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Introduction

 

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Journal of the International Neuropsychological Society (2007), 13, 1–18.
Copyright © 2007 INS. Published by Cambridge University Press. Printed in the USA.
DOI: 10.10170S1355617707070841

The NIH MRI study of normal brain development:
Performance of a population based sample
of healthy children aged 6 to 18 years
on a neuropsychological battery



DEBORAH P. WABER,1 CARL DE MOOR,1,2 PETER W. FORBES,2 C. ROBERT ALMLI,3 KELLY N. BOTTERON,4 GABRIEL LEONARD,5 DENISE MILOVAN,5 TOMAS PAUS,5,6 JUDITH RUMSEY,7 and THE BRAIN DEVELOPMENT COOPERATIVE GROUP
1 Department of Psychiatry, Children’s Hospital, Harvard Medical School, Boston, Massachusetts
2 Clinical Research Program, Children’s Hospital, Harvard Medical School, Boston, Massachusetts
3 Program of Occupational Therapy, Neurology and Psychology, Washington University School of Medicine, St. Louis, Missouri
4 Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri
5 Cognitive Neuroscience Unit, McGill University, Montreal, Quebec, Canada
6 Brain and Body Centre, University of Nottingham, Nottingham, UK
7 Neurodevelopmental Disorders Branch, National Institute of Mental Health, Bethesda, Maryland
   (Received May 8, 2006; Final Revision February 2, 2007; Accepted March 2, 2007)


Abstract

The National Institutes of Health (NIH) Magnetic Resonance Imaging (MRI) Study of Normal Brain Development is a landmark study in which structural and metabolic brain development and behavior are followed longitudinally from birth to young adulthood in a population-based sample of healthy children. The neuropsychological assessment protocol for children aged 6 to 18 years is described and normative data are presented for participants in that age range (N 5 385). For many measures, raw score performance improved steeply from 6 to 10 years, decelerating during adolescence. Sex differences were documented for Block Design (male advantage), CVLT, Pegboard and Coding (female advantage). Household income predicted IQ and achievement, as well as externalizing problems and social competence, but not the other cognitive or behavioral measures. Performance of this healthy sample was generally better than published norms. This linked imaging-clinical0behavioral database will be an invaluable public resource for researchers for many years to come. (JINS, 2007, 13, 1–18.)


Keywords: Psychol tests, Child behavior, Child development, Adolescent development, MRI scans, Neuropsychology

INTRODUCTION

The National Institutes of Health (NIH) Magnetic Resonance Imaging (MRI) Study of Normal Brain Development is a landmark study that documents structural brain development and behavior longitudinally from birth to young adulthood in a population-based sample of healthy children targeted to the United States 2000 census distribution. The goal is to establish a public database of pediatric anatomic MRI, magnetic resonance spectroscopy (MRS), and diffusion tensor imaging (DTI) with coordinated neuropsychological, neurological, and psychiatric data. The database will be used to describe the normative structural development of the human brain and to correlate developmental and individual variation in brain structure with behavior and cognition. This database will be released to the scientific and clinical community at a future date.

The findings from the neuropsychological testing are themselves of interest, independent of the imaging data, because they portray the neuropsychological status of this healthy, diverse, and representative sample of children of the United States as a point of reference for both developmental and clinical studies. Acomprehensive description of the data will also support users of the database.

his project is supported by the National Institute of Child Health and Human Development (Contract N01-HD02-3343), the National Institute on Drug Abuse, the National Institute of Mental Health (Contract N01- MH9-0002), and the National Institute of Neurological Disorders and Stroke (Contracts N01-NS-9-2314, -2315, -2316, -2317, -2319 and -2320). The views stated herein do not necessarily represent the official views of the National Institutes of Health (National Institute of Child Health and Human Development, National Institute on Drug Abuse, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke), or the Department of Health and Human Services, nor any other agency of the United States government. 

Correspondence and reprint requests to: Deborah P. Waber, Department of Psychiatry, Children’s Hospital Boston, 300 Longwood Avenue, Boston, MA 02115. E-mail: deborah.waber@childrens.harvard.edu


2  D.P. Waber et al.

Children were carefully screened for medical, neurological, genetic, and psychiatric conditions that could influence brain development. Although development of a truly normative database was considered, the sample would have been substantially larger than resources allowed, and so we focused on describing a healthy population. The data collection sites are located in six urban regions. The sample is generally representative of the healthy United States population and provides a baseline for comparison with clinical groups where the primary questions involve suspected neurological, developmental, genetic or psychiatric impairment or disorder.

The project is divided into two “Objectives.” Objective 1 includes children from 4 years 6 months through 18 years at the time of recruitment. Objective 2 includes children from birth to 4 years 5 months at recruitment (Almli et al., 2006). Children between the ages of 4 years 6 months and 5 years 11 months are excluded from this report because the test battery differed from that of the rest of the Objective 1 children.

The present manuscript describes the first wave of crosssectional neuropsychological data from Objective 1. The sample, test battery, and descriptive results are presented for children between the ages of 6 and 18 years. The imaging and database procedures are described in detail elsewhere (Evans, 2006).

The neuropsychological evaluation was developed to sample a range of cognitive and behavioral functions that are typically included in a standard neuropsychological assessment: intellectual level, language, visuospatial function, memory, executive functions, academic skills, and psychosocial adjustment. The battery included both performance based testing and questionnaires. In general, the tests chosen are widely used, have good reliability and validity, and can be administered reliably across sites. Some measures that did not meet all these criteria were chosen because they measure aspects of cognition relevant for brain-behavior correlation. A rigorous quality control procedure guarantees consistency across sites.

The present report has two aims: (1) to document the methods used to acquire the sample and collect the neuropsychological data and (2) to present descriptive data on the neuropsychological battery and to evaluate effects of age, sex, and income level on performance.

Because the primary goal of this project is to describe processes of structural and functional brain development, we focused on raw scores rather than standard scores in our evaluation of age effects. Standard scores convey the standing of an individual relative to peers of the same age. Although they effectively capture individual differences, they are necessarily insensitive to developmental differences, which will be best correlated with absolute performance on the task.

METHODS

Study Organization

Data are collected at 6 Pediatric Study Centers (PSCs) across the United States: Children’s Hospital, Boston; Children’s Hospital Medical Center of Cincinnati; Children’s Hospital of Philadelphia; University of California at Los Angeles; University of Texas, Houston; and Washington University, St. Louis. A Clinical Coordinating Center (CCC) at Washington University, St. Louis coordinates the clinical / behavioral aspects of the project, including sampling plan and methods, recruitment, implementation of inclusion/ exclusion criteria, screening and assessment, and quality control (QC) for all clinical and behavioral measures. The Data Coordinating Center (DCC) at the Montreal Neurological Institute, McGill University, coordinates the image acquisition protocols, imaging data quality and control, and image analysis and maintains a purpose-built database that consolidates and analyzes clinical/behavioral and structural MRI data.

Design

Participants were evaluated at baseline and followed at twoyear intervals spanning a total of four years, ultimately accruing longitudinal data across the range from 4–22 years. More children are recruited in age ranges when rapid developmental changes are expected, and fewer when development is believed to be more stable. Power analyses were conducted to determine the minimum sample size in relation to potential change in the size of a brain structure in standard deviation units based on growth curve analyses spanning 3 time points. With 80% power, 340 subjects are required to detect 5% change and 532 to detect 4% change. The actual number of subjects was midway between these two target numbers. This report describes the baseline evaluation for children between the ages of 6 and 18 years.

Participants

The sample was recruited between February 2001 and October 2003 using a population-based sampling method that seeks to minimize biases that can be present in samples of convenience. The sampling plan was based on US Census (“Distribution of Income by Families and Race/Nationality, Census 2000,”) data to define low, medium, and high income categories for families in the overall population and to divide the United States income distribution for families into approximately equal thirds (;33% in each category): less than $35,000 per year; $35,000 to $75,000 per year; and over $75,000 per year and to subdivide these groups based on the expected distribution of race/ethnicity within each income category. These race/ethnicity3income categories were then distributed across age, based on the planned age distribution, with males and females represented equally for each age category. The result was a table comprised of cells representing a target sample distributed by age, sex, race/ethnicity, and income. 


NIH MRI study of normal brain development  3 

Regionally specific target tables were then created in a multi-step process for each PSC. First, the demographics in the region of each PSC were characterized based on postal code census data to yield a local PSC race/ethnicity distribution table with specific age- and sex-based demographic targets. These tables were then adjusted so that they collectively approximated the national target distribution. The actual sample was recruited to match these targets as closely as possible.

Census data were used to identify postal codes within a 30 to 60 mile radius (depending on site) of each PSC that could be targeted to reach families likely to meet specific demographic criteria. Addresses of families within postal codes were obtained from a direct marketing agency (InfoUSA). Each PSC recruited to its target table until approximately 50% of the total sample had been accrued, after which recruiting was pooled across sites. The CCC maintained a real-time record of “open” and “filled” cells, and sites obtained approval for each new candidate. Because filled “cells” were closed to recruitment, some families who met eligibility criteria and were willing to participate could not be recruited. Because the recruitment period was ending, some participants were enrolled whose characteristics only approximated those of open cells.

Families were carefully screened for potential exclusionary criteria, as detailed in Table 1. Children with a condition that could pose safety or artifact issues for MRI scanning (e.g., metal implants) were also excluded.

As families were screened for recruitment, further adjustments were made to account for regional differences in cost of living. Methods established by the Department of Housing and Urban Development (HUD) were used to adjust family income levels based on regional cost of living and family size. These “HUD-adjusted” incomes better equate income across sites and regions, thus providing a more meaningful indicator of socioeconomic status.

Families whose child met all inclusion and no exclusion criteria and whose demographic characteristics were compatible with an available cell were invited to the PSC for neurological evaluation, neuropsychological testing, and structural MRI imaging, typically performed in one day. Informed consent was obtained in compliance with research standards for human research for all participating institutions and in accordance with the Helsinki Declaration.

Table 1. Exclusionary criteria

Category  Specific criteria
Demographic  Children of parents with limited English proficiency. Adopted children excluded due to inadequate family
histories.
Pregnancy, birth and
perinatal history
Intra-uterine exposures to substances known or highly suspected to alter brain structure or function
(certain medications, any illicit drug use, smoking > 1/2 pack per day or >2 alcoholic drinks per week
during pregnancy); Hyperbilirubinemia requiring transfusion and/or phototherapy (> 2 days); gestational
age at birth of < 37 weeks or > 42 weeks; multiple birth; delivery by high forceps or vacuum extraction;
infant resuscitation by chest compression or intubation; maternal metabolic conditions (e.g.,
phenylketonuria, diabetes); pre-eclampsia; serious obstetric complication; general anesthesia during
pregnancy/delivery; C-section for maternal or infant distress
Physical/medical or
growth
Current height or weight ,3rd percentile or head circumference ,3rd percentile by National Center for
Health Statistics 2000 data (charts at http://www.cdc.gov/nchs/about/major/nhanes/growthcharts/
charts.htm); history of significant medical or neurological disorder with CNS implications (e.g., seizure
disorder, CNS infection, malignancy, diabetes, systemic rheumatologic illness, muscular dystrophy,
migraine or cluster headaches, sickle cell anemia, etc.); history of closed head injury with loss of
consciousness >30 min or with known diagnostic imaging study abnormalities; systemic malignancy
requiring chemotherapy or CNS radiotherapy; hearing impairment requiring intervention; significant visual
impairment requiring more than conventional glasses (strabismus, visual handicap); metal implants
(braces, pins) if likely to pose safety or artifact issues for MRI; positive pregnancy test in subject.
Behavioral/psychiatric  Current or past treatment for language disorder (simple articulation disorders not exclusionary); lifetime
history of Axis I psychiatric disorder (except for simple phobia, social phobia, adjustment disorder,
oppositional defiant disorder, enuresis, encopresis, nicotine dependency); any CBCL subscale score => 70;
WASI IQ < 70; Woodcock-Johnson Achievement Battery subtest score < 70; current or past treatment for
an Axis I psychiatric disorder.
Family history  History of inherited neurological disorder; history of mental retardation caused by non-traumatic events in
any first-degree relative; one or more first degree relatives with lifetime history of Axis I psychiatric
disorders; schizophrenia, bipolar affective disorder, psychotic disorder, alcohol or other drug dependence,
obsessive compulsive disorder, Tourette’s disorder, major depression, attention deficit hyperactivity
disorder or pervasive developmental disorder.
Neuro examination  Abnormality on neurological examination (e.g., hypertonia, hypotonia, reflex asymmetry, visual field cut,
nystagmus, and tics).

 


4    D.P. Waber et al.


Figure 1 displays a schematic of the recruitment process, starting from the more than 35,000 packets sent to target families and ending with the 385 participants who are the subject of this report. Approximately 75% of the families contacted either actively or passively declined to participate or were not pursued, and another 21% met at least one exclusion criterion. The final sample comprised approximately 1.2% of the initial zip code based mailed letters, and 1.1% were in the age range included in the present report.


Table 2 displays the demographic characteristics of the sample, and Table 3 shows the sample distribution by race/ ethnicity and income against the target distribution. Overall, the actual distribution nicely tracks the targets. Low income white children, however, are somewhat under represented and high income white children over-represented. These deviations may reflect the relatively lower prevalence of low income white families in urban areas and the minor adjustments made to accrue the sample within time limitations, as indicated later.

Fig. 1. Recruitment scheme illustrating derivation of sample from initial zip code lists. Note that because the children were recruited to meet certain demographic criteria to fill specified “cells,” there were several points at which recruitment was not pursued because of sampling criteria and not exclusionary factors. Dashed lines indicate families that were excluded or chose not to continue with the process.

 




Children were screened on several behavioral and cognitive
instruments in addition to the extensive history-based
screening. The following test score criteria were exclusionary:
T-score greater than 70 on any sub-scale from the Child
Behavior Checklist (CBCL, Achenbach, 2001); Axis I
psychiatric disorder based on the Diagnostic Interview
Schedule for Children (C-DISC-4, Shaffer et al., 2003),
except for simple phobia, social phobia, adjustment disorder,
oppositional defiant disorder, enuresis, encopresis,
and nicotine dependency (not exclusionary because no evidence
was found linking these to structural brain development);
Full Scale IQ below 70 on theWechsler Abbreviated
Scale of Intelligence (WASI, 1999); standard score below
70 on any of the administered subtests (Letter-Word Identification,
Passage Comprehension, Calculation) from the
Woodcock-Johnson III (WJ-III, Woodcock, et al., 2001).
The Full Scale IQ lower limit was set at 70 to allow for
inclusion of as broad a range of cognitive variability as
possible but to exclude children with frank mental retardation.
No child was excluded based on the WASI or
Woodcock-Johnson test scores or the DISC-IV, presumably
because those who would have met exclusionary criteria
had already been screened out. (One child who obtained
a score of 69 on one WJ-III subtest was retained because
the child deviated by only one standard score point on
only one subtest).
Although the rates of successful contact were similar
across income groups, higher income families had higher
rates of combined active and passive refusal (high, 60.8%;
medium, 55.9%; low 44.1%). In contrast, lower income children
were more likely to be excluded based on either the

Table 2. Sample characteristics (Total N 5 385)
Characteristic  Distribution
Age in years  
64 (16.6%)
7 42 (10.9%)
8 36 (9.4%)
9 36 (9.4%)
10 35 (9.1%)
11 28 (7.3%)
12 24 (6.2%)
13 27 (7.0%)
14 23 (6.0%)
15 23 (6.0%)
16 20 (5.5%)
17 21 (5.5%)
18 6 (1.6%)
Sex (% male)  187 (48.6%)
Handedness
(% righthanded)
336 (87.7%)
Family 
income 
Low 94 (24.4%)
Medium 156 (40.5 %)
High 135 (35.0 %)
Racial/ethnic
group 
 White 281 (73.0%)
African-American 35 (9.1%)
Asian 8 (2.1%)
Native Hawaiian0Other Pacific Islander 3 (0.8%)
American Indian0Alaskan Native 8 (2.1%)
Hispanic 50 (13.0%)
Site  Boston 66 (17.1%)
Cincinnati 70 (18.2%)
Houston 76 (19.7%)
Los Angeles 51 (13.3%)
Philadelphia 47 (12.2%)
St. Louis 75 (19.5%)








Table 3. Distribution of sample by race0ethnicity and income level and distribution by race0ethnicity
based on United States Census 2000 (% Total Sample)
Low Medium High
Race0Ethnicity
Sample
% (N)
Census
%
Sample
% (N)
Census
%
Sample
% (N)
Census
%
White 13.5 (52) 23.93 30.9 (119) 29.89 28.6 (110) 24.63
Black 5.4 (21) 5.84 2.5 (10) 3.85 1.0 (4) 1.79
Hispanic 4.1 (16) 5.03 5.4 (21) 3.62 3.3 (13) 1.42
Asian 0.2 (1) — 0.7 (3) — 1.0 (4) —
Native Hawaiian0Other Pacific Islander 0 (0) — 0.5 (2) — 0.2 (1) —
American Indian0Alaskan Native 1.0 (4) — 0.2 (1) — 0.7 (3) —
Total N 5 385
Note. Targets for Race0Ethnicity 3 Income cells for Asian, Native-Hawaiian0Other Pacific Islander, American Indian0Alaskan
Native not included because they were too small to be reliable.
Note. Census figures derived from United States Government document (“Distribution of Income by Families and Race0Nationality,
Census 2000,”)
NIH MRI study of normal brain development 5
early screening interview (high, 21.8%, medium, 27.0%;
low, 37.9%) or elevated CBCL subscale scores (High, 8.7%;
Medium, 15.0%; Low, 19.4%), reflecting the greater morbidity
in lower income populations.
Astandardized clinical neurological examination screened
children for abnormalities (e.g., hypertonia, reflex asymmetry,
visual field cut). No child was excluded based on the
neurological examination.
Measures
Table 4 displays the instruments used, the function measured,
and the age range to which it was applied. The battery
needed to be comprehensive but sufficiently brief that
the child could complete it on the same day as the neurological
examination and the MRI scan. The final battery
typically took approximately three hours to administer.
Measures were chosen to be representative of a broad
range of functions, to be familiar and widely available to
pediatric neuropsychologists, to have good reliability and
validity and to have appropriate norms provided by the test
publisher. Some instruments were modified for this study
(Handedness, NEPSY Verbal Fluency). For others, published
norms were incomplete across the age range (Purdue
Pegboard) or derived from samples of convenience
(CANTAB), but the instrument measured a sufficiently
important function to merit inclusion. Although the
CANTAB is not widely used clinically, it was included
because it measures functions that lend themselves well to
brain-behavior correlation and potentially to future functional
neuroimaging paradigms. There was no conflict of
interest on the part of any of the investigators in the choice
of any of the measures.
A quality confirmation (QC) procedure was implemented
by the CCC. Videotapes from the PSCs were systematically
reviewed to assure that all testers adhered to the
procedures in the study manuals. Examiners were required
to administer the tests to practice cases and submit materials
to the CCC for review before testing actual subjects.
Once testers achieved 90% agreement with QC reviewers,
they were certified. Ongoing QC review guarded against
drift. For each examiner, full QC was carried out for the
first five study participants, and thereafter for every sixth.
Comparison of data for children whose protocols were and
were not submitted for QC review did not differ for any
test, indicating that there had been no drift.
Further QC was implemented at the Data Coordinating
Center (DCC). Sites submitted a hard copy of every third
protocol, which was then reviewed against database entries
and examined for scoring errors and errors in table look-up.
The rate of errors was very low, .01% for scoring errors and
.5% for input errors. In addition, for some tests the database
automatically computed summary and standard scores, which
were then compared to manual look-up of derived scores.
Specific measures are as follows:
Intelligence
Wechsler Abbreviated Scale of Intelligence (WASI) (Wechsler,
1999). The WASI provides a brief measure of intelligence.
It yields a Verbal IQ (Vocabulary, Similarities),
Performance IQ (Matrix Reasoning, Block Design), and
Full Scale IQ score. Raw scores are available for the individual
subtests: Vocabulary (number and quality of correct
definitions); Similarities (number and quality of semantic
concepts correctly described); Matrix Reasoning (number
Table 4. Neuropsychological tests, function measured and relevant age group for Objective 1 of the NIH MRI study
of normal brain development
Test Function Age range
Wechsler Abbreviated Scale of Intelligence (WASI) Intelligence 6;00 and up
Wechsler Intelligence Scale for Children–III (WISC-III)—Coding Processing speed 6;0–16;11
Wechsler Adult Intelligence Scale–Revised (WAIS-R)—Digit Symbol Processing speed 17;0 and up
Wechsler Intelligence Scale for Children–III (WISC-III)—Digit Span Verbal short-term and working memory 6;0–16;11
Wechsler Adult Intelligence Scale–Revised (WAIS-R)—Digit Span Verbal short-term and working memory 17;0 and up
California Verbal Learning Test for Children (CVLT-C) Verbal learning 4;6–15:11
California Verbal Learning Test-II (CVLT-II) Verbal learning 16;0 and up
NEPSY Verbal Fluency–Semantic Verbal fluency 6;0 and up
NEPSY Verbal Fluency–Phonemic Verbal fluency 7;0 and up
Cambridge Neuropsychological Test Automated Battery (CANTAB)
Spatial Span Spatial short-term and Working memory 6;0 and up
CANTAB Spatial Working Memory Working memory 6;0 and up
Purdue Pegboard Fine motor dexterity 6;0 and up
Handedness Inventory Handedness 6;0 and up
CANTAB–Intradimensional0Extradimentional Shift Set shifting 6;0 and up
Behavior Rating Inventory of Executive Function–Parent Version Executive function 6;0 and up
Woodcock-Johnson III–(WJ-III)–Letter-Word Identification, Calculation,
Passage Comprehension Academic skill 6;0 and up
6 D.P. Waber et al.
of matrices correctly solved); Block Design (number and
speed of correctly solved items).
Processing speed
Wechsler Intelligence Scale for Children-III (WISC-III)
Coding (Wechsler, 1991). This task requires that the child
transcribe symbols that correspond to digits in a random
field. Both speed and accuracy of transcription are reflected
in the score. Raw scores indicate number of symbols accurately
transcribed within time limit.
Wechsler Adult Intelligence Scale–III (WAIS-III) Digit
Symbol (Wechsler, 1997). This is the adult version of the
Coding task from the WISC-III. Raw scores indicate number
of symbols accurately transcribed within time limit.
Verbal memory and fluency
Wechsler Intelligence Scale for Children-III (WISC-III)
Digit Span (Wechsler, 1991). This task requires that the
child repeat random digit strings of increasing length. There
is a forward condition, in which the digits are repeated as
presented (a measure of short-term memory), and a backward
condition, in which the child must repeat the digits
backward (a working memory task). Raw scores reflect the
number of strings correctly repeated.
Wechsler Adult Intelligence Scale–III (WAIS-III) Digit
Span (Wechsler, 1997). This is the adult version of the
Digit Span task from the WISC-III. Raw scores reflect the
number of strings correctly repeated.
California Verbal Learning Test for Children (CVLT-C)
(Delis et al., 1994). Children are asked to learn a list of 15
concrete nouns that is presented five times. Short and longdelay
retrieval, recognition memory, proactive interference
from a new list, and clustering are also assessed. Raw scores
reflect number of nouns correctly recalled for each condition.
California Verbal Learning Test-II (CVLT-II) (Delis et al.,
2000). This is the adult version of the CVLT-C. The structure
of the task is similar, but the categories are different
and the list is longer, 16 words. Raw scores reflect number
of nouns correctly recalled for each condition.
Verbal fluency
This task is based on the NEPSY Verbal Fluency Test. In
the semantic component, children name as many animals as
possible in one minute and similarly for a food0drink category.
In the phonemic component, they name words starting
with particular letters (F,A, S), each within a oneminute
time limit. As in the NEPSY, we started the phonemic
component at 7 years of age; however, we extended administration
through adolescence, whereas the NEPSY stops at
12 years. The raw score for each is the number of correct
words.
Spatial Short-Term and Working Memory
Cambridge Neuropsychological Test Battery (CANTAB)
(CeNeS, 1998). This is a computer based neuropsychological
test battery. Tasks are all non-verbal and children respond
using a touch screen. The test developer does not provide a
demographically balanced and comprehensive set of norms,
but normative data are compiled from a variety of published
and unpublished data sets. The following subtests
were administered:
Spatial Span. This task is modeled on the Corsi Block
Tapping Test (Milner, 1971), which is a spatial analogue of
the Digit Span task. The child is presented with boxes, some
of which change color one by one. The child is to point to
the boxes that changed color in the same order. The raw
score is the length of the longest sequence correctly recalled.
Spatial Working Memory. This is a serial order pointing
task (Petrides & Milner, 1982). The child is to point to
the boxes one by one to discover which ones contain a blue
square, without pointing to the same box more than once.
The number of boxes increases from two to a maximum of
eight. However, children who were 6 or 7 years old were
administered a maximum of six boxes based on prior reports
(Luciana & Nelson, 1998) as well as experience with the
measure early in the study in order to avoid undue frustration
and fatigue. The raw score is the total number of return
errors, both within and between items.
Fine motor dexterity
Purdue Pegboard (Gardner & Broman, 1979; Tiffin &
Asher, 1948). Children place pegs with the dominant hand,
the non-dominant hand, and both hands simultaneously
within a time limit. The score is the number of pegs placed.
For purposes of analysis, scores were converted to z-scores
based on age in years and sex for each condition, using the
Gardner and Broman (1979) norms, which extend only to
age 15. The raw score is the number of pegs accurately
placed within the time limit.
Handedness
Handedness inventory. The measure of hand preference
is loosely based on the Edinburgh Handedness Inventory
(Oldfield, 1971). It includes handwriting and seven
gestural commands (use a hammer, throw a ball, use a toothbrush,
point, eat with a spoon, cut with scissors, drink from
a cup). The score distribution was clearly bimodal. Based
on this distribution, the criterion for dominant hand preference
was defined as at least seven of eight responses with
the same hand.
Executive Functions
Intradimensional0ExtradimensionalShift. ThisCANTAB
task is similar to theWisconsin Card Sorting Test. The child
is shown two patterns and asked to choose the correct one
NIH MRI study of normal brain development 7
by guessing. The relevant dimension shifts without a signal,
and the child is to indicate the “correct” answer based
on feedback (correct0incorrect) provided on the screen. For
6- and 7-year-olds, the task could be terminated after the
Intradimensional Shift section because the Extradimensional
Shift trials were too difficult and frustrating for many
(Luciana & Nelson, 1998), especially in the context of a
whole day evaluation. The raw score is number of stages
successfully completed.
Behavior Rating Inventory of Executive Functions
(BRIEF) (Gioia et al., 2000). This questionnaire measures
dimensions of executive function as manifest in everyday
life. The parent version was administered. The BRIEF generates
three summary indices: Behavioral Regulation, Metacognition,
and the Global Executive Composite. T-scores
are generated for each index.
Academic skills
The Woodcock-Johnson III (Woodcock et al., 2001) is a
well-standardized test of academic achievement. Three subtests
were employed:
Letter-word identification. The child is asked to identify
letters and then single real words of increasing difficulty,
measuring single word reading competency. Raw score
is the number of letters or words accurately read.
Passage Comprehension. The child is asked to read brief
passages and respond to a question by providing the missing
word (cloze procedure), measuring comprehension. Raw
score is the number of items accurately completed.
Calculation. The child is given a series of calculation
problems of increasing difficulty and asked to solve them,
measuring calculation skills. Raw score is the number of
problems successfully completed.
Psychosocial function
Child Behavior Checklist (Achenbach, 2001). This questionnaire
asks parents to endorse child behavioral problems.
It yields composite Internalizing and Externalizing
scales, as well as a total behavior problems score. As indicated
earlier, children were excluded from the study based
on a T-score above 70 on any subscale (anxious0depressed,
withdrawn0depressed, somatic complaints, social problems,
thought problems, attention problems, rule breaking
behavior, aggressive behavior). Although there was no laboratory
measure of attention, the Attention Problems scale
serves as an indicator of attentional processes.
Procedure
After screening and enrollment were completed, children
were scheduled for a visit to the PSC. Neuropsychological
testing was typically carried out on the day of the MRI scan
or, in some instances, on a different day (within a 28 day
window).
Statistical methods
Means, standard deviations, and ranges were computed
for each measure for the entire sample and for individual
integer ages, using standardized scores for descriptive purposes.
To determine the influence of demographic characteristics,
we regressed scores for each measure on age, sex,
and income simultaneously. For composite scales (e.g., IQ),
standardized scores were regressed on sex and income.Analysis
of residuals and other indices of fit indicated a nonlinear
relationship between a number of the raw score measures
and age. Therefore, we modeled age using cubic regression
splines.
Cubic regression splines represent a flexible approach to
regression modeling that allows modeling of complex functions
with the loss of relatively few degrees of freedom.
They can be fitted and tested using any statistical software
that includes standard linear regression. To fit cubic regression
splines, the range of the predictor variable is divided
into several contiguous regions. Separate cubic polynomials
are then fitted to each region, but constrained so that the
separate polynomials are joined smoothly where the contiguous
regions meet. Standard regression procedures are
then used to evaluate statistical significance and goodness
of fit of the fitted line. The smoothing and other constraints
allow a minimum of degrees of freedom to be expended in
the modeling process while maintaining a clinically plausible
function between predictor and outcome. Cubic polynomials
have been recommended for use in epidemiologic
research as a flexible means of fitting complex functions
that avoid the loss of power associated with categorizing
covariates (Greenland, 1995). Using the cubic spline regression
models, we plotted the fitted regression lines for raw
score measures to facilitate interpretation.
RESULTS
Descriptive Data
Descriptive statistics for the standardized measures for the
sample as a whole are displayed in Table 5. These means
are consistently superior to published means by t-tests ( p ,
.0001). The WISC Coding subtest was somewhat closer to
the mean ( p , .05). The only exception to this pattern was
the Purdue Pegboard, for which scores were well below
published means ( p , .0001). Means and standard deviations
are presented by age (Table 6, Table 7, and Table 8)
for measures for which existing norms are less reliable (Purdue
Pegboard, CANTAB) or have a narrower age range
than obtained here (Verbal Fluency).
Effects of Sex and Income Level
on Performance
Table 9 displays the regression model for sex and income
level for the composite IQ and behavior rating scales. Sex
predicted only the WASI Performance IQ, boys achieving
8 D.P. Waber et al.
higher scores. There was a substantial effect of income level
for all three IQ scales. The CBCL Externalizing and Total
Competence scales, were also related to income level, as
was the Attention Problems scale. Although lower income
was associated with lower IQ, more externalizing behaviors
and lower social competence, the mean performance of
the Low Income group was better than the population means.
Mean scores for Full Scale IQ [Mean ~SD! Low, 105.1(12.8);
Medium, 110.8 (11.9); High, 115.1(11.4)] and CBCL Externalizing
[Mean ~SD!, Low, 46.8(8.5); Medium, 43.3(7.7);
High 43.4(7.5)] are representative.
Tables 10 and 11 display comparable models for raw
scores for specific subtests and cognitive measures, with
age in the model. Age, of course, was a highly significant
Table 5. Means, standard deviations and ranges of standardized scores for tests
and questionnaire measures with published norms
Test N Mean ~SD!
Minimummaximum
WASI Vocabulary (T-score) 382 55.95 (8.79) 28–80
WASI Similarities (T-score) 382 55.96 (9.57) 28–80
WASI Matrix Reasoning (T-score) 382 56.08 (8.02) 30–80
WASI Block Design (T-score) 382 54.65 (9.59) 31–80
WASI Verbal IQ (Standard Score) 382 109.85 (13.53) 73–151
WASI Performance IQ 382 108.98 (12.8) 72–157
WASI Full Scale IQ (Standard Score) 382 110.61 (12.49) 77–158
WISC-III0WAIS-III Coding (Scaled) 379 10.35 (3.19) 1–19
WISC-III0WAIS III Digit Span (Scaled) 379 10.62 (2.73) 3–19
WJ-III Letter Word ID (Standard Score) 384 109.96 (11.16) 71–148
WJ-III Passage Comprehension (Standard Score) 384 107.69 (10.94) 69–140
WJ-III Calculation (Standard Score) 382 110.15 (11.86) 70–152
NEPSY Verbal Fluencya (Scaled) 200 10.97 (2.97) 5–19
Purdue Pegboard–Preferred (Z-Score)b 334 2.93 (1.00) 25.6–1.82
Purdue Pegboard–Non-Preferred (Z-Score)b 334 2.70 (0.93) 24.38–3.42
Purdue Pegboard–Both (Z-Score)b 334 2.71 (.94) 23.57–2.47
*BRIEF–Behavioral Regulation Index (T-Score) 383 45.55 (7.54) 35– 68
*BRIEF–Metacognitive Index (T-Score) 382 47.29 (8.43) 30–74
*BRIEF–General Executive Composite (T-Score) 382 46.46 (8.08) 31–71
*CBCL–Externalizing (T-Score) 380 44.20 (7.94) 28– 65
*CBCL–Internalizing (T-Score) 380 44.93 (8.45) 29–70
CBCL-Total Competence (T-Score) 341 53.03 (9.12) 24–76
a7 to 12 year olds only, N 5 200 because norms not available for 6 or 13 to 18
b6 to 15 years olds only, N 5 334 because norms not available for 16 to 18.
*Higher score denotes poorer performance.
Table 6. Means and standard deviations of number of pegs by age in years, sex and preferred hand
for Purdue Pegboard
Females Males
N Preferred Non-Preferred Both N Preferred Non-Preferred Both
6 32 9.87 (2.00) 9.06 (1.65) 7.44 (1.44) 32 9.39 (1.33) 8.32 (1.60) 7.30 (1.73)
7 21 10.62 (1.86) 9.95 (1.47) 8.14 (1.53) 21 10.45 (1.39) 10.25 (1.37) 7.95 (1.43)
8 18 11.67 (1.08) 11.50 (1.29) 9.50 (1.34) 18 11.22 (1.40) 10.67 (1.91) 9.17 (1.25)
9 20 12.75 (1.33) 11.50 (1.28) 9.25 (1.37) 16 11.81 (1.47) 11.31 (1.30) 9.13 (1.15)
10 22 13.27 (1.98) 12.55 (2.02) 10.18 (1.74) 13 12.46 (1.61) 11.85 (1.14) 10.00 (1.83)
11 18 13.39 (2.70) 12.61 (1.46) 10.72 (1.71) 10 13.90 (1.85) 12.90 (2.02) 10.80 (1.87)
12 10 14.40 (1.90) 12.60 (1.51) 11.00 (1.89) 14 13.36 (1.69) 12.79 (1.12) 10.50 (1.29)
13 11 14.70 (1.34) 13.70 (1.57) 10.90 (0.99) 16 13.88 (1.41) 12.63 (1.36) 11.44 (1.36)
14 12 14.25 (2.22) 13.25 (2.14) 11.50 (2.35) 11 14.82 (1.54) 13.00 (1.67) 10.27 (1.10)
15 11 14.45 (1.21) 13.00 (1.61) 11.09 (1.58) 12 13.00 (1.13) 12.83 (1.19) 11.25 (1.22)
16 11 14.64 (1.21) 13.64 (3.78) 11.64 (0.67) 9 12.22 (1.20) 12.00 (1.58) 9.89 (1.17)
17 12 15.58 (1.51) 15.08 (2.07) 12.00 (1.28) 15 13.47 (1.30) 12.73 (1.28) 10.47 (2.33)
NIH MRI study of normal brain development 9
predictor for every measure. Sex was a significant predictor
for WASI Block Design (males higher), as well as for
Coding0Digit Symbol, Pegboard, and CVLT total correct
(females higher). Income predicted all the WASI IQ subtests,
as well as Coding and to a lesser extent Digit Span. In
terms of academic achievement, income predicted Passage
Comprehension and calculation but not Letter-Word ID. In
contrast, income was only weakly associated with the specific
neurocognitive measures, predicting only CANTAB
Spatial Working Memory and CVLT Long Delay Cued
Recall, with modest effect sizes.
For some measures, the effect of age was modified by
either sex or income, detected by significant interactions.
Interactions of age with income were detected for WASI
Matrix Reasoning ( p,.01), Pegboard Preferred Hand ( p,
.05), and Verbal Fluency Phonemic ( p , .05). Interactions
with sex were detected for CANTAB ID0ED, Pegboard Preferred
Hand, and the CVLT variables (all p , .05). The
interactions are described below in the discussion of the
cubic spline regression analyses.
Effects of Age on Raw Score Performance
The cubic spline regression analyses estimate the shape of
the function relating age to performance, adjusting for the
effects of sex and income level. Where interactions with
sex or income level were detected, as outlined earlier, the
spline regressions were also calculated separately for these
groups. In addition to the linear effects of age cited earlier,
non-linear effects emerged for most measures. The quadratic
effect was significant ( p , .01) for every measure
except WASI Block Design, Wechsler Coding and Digit
Span, CANTAB Spatial Span, and Verbal Fluency Phonemic
Condition. The quadratic effects were somewhat weaker
( p , .05) for W-J III Calculation, CANTAB Spatial WorkingMemory,
and Purdue Pegs (Both Hands, Preferred Hand).
Table 7. Means and standard deviations of scores by age
in years for CANTAB Subtests
Age N
Intradimensional0
extradimensional
shift (number
of shifts)
Spatial
working
memory
(number of
between
errors)
Spatial
span
(total span)
6 64 6.3 (2.3)a62 49.3 (23.0)61 4.1 (1.0)62
7 42 7.1 (1.7)41 45.4 (21.0)41 4.7 (1.1)41
8 36 7.8 (0.9)35 43.4 (15.3)35 4.9 (0.9)35
9 36 7.9 (1.0) 47.5 (15.1) 5.3 (1.0)
10 35 8.2 (1.0) 34.8 (18.2) 5.5 (1.4)
11 28 8.3 (1.0) 29.6 (15.7) 6.1 (1.2)
12 24 8.4 (0.9) 26.5 (15.4) 6.4 (1.4)
13 27 8.6 (0.8)25 18.6 (16.6)25 7.1 (1.9)
14 23 8.3 (0.9) 22.1 (13.7) 6.9 (1.6)
15 23 8.4 (0.9) 14.6 (10.7) 7.5 (1.1)
16 20 8.8 (0.6) 15.8 (15.4) 7.6 (1.2)
17 27 8.5 (1.5) 12.4 (10.9) 7.5 (1.9)
aIndicates actual number of subjects providing data if different from N.
Table 9. Standardized parameter estimates and probability levels for effects of sex
and socioeconomic status on standardized IQ and scores and behavioral scales
Sex
(male as baseline)
Income
(medium as baseline)
Test Female p Low High p
WASI Full Scale IQ (Standard Score) 2.06 n.s. 2.17* 0.20* ,.0001
WASI Verbal IQ (Standard Score) .02 n.s. 2.18* 0.13* ,.0001
WASI Performance IQ (Standard Score) 2.12 ,.05 2.10 0.19* ,.0001
BRIEF Behavioral Regulation Index (T-Score) .00 n.s. .09 .04 n.s.
BRIEF Metacognitive Index (T-Score) 2.02 n.s. .07 .00 n.s.
CBCL Externalizing Scale (T-Score) 0.0 n.s. .18* .00 ,.01
CBCL Internalizing Scale (T-Score) –.04 n.s. .01 .00 n.s.
CBCL Total Competence (T-Score) 2.01 n.s. 2.14* .04 ,.01
CBCL Attention Problems (T-Score) .04 n.s. .06 2.10 ,.05
*p , .05 difference from baseline medium group
Table 8. Means and standard deviations by age in years for total
number of words correct for Verbal Fluency task
Age N Phonemic Semantic Total
7 42 14.5 (6.6)a39 23.5 (7.6)40 37.7 (12.5)39
8 36 16.0 (5.4) 26.8 (6.8) 42.8 (10.3)
9 36 18.9 (7.6) 32.9 (7.4) 51.8 (11.5)
10 35 23.4 (9.4) 34.5 (7.7) 57.9 (14.2)
11 28 26.1 (6.2) 36.9 (7.7) 63.0 (11.4)
12 24 24.7 (7.5) 35.9 (7.8) 60.5 (12.3)
13 27 29.7 (8.3)26 39.7 (8.8)26 69.4 (13.8)26
14 23 28.2 (7.5)22 37.1 (9.4)22 65.3 (13.7)22
15 23 31.1 (8.1) 42.9 (8.0) 74.0 (14.2)
16 20 34.4 (7.4) 42.1 (11.5) 76.5 (17.0)
17 27 36.3 (10.9) 44.4 (13.6) 80.7 (20.9)
aIndicates actual number of subjects providing data if different from N.
10 D.P. Waber et al.
A significant cubic effect of age ( p , .01) was documented
for WASI Matrix Reasoning, W-J III Letter-Word
ID and Passage Comprehension, CANTAB ID0ED Shift,
Purdue Non-Preferred Hand, and Total Verbal Fluency.
Weaker cubic effects were detected for CANTAB Spatial
Working Memory and Verbal Fluency Semantic condition
( p , .05).
Functions for the WASI, WJIII, and WISC-III are displayed
in Fig. 2. For the WASI and WJ-III subtests, performance
climbed steeply from age 6, decelerating between 10
and 12 years of age. For Coding and Digit Span, there is a
linear effect through the entire period. For Matrix Reasoning,
the functions are illustrated separately by income level,
reflecting apparent catch up of the middle and low income
groups to the high income group by late adolescence.
Figure 3 shows trajectories for the CVLT-C. For total
words correct (Trials 1–5), the curve similarly decelerates
between ages 10 and 12 and then shifts direction, with performance
actually declining somewhat between 12 and 16.
The same pattern emerges also for Long Delay Free and
Cued Recall. The interaction with sex is illustrated for the
Trials 1 to 5 variable only but was present for all four variables.
Whereas the performance of the males rises monotonically
throughout the age period, that of females actually
declines throughout adolescence.
For the Purdue Pegboard (Fig. 4), performance increases
steeply until 10 and then decelerates between ages 10 and
12 for all three conditions. For the non-preferred hand, performance
further improves during adolescence, so that the
non-preferred hand approaches the dexterity of the preferred
hand late in adolescence. Interactions were observed
for the preferred hand condition only. As the figure illustrates,
the low income group catches up with the higher
income group by adolescence. The performance of females
Table 10. Standardized parameter estimates and probability levels for effects of age, sex and
socioeconomic status on raw score performance for IQ and achievement subtests
Age
(by year)
Sex
(male as baseline)
Income
(medium as baseline)
Test Year p Female p Low High p
WASI Vocabulary .84 ,.0001 .01 n.s. 20.07* 0.07* ,.0001
WASI Similarities .76 ,.0001 .02 n.s. 20.09* 0.04 ,.01
WASI Block Design .78 ,.0001 2.08* ,.01 20.05 0.08* ,.001
WASI Matrix Reasoning .70 ,.0001 2.01 n.s. 20.05 0.12* ,.0001
WISC0WAIS Coding0Digit Symbol .79 ,.0001 .08* ,.05 20.12* 0.06 ,.0001
WISC0WAIS Digit Span .64 ,.0001 .02 n.s. 20.04 0.07 ,.05
WJ-III Letter Word Identification .82 ,.0001 .01 n.s. 20.01 0.037 n.s.
WJ-III Passage Comprehension .80 ,.0001 .01 n.s. 20.04 0.04 ,.05
WJ-III Calculation 0.90 ,.0001 .01 n.s. 20.03 0.06* ,.001
*p , .05 group difference from baseline medium group
Table 11. Standardized parameter estimates and probability levels for effects of age, sex, and socioeconomic status
on raw score performance for miscellaneous neuropsychological tests
Age
(by year)
Sex
(male as baseline)
Income
(medium as baseline)
Test Year p Female p Low High p
CANTAB Set Shift (Number of Shifts) .38 ,.0001 2.09 n.s. 20.02 0.04 n.s.
CANTAB Spatial Working Memory (Errors) 2.59 ,.0001 .00 n.s. 0.10* 20.02 ,.05
CANTAB Spatial Span (Total Span) .67 ,.0001 2.02 n.s. 20.08* 0.01 n.s.
Purdue Pegs Both (# pegs) .61 ,.0001 .09 ,.05 20.04 0.01 n.s.
Purdue Pegs Preferred (# pegs) .64 ,.0001 .15 ,.0001 20.05 0.05 n.s.
Purdue Pegs Non-Preferred (# pegs) .63 ,.0001 .12 ,.01 .00 0.04 n.s.
CVLT-C Total Correct Trials 1–5 .58 ,.0001 .10 ,.05 2.04 0.02 n.s.
CVLT-C Trial 5 .51 ,.0001 .08 n.s. 2.09 0.00 n.s.
CVLT-C Long Delay Free Recall .54 ,.0001 .08 n.s. 2.06 0.05 n.s.
CVLT-C Long Delay Cued Recall .56 ,.0001 .08 n.s. 2.07 0.07 ,.05
Verbal Fluency Phonemic .65 ,.0001 .02 n.s. .00 0.08 n.s.
Verbal Fluency Semantic .57 ,.0001 .03 n.s. 2.01 0.06 n.s.
Verbal Fluency Total Correct Words .68 ,.0001 .03 n.s. .00 0.07 n.s.
*p , .05 group difference from baseline medium group
NIH MRI study of normal brain development 11
Fig. 2. Estimated relationship of age to raw scores for Wechsler Abbreviated Scale of Intelligence (WASI) and Woodcock-Johnson III (WJ-III) subtests
adjusted for sex and income level. In addition to the linear effects of age, there were significant quadratic effects of age forWASI Vocabulary, Similarities, and
Matrix Reasoning, as well as WJ-III Letter-Word (all p , .01) and WJ-III Calculation ( p , .05). Significant cubic effects were present for WASI Matrix
Reasoning and WJ-III Letter-Word and Passage Comprehension ( p , .01). The function forWASI Matrix Reasoning is displayed separately by income groups
(adjusted only for sex), reflecting the significant interaction of age with income for that variable.
12 D.P. Waber et al.
improves monotonically throughout the adolescent period,
but that of males declines.
The CANTAB tasks are displayed in Figs. 5a to 5c. For
ID0ED Shift (5a), the number of correct shifts increases
steeply until about 10 years of age, levels off and then
increases again beginning around age 14. The interaction
illustrated in the Figure indicates that the shape of this function
is largely because of the performance of the females.
In contrast to the pattern for other measures, Spatial Working
Memory errors decrease most rapidly between ages 10
and 14, not between 6 and 10. After age 14, the rate of
decrease in errors slows. Spatial Span shows a strikingly
similar pattern to Digit Span, increasing linearly through
late adolescence.
Finally, Verbal Fluency total words increases up to age
10, then levels off, but increases again later in adolescence
(Fig. 6). The semantic and phonemic conditions similarly
increase throughout the age span to late adolescence, with
the semantic condition showing a trajectory like the total
score. The interaction with income for the phonemic condition
indicates somewhat different shapes of the trajectories
for the three income groups, but the interpretation of
this finding is not clear, and so this interaction is not illustrated
in the Figure.
DISCUSSION
This report describes the sampling strategy, demographic
characteristics, and performance of the healthy school-age
children who participated in the NIH MRI Study of Normal
Brain Development on a standard neuropsychological battery.
The racial0ethnic and income distribution of the sample
generally approximates that of the 2000 United States
census. Not surprisingly, these children consistently outperformed
published norms, presumably because sources of
morbidity were screened out by the exclusionary criteria.
The only exception was the Purdue Pegboard; children in
our sample placed fewer pegs than did those in the large
normative sample of Gardner and Broman (1979). The reasons
for this difference are not obvious. Because Gardner
and Broman (1979) recruited their sample from a suburban
community, the difference could be related to socioeconomic
influences. We did not, however, find performance
to be related to income level. The difference is also unlikely
to reflect improper administration because of our rigorous
quality control procedures. Another possibility is a cohort
effect of unknown origin. In any event, the Gardner and
Broman (1979) norms appear to overestimate normative
performance, and caution should be used in applying them.
Effects of Sex on Task Performance
Girls performed better on measures of processing speed
and motor dexterity, and boys better at perceptual analysis,
consistent with prior studies (Halpern, 1997; Maccoby &
Jacklin, 1974). Consistent with data localizing the sexrelated
cognitive operation to decompositing the perceptual
cohesiveness of the designs (Waber, 1985), the findings
suggest that perceptual analysis (Block Design) is sensitive
to sex but perceptual reasoning (Matrix Reasoning) is not.
Girls showed a slight advantage on verbal learning, but
their performance actually declined through adolescence
relative to boys, an unexpected finding. Sex-related differences
in verbal fluency are reported in children and adults
(Hines, 2004; Kraft & Nickel, 1995; Rahman et al., 2003),
although not consistently (Harrison et al., 2000; Levin et al.,
1991). Our sample did not demonstrate such a difference,
nor were there differences for Calculation, indicating that
at least at the procedural level of mathematics, boys and
girls in this healthy sample do not differ.
Income Effects on Task Performance
Although household income level, not unexpectedly, predicted
IQ, our low-income group nevertheless out-
Fig. 3. Estimated relationship of age to raw scores for California
Verbal Learning Test for Children (CVLT-C). In addition to linear
effects of age, there were significant quadratic effects for all outcomes
( p , .01). (A) Estimated relationship of age to raw scores
for Total Words Trials 1–5 displayed separately for males and
females (adjusted for income) and (B) Estimated relationship of
age to raw scores for Trial 5, Long Delay Free and Long Delay
Cued Recall. Although the Age3Sex interaction is not displayed
the CVLT variables in Fig. 3B in the interest of simplicity, this
interaction was in fact significant for each of them and the shape
of the functions for males and females is very similar to that
displayed in 3A for Total Words Trials 1 to 5.
NIH MRI study of normal brain development 13
performed population norms. In terms of achievement,
income level was related to reading comprehension and
calculation but not to single word reading. The latter result
is surprising given the consistent association between socioeconomic
indicators and reading (Chatterji, 2006; Hecht
et al., 2000). Income level reliably predicted IQ and achievement,
but was only a weak predictor of performance on
other cognitive measures, such as verbal learning or set
shifting. Thus, income effects were more prominent for tasks
requiring greater integration (e.g., reading comprehension
and calculation versus single word reading), suggesting that
integrative skills are more vulnerable to experiential influences
associated with income. Screening out morbidity,
which occurred at a higher rate in the low income families,
may have allowed competencies of the healthy low income
children, like single word reading, to emerge.
In terms of behavioral outcomes, the low income children
exhibited more externalizing problems and lower social
competence ratings than either the medium or high income
groups. This difference was necessarily dimensional since
children with scores in the clinical range on any CBCL
scale were ineligible for the study. Scores on the BRIEF,
the behavioral measure of executive function, were not,
however, significantly related to income level. This result
is somewhat surprising, given reports of poorer executive
capacities in low income children (Howse et al., 2003;
Mezzacappa, 2004; Noble et al., 2005; Waber et al., 2006).
These reports, however, may reflect higher rates of morbidity
in samples that were not as thoroughly screened as this
one.
Age-Related Trajectories of Cognitive
Task Performance
Perhaps most intriguing are the age-related trajectories for
raw score performance. For most tasks, proficiency improved
dramatically between 6 and 10 years of age, leveling off
during early adolescence (approximately 10 to 12 years of
age), suggesting that for many neurocognitive tasks, children
approach adult levels of performance at that age. For a
Fig. 4. Estimated relationship of age to number of pegs correctly placed on Purdue Pegboard. (A) Estimated relationship
of age to number of pegs for preferred hand, non-preferred hand, and both hands adjusted for sex and income level.
In addition to linear effects of age, there were significant quadratic effects for the preferred and both conditions ( p ,
.05); a significant cubic effect was documented for the non-preferred condition ( p , .05). Interactions of age with sex
and income level were observed for the Preferred Hand condition only. (B) Estimated relationship of age to number of
pegs correctly placed with preferred hand displayed separately for income level (adjusted for sex). (C) Estimated
relationship of age to number of pegs correctly placed with preferred hand displayed separately for males and females
(adjusted for income).
14 D.P. Waber et al.
few measures, scores increased linearly throughout the age
range. These were tasks that assessed basic information processing,
such as Coding, Digit Span, and Spatial Span. Still
others were associated with a non-linear component during
adolescence. Some showed a flattening of the curve followed
by another period of acceleration, suggesting another
spurt in mid-adolescence. Verbal learning actually reversed
direction with performance declining in later adolescence.
Moreover, this effect appeared to be attributable to the performance
of females. For a number of other measures as
well, these age trajectories were modified by either sex or
income level, in ways that may prove to be of greater interest
vis-à-vis possible neural substrates.
Because these data are cross-sectional, these age-related
functions must be viewed as preliminary. We cannot discriminate
whether non-linear age profiles are typical of most
Fig. 5. Estimated relationship of age to outcomes for CANTAB
subtests. (A) Estimated relationship of age to Intradimensional0
Extradimensional Shift number of set shifts achieved displayed
separately for males and females (adjusted for income); (B) Estimated
relationship of age to spatial working memory total errors
(adjusted for sex and income); (C) Estimated relationship of age
to Spatial Span length of memory span (adjusted for sex and
income). In addition to linear effects of age, there were significant
quadratic ( p , .01) and cubic ( p , .01) effects for ID0ED Shift
number of shifts. Fig. 5Asuggests that this cubic effect is accounted
for primarily by the females. There were also significant quadratic
( p , .05) and cubic ( p , .05) effects for Spatial Working Memory
errors.
Fig. 6. Estimated relationship of age to number correct words
adjusted for sex and income level for Verbal Fluency task (Phonemic,
Semantic, and Total). There were significant quadratic effects
( p , .01) and cubic effects ( p , .05) for Semantic and Total. The
interaction between age and income level (adjusted for sex) for
the Phonemic condition is depicted below.
NIH MRI study of normal brain development 15
individuals, or whether differentiation occurs in adolescence
such that some children continue to progress, whereas
others level off, yielding the observed group patterns. We
also do not know whether specific effects, especially those
related to sex or income level, are truly developmental or
reflect the performance of the particular individuals who
provided data at specific ages. Potential ceiling effects for
some measures also merit consideration. Longitudinal data
from the second and third visits will allow us to disambiguate
these questions.
These age-related functions highlight epochs of potential
interest for brain-behavior correlation. The forthcoming longitudinal
data set will provide an opportunity to examine
the natural course of development of these functions in tandem
with structural brain development.
Limitations
This study provides normative behavioral and neuroimaging
data on a diverse sample of healthy US children.Awide
range of general intellectual functioning (WASI IQ scores
ranged from 77 to 158) as well as economic and ethnic
diversity is represented. Nonetheless, the thorough screening
procedure resulted in a sample that is not representative
of the population at large since children with potential threats
to brain development were screened out. The direct marketing
lists may have introduced bias because they are not
epidemiologically compiled, and families without wire-line
telephones could not be contacted, another potential source
of bias. Another limitation is that only 1.5% of the more
than 35,000 families initially solicited actually participated.
Furthermore, because PSCs were located in urban
centers, families from rural communities were less likely to
be recruited, possibly resulting in the observed underrepresentation
of low income white children.
Any strategy for recruiting healthy children for a study
requiring multiple trips to the medical center and a lengthy
evaluation, however, is inevitably vulnerable to self-selection
bias. This bias was potentially minimized by the populationbased
sampling strategy, rather than recruiting samples of
convenience or volunteers to advertisements. The rigorous
screening procedures also limited the potential overrepresentation
of families who volunteer because of concerns
about their children.
CONCLUSION
Clinically, these data provide several points of reference.
First, the norms from this healthy sample differ from typical
norms, which include children with varying degrees of
risk and morbidity. These data thus provide a benchmark
for the performance of healthy children. Clinicians may
wish to use them as an adjunct to standard norms, in which
the prevalence of morbidity is not well documented, but
they should not replace standard norms. They are, however,
likely to be more informative than norms acquired from
samples of convenience. Second, these norms provide estimates
of the effects of sex and income level, so that performance
of an individual can be referenced not only to age,
but also to these other characteristics. Finally, the analysis
of raw scores portrays age-related variation in absolute levels
of performance, unlike standard scores, which mask
developmental change, providing a more informed basis
for estimating developmental trajectories in the clinical setting.
From a research perspective, these data provide a better
estimate of developmental trajectories than published
norms because unknown sources and rates of morbidity are
eliminated and socioeconomic characteristics of subgroups
are specified.
In sum, the NIH MRI Study of Normal Brain Development
provides a well documented normative description of
the behavioral and neuroanatomical development of a large
population-based sample of healthy children from diverse
backgrounds and regions of the United States. This database
will serve as an invaluable public resource for investigators
for many years to come.
ACKNOWLEDGMENTS
The authors are grateful to the anonymous reviewers for their
constructive insights and comments.
Researchers who are interested in using the database resulting
from this project are encouraged to contact rozie@bic.mni.
mcgill.ca. Deborah P.Waber, Department of Psychiatry, Children’s
Hospital, Boston and Harvard Medical School; Carl de Moor,
Department of Psychiatry and Clinical Research Program,
Children’s Hospital, Boston and Harvard Medical School,
Children’s Hospital, Boston; Peter W. Forbes, Clinical Research
Program; C. Robert Almli, Program of Occupational Therapy, Neurology
and Psychology, Washington University School of Medicine;
Kelly N. Botteron, Department of Psychiatry, Washington
University School of Medicine; Gabriel Leonard and Denise Milovan,
Cognitive Neuroscience Unit, McGill University; Tomas Paus,
Montreal Neurological Institute and Brain & Body Centre, University
of Nottingham; Judith Rumsey, National Institute of Mental
Health.
The MRI Study of Normal Brain Development is a cooperative
study performed by six pediatric study centers in collaboration
with a Data Coordinating Center (DCC), a Clinical Coordinating
Center (CCC), a Diffusion Tensor Processing Center (DPC), and
staff of the National Institute of Child Health and Human Development
(NICHD), the National Institute of Mental Health (NIMH),
the National Institute for Drug Abuse (NIDA), and the National
Institute for Neurological Diseases and Stroke (NINDS), Rockville,
Maryland. Investigators from the six pediatric study centers
are as follows: Children’s Hospital Medical Center of Cincinnati,
Principal InvestigatorWilliam S. Ball, M.D., Co-Investigators Anna
Weber Byars, Ph.D., Richard Strawsburg, M.D., Mark Schapiro,
M.D., Wendy Bommer, R.N., April Carr, B.Sc., April German,
B.A.; Children’s Hospital Boston, Principal Investigator Michael
J. Rivkin, M.D., Co-Investigators Deborah Waber, Ph.D., Robert
Mulkern, Ph.D., Sridhar Vajapeyam, Ph.D., Abigail Chiverton,
B.A., Peter Davis, S.B., Julie Koo, S.B., Jacki Marmor, M.A.,
Christine Mrakotsky, Ph.D., M.A., Richard Robertson, M.D.,
Gloria McAnulty, Ph.D; University of Texas Health Science Center
at Houston, Principal Investigator Michael E. Brandt, Ph.D.,
Co-Principal Investigators Jack M. Fletcher, Ph.D., Larry A.
16 D.P. Waber et al.
Kramer, M.D., Co-Investigators Kathleen M. Hebert, Grace Yang,
Vinod Aggarwal, M.D., Sushma V. Aggarwal; Washington University
in St. Louis, Principal Investigators Kelly Botteron, M.D.,
Robert C.McKinstry,M.D., Ph.D., Co-InvestigatorsWilliamWarren,
Tomoyuki Nishino, M.Sc., C. Robert Almli, Ph.D., Richard
Todd, Ph.D., M.D., John Constantino, M.D.; University of California
Los Angeles, Principal Investigator James T. McCracken,
M.D., Co-Investigators Jennifer Levitt, M.D., Jeffrey Alger, Ph.D.,
Joseph O’Neil, Ph.D., Arthur Toga, Ph.D., Robert Asarnow, Ph.D.,
David Fadale, Laura Heinichen, Cedric Ireland; Children’s Hospital
of Philadelphia, Principal Investigator Dah-JyuuWang, Ph.D.,
Co-Principal Investigator Edward Moss, Ph.D., Co-Investigators
Robert A. Zimmerman, M.D., Brooke Bintliff, B. Sc., Ruth Bradford,
Janice Newman, M.BA. The Principal Investigator of the
data coordinating center at McGill University is Alan Evans, Ph.D.,
Co-Investigators G. Bruce Pike, Ph.D., D. Louis Collins, Ph.D.,
Gabriel Leonard, Ph.D., Tomas Paus, M.D., Alex Zijdenbos, Ph.D.,
Rozalia Arnaoutelis, B.Sc, Lawrence Baer, M.Sc., Matt Charlet,
Samir Das, B.Sc., Jonathan Harlap, Matthew Kitching, Denise
Milovan, M.A., Dario Vins, B.Com., and at Georgetown University,
Thomas Zeffiro, M.D., Ph.D. and John Van Meter, Ph.D.
Nicholas Lange, Sc.D., Harvard University0McLean Hospital, is
a statistical study design and data analysis Co-Investigator to the
data coordinating center. The Principal Investigator of the Clinical
Coordinating Center at Washington University is Kelly Botteron,
M.D., Co-Investigators C. Robert Almli Ph.D., Cheryl Rainey,
B.Sc., Stan Henderson M.S., Tomoyuki Nishino, M.S., William
Warren, Jennifer L. Edwards M.SW., Diane Dubois R.N., Karla
Smith, Tish Singer and Aaron A. Wilber, M.Sc. . The Principal
Investigator of the Diffusion Tensor Processing Center at the
National Institutes of Health is Carlo Pierpaoli, MD, Ph.D.,
Co-Investigators Peter J. Basser, Ph.D., Lin-Ching Chang, Sc.D.,
and Gustavo Rohde. The Principal Collaborators at the National
Institutes of Health are Lisa Freund, Ph.D. (NICHD), Judith Rumsey,
Ph.D. (NIMH), Laurence Stanford, Ph.D. (NIDA), and from
NINDS, Katrina Gwinn-Hardy, M.D., and Giovanna Spinella, M.D.
Special thanks to the NIH contracting officers for their support.
We also acknowledge the important contribution and remarkable
spirit of John Haselgrove, Ph.D. (deceased).
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