Developmental Aspects of Pediatric fMRI: Considerations for Image
Acquisition, Analysis, and Interpretation
William Davis Gaillard,*,† Cecile B. Grandin,†,‡ and Benjamin Xu†
*Department of Neurology, The Children’s National Medical Center, The George Washington University School of Medicine, Washington
DC; †The Epilepsy Research Branch, NINDS, NIH Bethesda, Maryland; and ‡Department of Radiology, St Luc University Hospital,
Universite ´Catholique de Louvain, Belgium
Received J anuary 21, 2000
F unctional MR I provides a powerful means to iden-
tify and trace the evolution, development, and consol-
idation of cognitive neural networks through normal
childhood. Neural network perturbations due to dis-
ease and other adverse factors during development
can also be explored. Studies performed to date sug-
gest that normal children older than 5 years show
activation maps comparable to adults for similar cog-
nitive paradigms. Minor differences in adult and pedi-
atric activation maps may reflect age dependent strat-
egies or maturation of cognitive networks. However,
there are important physiologic and anatomic differ-
ences in children, varying with age, that may affect
the acquisition, analysis, and interpretation of pediat-
ric fMR I data. Differences between children and adult
fMR I comparison studies may reflect technical aspects
of data acquisition as much as developmental and
brain maturation factors.
© 2001 Academic Press
Functional MRI (fMRI) provides a powerful means to
map neural networks that underlie cognitive functions
in adults and children. Unlike
sion tomography (PET), fMRI does not involve radia-
tion, and thus can be used to study normal children.
MRI studies can be repeated, and children trained to
remain still in the MRI environment. fMRI is well
suited toidentify and tracetheevolution, development,
and consolidation of cognitiveneural networks through
normal childhood. Furthermore, the effect of disease
states, such as epilepsy, and disorders, such as dys-
lexia and learning disabilities, on developing neural
networks can be explored.
A number of recent studies have used fMRI to iden-
tify the neural networks associated with cognitive, mo-
tor, and sensory function in children; they include
15O-water positron emis-
working memory, spatial memory, verbal fluency,
reading visual recognition, imagery, motor and sensory
tasks (Casey, 1995, 1997; Hertz-Pannier, 1997; Staple-
ton, 1997; Thomas, 1999; Pugliese, 1999; Booth, 1999;
Vaidya, 1998; Lee, 1999; Baird, 1999; Gaillard, 1999,
2000a; Nelson, 2000). Although some of these investi-
gations describe intriguing differences that may reflect
developmental strategies for task performance or mat-
uration of cognitive networks, they suggest that acti-
vation maps are fundamentally the same in normal
children older than 8 years and adults, when similar
paradigms are used.
Brain mapping is based on the observations of Roy
and Sherrington (1890), that cerebral activity is accom-
panied by an increase in cerebral blood flow (CBF). Fox
and colleagues (1986) used
sory task and found that local CBF and oxygen delivery
exceeded oxygen extraction and demand in activated
cortex. Optical imaging studies show that after stimu-
lus onset, initial increased oxygen extraction, de-
creased oxyhemoglobin, and concomitant increase in
deoxyhemoglobin is followed within 2–4 s, by “luxury
hyperperfusion” with an over abundance of oxygenated
hemoglobin. It is this physiologic epiphenomenon, with
a delayed change in oxy/deoxy hemoglobin ratio, that
provides the basis for blood oxygen level-dependent
(BOLD) fMRI (Malonek, 1997). Regional needs and
regulation of cerebral blood flow occur at the microvas-
cular level and may be restricted toregions as small as
250 ?m (Lou, 1987). The mediator of this response is
not known but may be a third factor rather than a
direct link between perfusion and metabolism (Lou,
1987). It is important to recall that current fMRI tech-
niques do not measure synaptic metabolic activity di-
rectly and that the BOLD response is detected as a
relative change in MRsignal and corresponding
change in blood flow: it is not an absolute measure and
depends heavily on the cognitive difference between
15O-water PET and a sen-
NeuroImage 13, 239–249 (2001)
doi:10.1006/nimg.2000.0681, available online at http://www.idealibrary.com on
Copyright © 2001 by Academic Press
All rights of reproduction in any form reserved.
control and task conditions. Furthermore, the statisti-
cal thresholds used to determine a significant signal
change are derived from adult studies. Identifying true
activation also depends on identifying factors that ob-
scure detection of signal, such as motion.
Many issues remain tobe clarified for proper interpre-
tation of fMRI in children. A wide range of anatomic,
physiological, and cognitive factors change during child
development, and may confound functional neuroimag-
ing data acquisition, analysis, and interpretation. They
may affect theability todetect a signal, influencehow the
signal is processed and analyzed, and determine its loca-
tion and magnitude. The particular challenge with child
studies is to take into account the constant growth and
change in physical as well as psychological capacity.
Studies comparing adults and children may also suffer
fromtechnical challenges that areunder recognized, such
as the common practice of using equipment originally
designed for adults that may not be optimal when used
with children. As developmental studies using fMRI in
children are in their infancy, it is time to identify and
consider issues that merit investigation and consider-
ation for future studies.
BOLD RESPONSE IN NEONATES, INFANTS,
fMRI studies of higher cortical function—working
memory, verbal fluency, reading—in awake children
between 7 and 15 years, relying on the BOLD fMRI
technique, provide empirical evidence that the princi-
ples underlying adult studies resemble those in chil-
dren (Casey, 1995, 1999; Hertz-Pannier, 1997; Staple-
ton, 1997; Booth, 1999; Lee, 1999; Pugliese, 1999;
Baird, 1999; Thomas, 1999; Gaillard, 1999, 2000a). The
hemodynamic response, seen in 2- to 3-year-olds dur-
ing passive sensory tasks (photic stimulation, tactile
stimulation, passive listening tosound) and in children
as young as 5 years whileperforming cognitivetasks, is
also similar (Stapleton, 1997; Logan, 1999a; Souwei-
dane, 1999) (Fig. 1). There is little cause to believe the
physiology of the BOLD response, or its detection in
children, is remarkably different than in adults.
Whether there are minor differences in threshold of
response, reactivity, or robustness of response, how-
ever, is less certain. Maturation of the response to
adult levels probably occurs at a young age. None of
these studies, however, have specifically examined the
time course or pattern of the BOLD response as has
D’Esposito, 1999); and it is not known whether the
developmental differences in myelination and synapse
formation discussed below affect the pattern and tem-
poral delay of the BOLD effect.
There is some evidence to suggest, however, that
neonates and infants may exhibit different vascular
responses than older children and adults (Yamada,
1997; Born, 1998; Martin, 1999). Born et al. (1998)
studied 17 neonates, infants, and toddlers, ranging
from 3 days to48 months, with BOLD fMRI. All studies
took placein thesleep (6) or sedated (11) state; thetask
monitored a response to a photic flicker compared to
rest. Contrary to expectations, they found a mean de-
crease in signal in 10 subjects during the photic flash
condition and a mean decrease in signal of 2.2% for the
group (Born, 1998). Yamada et al. (1997), also using
the same paradigm in 15 sedated children between 1
and 54 weeks, found an increase in signal in children
younger than 5 weeks and a decrease in signal in
children older than 8 weeks. The authors interpreted
their results as evidenceeither for decreased blood flow
or increased oxygen extraction. Martin et al. (1999),
whosuccessfully studied 58 of 75 children (47 sedated)
between 1 day and 12 years of age, found mixed results
of either increased or decreased signal in occipital cor-
tex in all populations. In contrast to BOLD fMRI, op-
tical imaging in neonates using visual response to
checkerboard pattern shows a hemodynamic response
similar to those in older humans and is similar to that
described by Malonek et al. (1997) in adult cats (Meek,
1998). Meek and colleagues (1998) obtained data in 20
of 58 children (10 control, 10 subject) who ranged be-
tween 2 days and 3 months. They found a mean 9%
signal increase, with contributions of 67% by oxygen-
ated hemoglobin. Thus, they describe an increase in
oxygen extraction but an overabundant supply of oxy-
genated hemoglobin similar to adult-based studies.
The varied and inconsistent responses found with
BOLD fMRI suggest that methodological factors may
be important in data acquisition and analysis in neo-
nates and infants. Sedation, which was used in nearly
all the younger children studied, significantly de-
presses CMRGlc on the order of 25–30% and may alter
blood flow responses (Theodore, 1989).
PEDIATRIC ANATOMICAL AND
Many physical and physiological differences between
children and adults continue tochange during a child’s
growth and maturation and may influence how data
can be collected, analyzed, and interpreted. Among the
most relevant factors are body size and morphologic
differences in children’s brain structure, including the
proportion of gray to white matter. Some factors, such
as the cardiorespiratory cycle, will increase motion ar-
tifact, which is always problematic in young children
who may be less likely to remain still than many
adults. Other factors, such as synaptic density and
differences in resting blood flow and metabolism, may
influence signal detection and subsequent analysis.
The most obvious difference is that children are
smaller than adults. Proportionately, head size differs
less than does body size, but for a 5 to 7-year-old child
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DEVELOPMENTAL ASPECTS OF PEDIATRIC fMRI