The MRI Study of Normal Brain Development

The MRI Study of Normal Brain Development

(needs our study logo)

SponsorSponsored by

The National Institute of The National Institute of The National Institute of

Neurological Disorders And Stroke Mental Health Child Health and Human

And StrokeDevelopment

United States Department of Health National Institutes of Health

and Human Services

November 2006FebruaryMarch 20035

To Interested Researchers,

Thank you for your interest in the protocol for the multi-site study: MRI Study of Normal Brain Development. The NIH and the investigators of the Steering Ccommittee welcome the opportunity to share the protocol with other investigators doing related work.

The attached protocol has been developed as a collaborative effort of the seven involved pediatric study centers and the two coordinating centers

Please complete the attached registration form so we can be aware of who is interested in or implementing portions of this protocol. This registration will be used to send updated information in the future.

Thank-you again for your interest!

Currently we have developed a protocol which we are just beginning to use in the field to collect and evaluate subjects. Therefore, although this is our current protocol, we would like to emphasize that the protocol outlined in the attached document should only be viewed as a pilot protocol. Because we have been receiving inquiries from a number of investigators who are currently beginning their own pediatric imaging studies, we have decided to release this pilot protocol for those who may be interested in beginning a protocol similar to the protocol for this project. However, we would like to be clear that we anticipate that following our initial experience in the field, we will likely make some modifications in the Protocol. We anticipate that these modifications will be minor and will be implemented prior to the collection of the full sample for inclusion in the normal pediatric MRI database which will be created in this project. Therefore, if you indicate that you plan to use this protocol in a project we will plan to inform you when the updated finalized protocol is available.

Sincerely,

Kelly Botteron M.D.

Giovanna Spinella MD

Principal InvestigatorProject Officer

Clinical Coordinating Center National Institute of Neurological

for the Steering CommitteeDisorders and Stroke

MRI Study of Normal Brain Development

Alan Evans, Ph.D.

Principal Investigator

Data Coordinating Center

Lisa Freund, Ph.D.

Project Officer

National Institute of Child Health and Human Development

Katrina Gwinn-Hardy, MD

Project Officer

National Institute of Neurological Disorders and Stroke

Judith Rumsey, Ph. D.

Project Officer

National Institute of Mental Health

Laurence Stanford, Ph. D.

Project Officer

National Institute on Drug Abuse

Karen Sirocco Ph. D.

Project Officer

National Institute on Drug Abuse

Giovanna Spinella, M.D.

Project Officer

National Institute of Neurological

Disorders and Stroke

The MRI Study of Normal Brain Development

Participating Centers

Pediatric Study Centers (PSC)

Children's Hospital, Boston

Principal Investigator: Michael Rivkin, M.D.

Associate Investigators: Heidelise Als, Ph.D.,Jacki Marmor, M.Ed.

Gloria B. McAnulty, Ph.D., Robert Mulkern, Ph.D.

Deborah Waber, Ph.D.

Cincinnati Children’s Hospital Medical Center

Principal Investigator: William S. Ball, Jr., M.D.

Associate Investigators: Wendy A. Bommer, RN, BSN, CPN

Anna Weber-Byars, Ph.D.

The Children's Hospital of Philadelphia

Principal Investigator: DJ Wangohn Haselgrove, Ph.D.

Associate Investigators: Marshay Best Gerdes, Ph.D.

Molly McDaniel, Ed Moss, Ph.D.,

D. J. Wang, Ph.D.

University of California, Irvine

Principal Investigator: Pauline A. Filipek, M.D.

Associate Investigators: Rosalind B. Dietrich, M.D.,

Jenifer Juranek, Ph.D., Chris Majors, Psy.D.

University of California, Los Angeles

Principal Investigator: James T. McCracken, M.D.

Associate Investigators: Jeffry R. Alger, Ph.D.,

Robert Asarnow, Ph.D., Jennifer Levitt, M.D.

Renee Marquardt, M.D.,

Joseph O'Neill, Ph.D.

University of Texas Health Science Center at- Houston

Principal Investigator: Michael E. Brandt, Ph.D.

Associate Investigators: Jack Fletcher, Ph.D.,

Kathleen M. Hebert, Larry Kramer, M.D.

Washington University St. Louis

Principal Investigators: Kelly Botteron, M.D., Kelly Botteron, M.D., Robert McKinstry, M.D., Ph.D.,

Associate Investigators: C. Robert Almli, Ph.D., Kelly Botteron, M.D.,

John Constantino, M.D., Jeffrey Neil, M.D., Ph.D., Tisha Singer

Richard Todd, M.D., Ph.D.,William Warren

Clinical Coordinating Center (CCC)

Washington University St. Louis

Principal Investigators: Kelly Botteron, M.D.,

Associate Investigator: C. Robert Almli, Ph.D.

Data Coordinating Center (DCC)

Montreal Neurological Institute

Principal Investigator: Alan Evans, Ph.D.

Associate Investigators: Louis Collins, Ph.D.,

Gabriel Leonard, Ph.D., Tomas Paus, M.D., Ph.D.,

Bruce Pike, Ph.D., Alex Zijdenbos, Ph.D.

Harvard University/McLean Hospital

Associate Investigator: Nicholas Lange, Sc.D.

University of California, Los Angeles

Associate Investigators: John Mazziotta, M.D., Ph. D.,

Arthur Toga, Ph.D.

ArgoGeorgetownsy

Associate Investigator: Thomas Zeffiro, M.D., Ph. D.

Diffusion Tensor Processing Center (DPC)

National Institute of Child Health and Human Development, NIH

Principal Investigator: Carlo Pierpaoli, M.D. Ph.D.

Spectroscopy Processing Center (SPC)

University of California, Los Angeles

Principal Investigator: James T. McCracken , M.D.

Associate Investigators: Jeffry R. Alger, Ph.D.,

Jennifer Levitt, M.D., Joseph O'Neill, Ph.D.

GENERAL OVERVIEW

Introduction

The purpose of the study is to collect a representative sample of normal, healthy infants, children and adolescents for a magnetic resonance imaging study that will serve several purposes: 1) It will provide a resource database of normal anatomic and metabolic brain development, provide ranges of normal values and define key developmental periods, 2) It will provide a needed, representative and reliable source for multiple research institutions of normal control data for studies of childhood disorders and diseases which affect the brain. (3) It will provide for the construction of normal growth curves for brain structures and metabolites for clinical applications such as for use with clinical MRIs in comparing specific regional structures and metabolite values. (4) Finally, such a database will serve as a repository to aid in the development of new diagnostic imaging tools. Scientists involved in the development of new diagnostic tools will be able to take advantage of this data set to facilitate the development of techniques for deriving measures which are sensitive to neurodevelopmental changes.

The study involves sixeven sites or Pediatric Study Centers (PSC) in the United States, a Clinical Coordinating Center (CCC) in St. Louis, Missouri and a Data Coordinating Center (DCC) in Montreal, Canada. The U.S. sites include three Children’s Hospitals (Boston, Cincinnati and Philadelphia), and the Universities of Washington in St. Louis, Texas at Houston, California at Irvine, and California at Los Angeles. These sites will collaborate in the recruitment of a representative sample of approximately 52546 children, ages 10 days through 18 years 3 months (at first scan), who will be studied using anatomic magnetic resonance imaging (aMRI), diffusion tensor imaging (DTI), magnetic resonance spectroscopy (MRS) and clinical/behavioral measures at three (or more) different time points over a five to six year period. The children will be scanned with techniques that will provide state of the art information concerning the structural and metabolic development of the brain, including the development of specific structures. Developmental changes in the brain and in specific regions of the brain will be related to maturational changes in behavior and cognition. Image analysis tools sensitive to brain developmental changes will be developed as part of this effort. A goal is to develop growth curves for various aspects of brain development. The information gained will be made widely available to researchers and clinicians. This will permit physicians and researchers to determine possible differences in brain structure and metabolism in children with known or suspected brain-based problems. The information and tools produced may also allow physicians to track brain-related changes associated with disease and to evaluate the effects of various treatments on the brain. The purpose of the study is to collect a representative sample of normal, healthy infants and children for a magnetic resonance imaging study that will serve two purposes: 1) to provide the largest normative database to date of the developing human brain for comparison with brain scan studies of children with neurological, developmental, and psychiatric disorders; and 2) provide longitudinal data for investigating brain maturation in relationship to behavioral and cognitive development in a normal sample. Such data will allow a greater understanding of deviations in brain structural development associated with pediatric brain disorders.

The study involves six different sites in the United States, as well as a Data Coordinating Center (DCC) in Montreal, Canada, and a Clinical Coordinating Center (CCC) in St. Louis, Missouri. The U.S. sites include three Children’s Hospitals (Boston, Cincinnati and Philadelphia), and Washington University in St. Louis, the University of Texas Health Science Center in Houston, and the University of California in Los Angeles. A seventh center, the University of California in Irvine, was initially involved in recruiting subjects who were subsequently followed at UCLA.

These sites will collaborate in the recruitment of a representative sample of approximately 546 children, ages 10 days through 18 years 3 months (at first scan), who will be studied using anatomic magnetic resonance imaging (aMRI), diffusion tensor imaging (DTI), magnetic resonance spectroscopy (MRS) and behavioral testing at three (or more) different time points over a five to six year period. The children will be scanned with techniques that will provide state of the art information concerning the structural and metabolic development of the brain, including the development of specific structures. Developmental changes in the brain and in specific regions of the brain will be related to maturational changes in behavior and cognition. Image analysis tools sensitive to brain developmental changes will be developed as part of this effort. A goal is to develop growth curves for various aspects of brain development.

The information gained will be made widely available to researchers and clinicians. This will permit physicians and researchers to determine possible differences in brain structure and metabolism in children with known or suspected brain-based problems. The information and tools produced may also allow physicians to track brain-related changes associated with disease and to evaluate the effects of various treatments on the brain.

Objectives

The MRI study of Normal Brain Development has two main objectives and two ancillary objectives.

Objective 1: Anatomic MRI and clinical/behavioral cross-sectional and longitudinal studies of children between the ages 4 years, 6 months and 18 years, 3 months (at time of first scan).

Objective 2: Anatomic MRI and clinical/behavioral cross-sectional and longitudinal studies of children between the age of newborn and 4 years, 65 months (at time of first scan).

Ancillary A: MR Spectroscopy (MRS) of children between the ages of newborn to 18 years, 3 months (at time of first scan). May include MRSI at specific sites.

Ancillary B: Diffusion Tensor Imaging (DTI) of children between the ages of newborn and 4 years, 6 months (at time of first scan). This will be expanded at selected sites to include subjects between the ages of 4 years, 6 months and 18 years, 3 months.

The Pediatric MRI study of Normal Brain Development has two main objectives and two ancillary objectives.

Objective 1: Anatomic MRI and cognitive/behavioral cross-sectional and longitudinal studies of children between the ages 4 years, 6 months and 18 years, 3 months (at time of first scan).

Objective 2: Anatomic MRI and cognitive/behavioral cross-sectional and longitudinal studies of children between the age of newborn (10-14 days) and 4 years, 5 months (at time of first scan).

Ancillary A: MR Spectroscopy (MRS) of children between the ages of newborn (10-14 days) and 18 years, 3 months (at time of first scan).

Ancillary B: Diffusion Tensor Imaging (DTI) of children between the ages of newborn (10-14 days) and 4 years, 5 months (at time of first scan). However, this was been expanded to include subjects of all ages.

However, this was broadened to include subjects of all ages. An expanded DTI (eDTI) protocol was developed and acquisitions began in early 2006.

Inclusion Criteria

Healthy cChildren from birth to age 18 (at time of enrollment). Subjects are going to be selected to be demographically representative of the U.S. population and include males and females and right and left handed individuals.

Exclusion Criteria for Objectives 1 and 2

Below is a overview of some exclusion criteria.

Exclusion CategoriesExamples

I. DemographicAdopted, EEnglish fluency/lLanguage, pParental history unknown

II. PregnancyMother’s age at birth of child: <16 years or >44 years

Exposure: SmokeTobaccoAalcohol (as specified in each manual),

any illicit drug use: specified prescription medications,Meds & Drugs

Maternal medical conditions such as Medical: Ppre-eclampsia, Agestational nesthesia, Gestational diabetes requiring treatment; general anesthesia.

III. DeliveryMultiple births, Malpresention,non-elective cesarean section for fFetal distress, high fForcept or sv/Vacuum exctraction delivery

IV. Birth-Neonatal<37 wks 4 dys or >42 wks 3 days, Growth (outside acceptable limits specified in manuals), AS<8@5m

Seizures, Hyperbiliarubinemia with >48 hours phototherapy: head and neck abnormalities, Abnormal face/limbs,; PKU, RDS., Infection

V. Child DevelopmentGrowth (below acceptable limits specified in manuals), non-English speaking, specified medication during , breastfeedingBreast-drugs.

VI. Medical: Major medical illness with known or hypothesized CNS implications, cCongenital abnormalities, Hheart problems, Cancermalignancy, Llead poisoning.

Neuro: sSeizures, CNS iInfection, serious Hhead injury, sSignificant hearing loss requiring intervention, visual impairment requiring more than glasses.

VII. Psychiatric-Child:Interven: Language disorder

Psychiatric: Mood disorder, Conduct, AD/HD, Tic, Eating disorders, Current or prior treatment for any Axis I disorder; or current or previous history of major Axis I disorders including: Conduct, AD/HD, major depression; Tic disorders, Eating disorders and specified others.

VIII. Psychiatric—1st DegreeBipolar, Cchronic major depressionve disorders, PsychoticSchizophrenia, AD/HD, dDrug dependence, PDD and specified others.

IXVII. Child Testing / ParentalIntelligence, Achievement, BSID & PLS-3 (<70), CBCL (>70)

VIIIX. Child Neuro ExamHyper/Hypo-tonia, Ocular motility abnormalities, Face, Motor or reflex abnormalities, tTics

Exclusion Criteria

Below is a general outline of exclusion criteria. A more comprehensive list will be available in the future.

Demographic: Children of parents with limited English proficiency i.e., no parent or caregiver available with a minimum of 6th grade English reading proficiency, are excluded. Adopted children will not be included in the study.

Birth and Development: Intra-uterine exposures to substances known to alter brain structure or function (drugs, alcohol, medications), or hyperbilirubinemia requiring transfusion and/or phototherapy are exclusionary criteria. A gestational age between 37 weeks and 4 days and 40 weeks and 3 days is required. Multiple births, children born by forceps delivery, or vacuum extraction will be excluded. Metabolic conditions such as phenylketonuria or diabetes; as well as preeeclampsia, or serious obstetrical complications such as placental abruption are also exclusionary. General anesthesia during pregnancy or delivery is exclusionary. Specialized neonatal care would also constitute an exclusionary criterion. A need for resuscitation would exclude the subject. Non electiveNon-elective C-section is exclusionary.

Physical/Medical: If height, weight less than the 5th or greater that the 95th percentile, or head circumference <3rd% or >97th% by National Center for Health Statistics data then the child will not be included in the study (refer to our WEB site under Growth Charts for charts taken from NCHS, or go to their site at:

A history of significant medical or neurological disorder requiring intervention and with known or hypothesized CNS implications (e.g., seizure disorder, CNS infection, malignancy, diabetes, systemic rheumatologic illness, muscular dystrophy, myotonic dystrophy, sickle cell anemia), and history of closed head injury with loss of consciousness >530 minutes or known neuroimaging abnormalities are exclusionary. In addition, systemic malignancy requiring chemotherapy and CNS radiotherapy are both exclusionary criteria.

Subject with reported hearing impairment, significant visual impairment requiring more than conventional glasses (strabismus, visual handicap) will not be included. Metal implants (braces, pins) would not be included, for both safety and image quality reasons.

Behavioral/Psychiatric Conditions: The child would be excluded if currently receiving, or if he/she had had past treatment for a psychiatric or a language disorder. Simple articulation disorders are not excluded. A lifetime history of Axis I psychiatric disorder or any Childhood Behavior Checklist (CBCL) subscale score > 70, or a WASI IQ < 70, or any achievement score >2SD below age norms (Woodcock Johnson subtests, see list of measures below) would preclude the child from entry into the study.

Family History: One or more first-degree relatives with current or past historyies of any of the following Axis I psychiatric disorder: schizophrenia, bipolar disorder, psychotic disorder, alcohol dependence, other drug dependence, OCD, Tourette Disorder, recurrent or chronic major depression, ADHD, and PDD in any first-degree relative will constitute an exclusion criterion. A history of inherited neurological disorder, or a history of mental retardation due to non-traumatic events in any first-degree relative, would also be exclusionary.

Neurological Exam: Certain abnormalities on the standardized neurological exam are exclusionary.

Behavioral Measures: The primary purpose of the behavioral tests included in the battery is to ensure selection of a normal sample and to document the cognitive ability of this subjectresearch group. Some of the behavioral measures chosen will allow for brain behavior correlations.