AJR 2003; 180:851-859
© American Roentgen Ray Society
Diffusion-Tensor MR Imaging of Normal Brain Maturation: A Guide to Structural Development and Myelination
Jeffrey H. Miller1,
Robert C. McKinstry1,
Joseph V. Philip1,
Pratik Mukherjee1 and
Jeffrey J. Neil1,2
1 Mallinckrodt Institute of Radiology, Washington University School of Medicine,
Campus Box 8131, Neuroradiology, 510 S. Kingshighway Blvd., St. Louis, MO
63110.
2 Division of Pediatric Neurology, St. Louis Children's Hospital, One Children's
Place, St. Louis, MO 63110.
Received January 14, 2002;
accepted after revision July 31, 2002.
Presented in part at the annual meeting of the Radiological Society of
North America, Chicago, November 2001.
Address correspondence to R. C. McKinstry.
Introduction
Conventional T1- and T2-weighted MR imaging is widely used for the visual
assessment of maturational changes in the developing brain. The well-defined
contrast changes between gray and white matter are thought to result largely
from highly predictable patterns of myelination. Specific qualitative features
have been established for conventional MR imaging that can be used to
distinguish normal from abnormal brain development
[1]. Although conventional MR
imaging has proven useful for assessing brain maturation, its evaluation is
subjective. Newer quantitative diffusion MR imaging techniques have shown
potential for more objective and sensitive detection of subtle developmental
changes
[2,3,4,5,6].
Diffusion-Tensor Imaging of Brain Development
Diffusion-tensor MR imaging is a quantitative technique that has proven
sensitive to maturational changes over a longer period of development than T1-
and T2-weighted MR imaging
[2,3,4,5,6].
Because diffusion-tensor imaging is a relatively new MR imaging modality, most
radiologists are not yet familiar with the visual progression of changes on
diffusion-tensor images during normal brain development. We provide a
pictorial representation of the changes in brain water diffusion in children
from 26 weeks' estimated gestational age to 16 years old (postnatal age) and
compare them with the wellknown changes of brain maturation found on T1- and
T2-weighted MR imaging. The diffusion-tensor images in this essay were
collected as part of previous studies of normal brain development using
single-shot spin-echo, echo-planar image pulse sequences
[2,
3]. Because the assessment of
normal brain maturation is an established clinical application of MR imaging,
an understanding of the evolution of developmental changes in brain water
diffusion may improve the ability of radiologists to distinguish normal from
abnormal maturation.
We have chosen two widely used measures of water diffusion that can be
derived from diffusion-tensor MR imaging: the apparent diffusion coefficient
and diffusion anisotropy. The apparent diffusion coefficient is the spatially
averaged magnitude of water diffusion. Diffusion anisotropy provides
additional information regarding the directionality of diffusion. Because
anisotropy is greater in ordered structures such as myelinated axons, these
images provide useful information regarding white matter myelination.
Human Brain Development
Preterm Neonates
The brain of a neonate born at 26 weeks' gestation is lissencephalic (Fig.
1A,1B,1C,1D).
At this early developmental stage, white matter has low signal intensity
relative to gray matter on T1-weighted images and high signal intensity on
T2-weighted images. The T1 and T2 relaxation rates of the neonatal brain are
longer than those of the adult because of the higher water content and
structural immaturity of the developing myelin sheath. Diffusion-tensor
apparent diffusion coefficient images show strong gray matter—white
matter contrast because of the higher rate of diffusion in white matter than
in gray matter [2,
3]. This contrast will
disappear during the first year of life. Despite the histologic absence of
myelin in the cerebral hemispheres at 26 weeks' gestational age, anisotropy
can be detected in the posterior limb of the internal capsule
[7]. A thin cortical ribbon of
anisotropy is also seen, but it vanishes before term. This transient cortical
anisotropy may reflect the presence of radial glial fibers at this early
developmental stage [8].
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Fig. 1A. —Conventional and diffusion-tensor MR images from newborn boy
of 26 weeks' estimated gestational age. Single arrows = occipital horns of
lateral ventricles. Axial T1-weighted image (TR/TE, 500/12) shows small amount
of blood layering dependently in occipital horns of lateral ventricles. At
this early developmental stage, unmyelinated white matter is hypointense
relative to hyperintense ribbon of cortical gray matter.
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Fig. 1B. —Conventional and diffusion-tensor MR images from newborn boy
of 26 weeks' estimated gestational age. Single arrows = occipital horns of
lateral ventricles. Axial T2-weighted image (TR/TE, 5000/96) shows
unmyelinated white matter as hyperintense relative to hypointense ribbon of
cortical gray matter.
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Fig. 1C. —Conventional and diffusion-tensor MR images from newborn boy
of 26 weeks' estimated gestational age. Single arrows = occipital horns of
lateral ventricles. Axial apparent diffusion coefficient image shows high
intensity throughout parenchyma because of high rate of water diffusion in
structurally immature human brain at 26 gestational weeks. Lower rate of
diffusion in gray than in white matter causes cortex to appear darker than
underlying subcortical white matter (double arrows). Note that window
and level settings used here are maintained in diffusion-tensor axial apparent
diffusion coefficient MR images in successive figures to allow direct
comparisons of signal intensity throughout development.
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Fig. 1D. —Conventional and diffusion-tensor MR images from newborn boy
of 26 weeks' estimated gestational age. Single arrows = occipital horns of
lateral ventricles. Axial anisotropic image shows anisotropy in posterior limb
of internal capsule (arrowhead) and pre-dates histologic appearance
of myelin. Because diffusion anisotropic contrast reflects changes in cellular
structural organization, axonal structures can be visualized before they are
myelinated. Thin cortical ribbon of high diffusion anisotropy (double
arrows) is also present at this early developmental stage. This cortical
anisotropy vanishes before term.
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Neonates Born at Term
In neonates born at term, contrast between gray and white matter on T1- and
T2-weighted MR images of the brain remains opposite that of the adult brain
(Fig.
2A,2B,2C,2D).
Although some T1 hyperintensity and T2 hypointensity is present in the
partially myelinated posterior limb of the internal capsule, such changes are
not yet evident in the unmyelinated portions of central white matter, such as
the corpus callosum and the anterior limb of the internal capsule. In neonates
born at term, diffusion-tensor imaging clearly shows visible anisotropy in the
posterior limb of the internal capsule and the splenium of the corpus
callosum.
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Fig. 2A. —Conventional and diffusion-tensor MR images of 2-day-old boy
born at term. Axial T1-weighted image (TR/TE, 550/12) shows relatively
homogenous low signal in immature white matter compared with gray matter.
Infant white matter T1 relaxation times are longer than those in adult,
resulting in "reverse contrast" in this neonate. White matter
signal increases with increasing white matter maturation. T1 hyperintensity
resulting from early changes of myelination is detectable only in posterior
limb of internal capsule (arrow).
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Fig. 2B. —Conventional and diffusion-tensor MR images of 2-day-old boy
born at term. Axial T2-weighted image (5000/96) shows high signal in immature
white matter compared with that of gray matter. As myelinated white matter
replaces unmyelinated white matter, signal intensity contrast will reverse. No
discernible T2 hypointensity signal changes resulting from early changes of
myelination are present.
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Fig. 2C. —Conventional and diffusion-tensor MR images of 2-day-old boy
born at term. Axial apparent diffusion coefficient image shows gray
matter—white matter contrast continues to be visible because of higher
rate of water diffusion in white matter than in gray matter.
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Fig. 2D. —Conventional and diffusion-tensor MR images of 2-day-old boy
born at term. Axial anisotropic image shows more white matter structures
visible as areas of high anisotropy than are visible as T1-weighted
hyperintensity (A). Increased anisotropy is identified in posterior
limb of internal capsule (arrow). Anisotropy is also visible in
splenium of the corpus callosum (arrowhead).
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Infants 3-4 Months Old
During this period of rapid myelination, MR images at the level of the
basal ganglia show T1 hyperintensity throughout the internal capsule, splenium
of the corpus callosum, and proximal optic radiations (Fig.
3A,3B,3C,3D).
T2 hypointensity is present in the posterior limb of the internal capsule and
proximal optic radiations [1,
7].
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Fig. 3A. —Conventional and diffusion-tensor MR images of 4-month-old
girl. Axial T1-weighted image (TR/TE, 500/12) shows that cerebral myelination
progresses rapidly during first months after birth. In general, myelination
progresses from caudal to cephalal, dorsal to ventral, and central to
peripheral. Fiber tracts carrying sensory information also generally myelinate
before those tracts controlling motor function
[1]. In infants 3-4 months old,
new T1 hyperintensity is generally visible in anterior limb of internal
capsule (arrowhead), splenium of corpus callosum (white
arrow), and proximal optic radiations (black arrow).
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Fig. 3B. —Conventional and diffusion-tensor MR images of 4-month-old
girl. Axial T2-weighted image (5000/96) shows T2-weighted hypointensity,
visible in posterior limb of internal capsule (white arrow) and
proximal portions of optic radiations (black arrow).
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Fig. 3C. —Conventional and diffusion-tensor MR images of 4-month-old
girl. Axial apparent diffusion coefficient image shows decrease in apparent
diffusion coefficient throughout brain parenchyma compared with that in
younger subjects (Figs.
1A,1B,1C,1D
and
2A,2B,2C,2D),
which is accompanied by reduced gray matter—white matter contrast.
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Fig. 3D. —Conventional and diffusion-tensor MR images of 4-month-old
girl. Axial anisotropic image shows rapid progression of myelination of
central white matter structures. Both limbs of internal capsule and splenium
are more easily visualized on anisotropic than on T1-weighted MR imaging. In
addition, external capsule (small arrow), genu of corpus callosum
(arrowhead), and more distal portions of optic radiations (large
arrow) are visible on anisotropic but not T1-weighted imaging.
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Diffusion-tensor MR imaging shows white matter structures at this age with
greater conspicuity. In addition to the white matter visible on conventional
MR imaging, anisotropy can be seen in the genu of the corpus callosum,
external capsule, and more distal optic radiations. Gray matter—white
matter contrast on diffusion-tensor apparent diffusion coefficient images is
diminished compared with that in newborns, reflecting a greater rate of
apparent diffusion coefficient reduction in white matter than in gray matter
during the first year of life
[2,
3,
7].
Infants 6-9 Months Old
At 6 months, new T1 hyperintensity is present in the genu of the corpus
callosum. T2-weighted images are of greater utility for assessing brain
maturation in infants older than 6 months. Hypointense myelinated white matter
is visible in the splenium at 6 months, in the genu at 8 months, and in the
anterior limb of the internal capsule after 9 months
[1,
7] (Fig.
4A,4B,4C,4D).
On anisotropic images, all major central and deep white matter of the cerebral
hemispheres is visible by 6 months. Peripheral commissural fibers (forceps
major and minor) become more conspicuous at approximately 9 months. By 9
months old, gray matter—white matter contrast has vanished on apparent
diffusion coefficient images, whereas apparent diffusion coefficient values
continue to decrease throughout the brain parenchyma
[3].
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Fig. 4A. —Conventional and diffusion-tensor MR images of 9-month-old
boy. Axial T1-weighted image (TR/TE, 500/12) shows hyperintensity in all
central white matter tracts. Genu of corpus callosum (arrow) is
usually hyperintense after 6 months of age.
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Fig. 4B. —Conventional and diffusion-tensor MR images of 9-month-old
boy. Axial T2-weighted image (5000/96) shows substantial T2 shortening in
myelinated white matter occurs after 6 months of age. Central white matter T2
hypointensity is visible in splenium (white arrow) by 6 months and
genu (black arrow) by 8 months. Anterior limb of internal capsule
(arrowhead) is classically described as appearing hypointense at 11
months of age; it is clearly hypointense earlier in this 9-month-old
infant.
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Fig. 4C. —Conventional and diffusion-tensor MR images of 9-month-old
boy. Axial apparent diffusion coefficient image shows continued reductions in
apparent diffusion coefficient as well as loss of gray matter—white
matter contrast.
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Fig. 4D. —Conventional and diffusion-tensor MR images of 9-month-old
boy. Axial anisotropic image shows high anisotropy in all central white matter
structures before 6 months of age. Anisotropy has also progressed into the
peripheral white matter (arrows).
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Infants 12 Months Old
By the end of the first year of life, the mature pattern of myelination has
largely been achieved and is visible on T1-weighted MR images (Fig.
5A,5B,5C,5D).
On T2-weighted images, hypointensity begins to appear in areas of subcortical
white matter [1,
7]. On diffusion-tensor
imaging, new anisotropy is visible in the area of small association arcuate
fibers.
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Fig. 5A. —Conventional and diffusion-tensor MR images of 1-year-old
boy. Axial T1-weighted image (TR/TE, 500/12) shows development of white matter
hyperintensity on T1-weighted images is largely complete.
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Fig. 5B. —Conventional and diffusion-tensor MR images of 1-year-old
boy. Axial T2-weighted image (5000/96) shows hypointensity of central and deep
white matter tracts of cerebral hemispheres relative to gray matter.
Subcortical frontal white matter is becoming hypointense relative to gray
matter (arrows).
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Fig. 5C. —Conventional and diffusion-tensor MR images of 1-year-old
boy. Axial apparent diffusion coefficient image shows continued reductions in
apparent diffusion coefficient as decreased signal intensity throughout brain
parenchyma.
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Fig. 5D. —Conventional and diffusion-tensor MR images of 1-year-old
boy. Axial anisotropic image depicts continuing maturation of central and deep
white matter tracts as increasing anisotropy. Short peripheral white matter
arcuate fibers connecting adjacent gyri (arrows) can be detected.
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Children Older Than I Year
After the first year of life, T2-weighted imaging is the conventional MR
imaging technique most sensitive to the process of myelination
[1,
7] (Fig.
6A,6B,6C,6D).
By 18 months, T2 hypointensity is visualized in the area of association
arcuate fibers [1,
7]. By the time a child is 2
years old, the mature pattern of myelination is achieved and can be seen on
T2-weighted images except in the terminal zones of myelination adjacent to the
lateral ventricles [1,
7].
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Fig. 6B. —Conventional and diffusion-tensor MR images of 2-year-old
boy. Axial T2-weighted image (5000/96) shows mature pattern of signal
intensity on T2-weighted images is nearly complete with extension of
hypointensity into subcortical white matter. Short peripheral arcuate
association fibers (arrows) are now also hypointense relative to gray
matter.
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Fig. 6C. —Conventional and diffusion-tensor MR images of 2-year-old
boy. Axial apparent diffusion coefficient image shows apparent diffusion
coefficient values continue to decrease beyond 2 years of age, but they remain
largely homogeneous throughout gray matter and white matter regions of brain
into adulthood.
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Fig. 6D. —Conventional and diffusion-tensor MR images of 2-year-old
boy. Axial anisotropic image shows progressively increasing anisotropy
throughout all white matter regions, with newly visible subcortical white
matter throughout both cerebral hemispheres. Regional heterogeneity of white
matter anisotropy increases during development, with highest anisotropy found
in commissural fibers of corpus callosum, somewhat lower values in
projectional fibers of corticospinal tracts, and lowest anisotropy in
association fibers of subcortical white matter. However, cortical gray matter
anisotropy is undetectable at this age.
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At the diffusion-weighting factors currently in clinical use (b values 
1000 sec/mm2), apparent diffusion coefficient images remain
homogeneous throughout gray and white matter into adulthood
[3]. In contradistinction,
anisotropy becomes more heterogeneous, with the lowest values found in gray
matter and with progressively greater values found in association fibers
(e.g., arcuate fibers), projectional fibers (e.g., corticospinal tracts), and
commissural fibers (e.g., corpus callosum)
[3,
5] (Fig.
7A,7B,7C,7D).
On diffusion-tensor imaging, this change is reflected by the continued
increase in anisotropy in the rapidly maturing central white matter tracts of
the internal capsule and corpus callosum and by the progression of anisotropy
into more slowly maturing peripheral white matter regions, chiefly subcortical
white matter, which continue through at least the first two decades of life
[4,
6] (Fig.
8A,8B).
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Fig. 7C. —Conventional and diffusion-tensor MR images of 6-year-old
boy. Axial apparent diffusion coefficient image shows image contrast is
largely unchanged from that at 2 years of age (Fig.
6A,6B,6C,6D).
However, quantitative studies indicate that apparent diffusion coefficient
values continue to decline well into second decade of life.
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Fig. 7D. —Conventional and diffusion-tensor MR images of 6-year-old
boy. Axial anisotropic image shows increased intensity and extent of white
matter anisotropy compared with that at 2 years of age (Fig.
6A,6B,6C,6D).
T1- and T2-weighted MR images (A and B) do not show changes in
signal intensity patterns at this later stage of development. Several
quantitative studies indicate that white matter anisotropic values continue to
increase well into second decade of life.
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Fig. 8A. —Diffusion-tensor MR anisotropic images at level of centrum
semiovale at two ages for comparison. Axial image of 2-year-old girl shows
immature anisotropy of developing centrum semiovale.
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Fig. 8B. —Diffusion-tensor MR anisotropic images at level of centrum
semiovale at two ages for comparison. Axial image of 18-year-old man shows
anisotropy in centrum semiovale increases by approximately 30% during first
two decades of life. Progression of anisotropy into more slowly maturing
subcortical white matter is also evident.
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Introduction
Diffusion-Tensor Imaging of...
