infant’s head. The plastic and foam orthosis (known as a Helmet therapy) is made of a 
plastic flexible shell lined with polyethylene foam. The orthosis is modified over time to 
allow for growth and provide a pathway for the infant’s head to grow into a more 
symmetrical shape. 
 
As part of their routine helmet therapy treatment for DP, study participants will be sent to 
the NOPCO brace center at BCH or CH Waltham for head shape measures including a 
laser scan of their head. Participants will also have cerebral tissue oxygenation 
monitoring completed (FDNIRS/DCS) while waiting for the head shape measures to be 
obtained or following the measures.  If recruited at CH Waltham or Weymouth, parents 
may be asked to go to BCH for the cerebral tissue oxygenation monitoring at a later 

date. Next, arrangements will be made for the study subjects to go to CH Waltham at 
later date (at a time convenient to the parents and during normal business hours) for 
MSEL assessment and non-sedated brain MRI.  Parents of study subjects will receive 
instructions on preparation for their day of testing and what they are to expect when they 
arrive. Parents will be informed that a study team member will be available on the day of 
the testing and will remain with them throughout the brain MRI.   After all initial measures 
(head shape measures, laser scan, FDNIRS/DCS, MSEL, and Brain MRI) are obtained 
the study subjects will begin treatment with their helmets.  During this time, study 
subjects will receive routine care and management for correction of the DP, including 
routine visits with the Neurosurgery or Plastic Surgery clinic physicians, and routine 
readjustments of their helmets.  Upon completion of treatment and resolution of the DP 
study subjects will have their head shape measures obtained, including a laser scan of 
their head, cerebral tissue oxygenation monitoring, MSEL and a non-sedated brain MRI. 
Once again these visits will occur during normal business hours, at a time convenient to 
the parents. If the subject’s routine care and helmet readjustments are taking place at 
CH Waltham or Weymouth, the subject and their parents may be asked to go to BCH for 
cerebral tissue oxygenation monitoring. At the end of the second MRI appointment, 
parents will be offered a CD of their infant’s MRI images. These images are not meant 
for diagnostic purposes and should not be used to inform future treatment decisions for 
the infant.  In the event that the study team is unable to complete the required cerebral 
oxygen monitoring measures or developmental assessment due to time limitations, 
parents will be given the option of scheduling additional appointments to complete these 
measures. There will be no obligation to attend these appointments. 
 
Families who attend/complete both sets of MRI measures (pre and post), will be offered 
a $50 gift card at the end of the study to offset some of the gas costs incurred driving to 
the MRI appointments. In instances where families attempt the MRI but the baby cannot 
be effectively scanned due to movement, the families will still receive their gift card.  
Families who do not wish to attend the MRI, cancel their MRI appointments without 
rescheduling, or fail to arrive at their MRI appointments will not be eligible for the gift 
cards. The gift card may be given to the family at the end of their last MRI appointment if 
available, or will be mailed to them after they complete the study.  If mailed to the family, 
they will receive a written thank you letter along with the gift card. 
 
Comparison sample: To identify infants with similar characteristics but less severe or no 
DP, our neuroradiology team members will conduct a retrospective chart review from 
within BCH medical records. Infants with similar characteristics but with no or less 
severe DP as measured according to Cranial Index and Cranial Symmetry Measures 
(see Head Shape Measures section below) will be identified as our comparison sample. 
This will enable us to provide descriptive comparisons of Brain MRI axonal pathway 
myelination between infants with less severe or no DP. 
 
Study Timeline 
 
This pilot study will take approximately 1.5 years to complete.  
 
Table 2. 
Month 1 
Month 2-4 
Month 2-10 
Month 8-10 
Month 11+ 
IRB Application, 
Approval, 
Education of 
Enrollment, 
Head Shape 
Measures 
Treatment for 
DP 
Head Shape 
Measures 
Brain MRI 
Data Analysis  
& 

clinical and study 
staff 
Brain MRI 
FDNIRS/DCS 
MSEL 
FDNIRS/DCS 
MSEL 
Manuscript 
Preparation 
• 
Average time for treatment of DP is 4-6 months. 
 
 
 
Head Shape Measures 
 
Cranial Index and Cranial Symmetry Measures:  To ascertain that correction of the 
infant’s head is achieved routine cranial index and cranial symmetry measures obtained 
at the NOPCO brace center, will be reviewed by the study team. The cranial index, is an 
objective measure that quantifies head shape by dividing the head width (M-L) by length 
(A-P) then multiplying it by 100% 18.  The normal cranial index measurement is between 
73%-85% is used to assess for brachycephaly or scaphocephaly.  To assess for DP, the 
right anterior-posterior measures and left anterior-posterior measures will be used.  For 
this measure, an 8mm difference in the right and left anterior-posterior measures will be 
indicative of asymmetry. In addition, and also as part of their routine care,  a licensed 
orthotist will use a surface laser scanner to secure a computer image of the infant’s 
head.  The FastSCAN Handheld Laser Scanner to quickly and conveniently digitize the 
three-dimensional surface of the infants’ head.  Scanning involves smoothly sweeping 
the FastSCAN Wand over the infant in a manner similar to spray painting.  An image of 
the object appears simultaneously on the computer screen. This type of measure, 
though fairly new, provides great detail, is reported to be nearly 100% accurate when 
used to make custom helmets and allows for a second set of measurements to be 
recorded.  Measurements including A-P (length), M-L (width), Right anterior-posterior, 
Left anterior-posterior, and head circumference will be obtained and recorded. 
 
Outcome Measures 
 
Brain Magnetic Resonance Imaging (MRI): Is a routine diagnostic exam that uses a 
large magnet, radio waves and a computer to produce 2- and 3-dimensional images of 
the child’s brain.  This exam is FDA and does not use ionizing radiation (as in xrays) and 
thus, is a way to better evaluate various parts of the body.  Furthermore this type of 
exam is painless, since the scanner takes pictures without touching the child's body.  
 
In this study MRI structural data will be obtained without sedation prior to and following 
correction of DP in infants <1 year of age using an age-appropriate neuroimaging 
protocol that has been previously tested and used at BCH (www.babymri.org).  This 
protocol includes intensive familiarization with MRI prior to the actual neuroimaging 
session, and the collection of whole brain images via MRI.  A trained staff member will 
be on-call for all scan sessions to make this experience as comfortable as possible for 
infant participants and their families. 57  
 
The procedure for the brain MRI includes scanning each subject on a 3T Siemens Trio 
scanner at Boston Children’s Hospital’s satellite at Waltham at times best matching nap 
times. Imaging sessions will begin with a 1-hour conditioning session in the Mock 
scanner. Infants will then be rocked to sleep in the scan room and placed on the table 
when they fall asleep using the preparation protocol outlined in www.babymri.org where 
we now have a success rate of ~ 75%.58 Once asleep in the MR scanner, imaging will be 

completed in less than 45 minutes for each subject, and will include the following 
sequences: 
3D motion corrected multiecho MPRAGE and 3D T2 SPACE. These images 
sequences will be used to perform semi-automatic assessment of regional and 
global brain volumes using FreeView.  
Diffusion Tensor Imaging (DTI). DTI (an advanced MRI technique based on 
detecting properties of free water diffusion) can help evaluate regional and global 
maturation of white matter. Tractography, a newer DTI method, allows for 
quantification of entire white matter tracts [using measures such as anisotropy 
(FA) and mean diffusivity (MD)].59 Diffusion Toolkit will be used to create the FA 
and MD maps and Trackvis will be used to create the tractography images.  
Pseudocontinuous arterial spin labeling (PCASL). PCASL allows for 
quantitative estimation of both regional and global cerebral perfusion. 
 
MRI:  
Cranial index measures will be performed on 3D volumetric reconstructions of the scalp 
and brain using both 3D images to determine which shows more potential in quantitating 
interval changes. In addition both 3D T1 and T2 images will be co-registered in 
FreeView for semi-automatic hemispheric volumetric analysis by a trained research 
assistant. Lobar parcellation will also be performed. 
 
MD and FA maps will be co-registered to the volumetric data sets with mean values for 
the regions segmented on the co-registered volumetric data determined. Bilateral 
projection fiber systems (i.e. axonal pathways) passing through the internal capsule, 
optic radiations and the arcuate fasciculus will be segmented using standard techniques 
with MD and FA for each tract determined.  
 
PCASL data sets will be co-registered to the volumetric data sets and mean perfusion 
values for regions segmented determined.  
 
Frequency Domain Near Infrared and Diffuse Correlation Spectroscopy (FDNIRS/DCS):   
FDNIRS/DCS is a non-invasive test that involves holding an optical probe over 7 
different locations on the infant’s head for 10-15 seconds in each location.  Data 
acquisition with each instrument requires repositioning of the probe due to hair and 
superficial large vessels to ensure that the measurement is representative of the 
underlying brain region. Measurement of FDNIRS/DCS may take up to 1 hour.   
 
MRI and FDNIRS Measures: These measures will be quantified according to their 
respective units of measure and the investigators will prepare a report of the pre and 
post exam (by FDNIRS/DCS, MRI) findings, and comparing the two.   
 
The Mullen Scales of Early Learning (MSEL): 
The Mullen (Scales of Early Learning) provides a profile of cognitive ability in five areas: 
Gross Motor, Fine Motor, Expressive Language, Receptive Language, and Visual 
Reception.  
 

This test assesses visual and language abilities at both receptive and expressive levels 
and provides an integrated framework within which infant development and interactional 
patterns can be determined. One of the theoretical features underlying the development 
of the MSEL is the linking of motor equilibration to early visual and language 
development. Central motor control and mobility have a primary role in the development 
of skills and abilities in the four cognitive domains of the Mullen Scales: visual reception, 
fine motor skills, and receptive and expressive language. 
 
The Gross Motor Scale measures central motor control and mobility. The early Gross 
Motor tasks asses such skills as sitting, creeping, pulling to stand, and walking. 
 
The Visual Reception Scale tests a child’s performance in processing visual patterns. 
The primary ability areas are visual discrimination and visual memory. The tasks present 
visual information in various forms and patterns, and assess visual processing skills. 
 
The Fine Motor Scale provides a measure of visual-motor ability: It reflects the output 
side of visual organization. The tasks require visually directed motor planning and 
involve visual discrimination and motor control. 
 
The Receptive Language Scale measures the child’s ability to process linguistic input. 
The abilities covered in this Scale are auditory comprehension and auditory memory. 
 
The Expressive Language Scale provides a measure of the child’s ability to use 
language productively. The primary areas covered in this Scale are speaking ability and 
language formation. These tasks also involve auditory comprehension and auditory 
memory. 
 
MSEL Reliability and Validity 
The MSEL has demonstrated positive results with test-retest and inter-rater reliability. In 
addition, the MSEL is strongly correlated with multiple assessment tools used to assess 
cognitive ability in the infant population. 
Reliability: According to Mullen, the median internal consistency split-half coefficients 
(Guilford’s formula) for the five Mullen scales range from .75 to .83 and for the 
composite, .91. (2) Test-retest reliability (with a 1- to 2-week interval between tests): for 
the Gross Motor Scale of the original Mullen scales, the correlation between tests was 
.96, and the median correlations on the “cognitive” scale were .84 (with a range of .82 to 
.85) for children ages 1 to 24 months and .76 (with a range of .71 to .79) for children 
ages 25 to 56 months. (3) Inter-rater reliability: correlations among raters ranged from 
.91 to .99 for age groups between 1 and 44 months.64 
Validity: According to Mullen, concurrent validity testing showed the Mullen scales to 
have stronger correlations with instruments that measured similar skills than those 
measuring different skills. The correlations of the Mullen ”cognitive” scales with the 
Bayley Mental Development Index (MDI) were higher (.53 to .59) than their correlations 
with the Bayley Psychomotor Development Index (PDI; .21 to .52). The ELC also was 
more strongly correlated with the MDI (.70) than with the PDI (.43). Conversely, the 
Mullen Gross Motor scale was more strongly correlated with the Bayley PDI (.76) than 

with the MDI (.30). Similarly, the Mullen Receptive Language scale had a higher 
correlation with the Preschool Language Assessment Auditory Comprehension (.85) 
than with Verbal Ability (.72), while the converse was true with the Mullen Expressive 
Language Scale (.72 for auditory and .80 for verbal). Finally, the Mullen Fine Motor scale 
was strongly correlated with the Peabody Fine Motor Scale, across four age groups of 
children between the ages of 6 and 36 months (correlations ranged from .65 to .82). (2) 
Predictive validity: no information available.64 
Brain MRI axonal pathway 
 
The identification of the comparison sample will enable us to provide descriptive 
comparisons of brain MRI axonal pathway myelination between with infants in our 
primary study sample against those with less severe or no DP.  
 
Using the Cranial Index and Cranial Symmetry Measures, a comparison sample of 
infants (gender, age and race/ethnicity) with less severe or no DP will be identified by 
our neuroradiology team members through retrospective chart review from within BCH 
medical records. Data collection will be limited to Brain MRI and infant characteristics’ 
data that already exists in the medical records. Data including brain MRIs and infant 
characteristics will be de-identified for storage. Members of the study team will maintain 
an electronic record of corresponding MRNs in the study log in the event that data 
verification or additional analyses are needed.  
 
Axonal pathways for infants with DP primary study sample undergoing helmet therapy 
and those of the comparison sample will be constructed then examined for differences 
axonal pathways.  
 
Data Management 
 
Data will be managed and stored by the Cardiology Clinical & Research Regulatory 
Group at BCH. Baseline cranial index and cranial symmetry measurements (obtained 
manually and by laser scan) for each of the study subjects will be examined by one the 
investigators (Neurosurgeon or Plastic Surgeon) to confirm correction. Then one of the 
other investigators (a neuroradiologist with experience in performing FDNIRS/DCS and 
Brain MRIs) will examine each of the study subjects independently for changes in brain 
volume/structure, myelination of axonal pathways, perfusion of cerebral structures and 
cerebral oxygen consumption for changes pre and post correction. FDNIRS/DCS, brain 
MRI and MSEL data will be stored into a password protected, secure computer.  
 
Data Analysis 
 
The measures will be quantified according to their respective units of measure and the 
investigators will prepare a report of the pre and post exam (by FDNIRS/DCS, MRI, and 
MSEL) findings.  The report will include case presentations for each of the study 
subjects and a description of their comparisons, as specified in the aims.  A collective 
presentation of the findings will be prepared using descriptive statistics (mean, median, 
mode, and frequencies). Tables and bar graphs will also be used to display the results.  
Also if the data permits, non-parametric tests (signed-rank) will be used to determine if 
differences are statistically different from zero when examining the paired observations.  
 

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