15

Assessment of Normal Myelination with

Magnetic Resonance Imaging
Kirk M. Welker, M.D. 1 Alice Patton, M.D. 1

1 Division of Neuroradiology, Department of Radiology, Mayo Clinic, Address for correspondence and reprint requests Kirk M. Welker,
Rochester, Minnesota M.D., Division of Neuroradiology, Department of Radiology, Mayo
Clinic, 200 First Street SW, Rochester, MN 55905 (e-mail: welker.
Semin Neurol 2012;32:15–28. kirk@mayo.edu).

Abstract White matter myelination is essential to postnatal neurologic maturation and can be
accurately evaluated by magnetic resonance imaging (MRI). Accordingly, MRI pulse
sequences should be optimized for detection of myelin in young children. T1-weighted
images are most useful during the first year of life. These demonstrate myelin-related
white matter hyperintensity consequent to increasing cholesterol and galactocerebro-

Downloaded by: Nationwide Childrens Hopsital. Copyrighted material.

side within myelin membranes. T2-weighted images are most useful in later stages of
Keywords myelination, during which time elaboration of myelin leads to reduction in brain water
► myelination content with associated T2 hypointensity. Additional information regarding the status
► development of myelination can be obtained from T2-weighted fluid attenuation inversion recovery
► brain (FLAIR) and diffusion tensor imaging (DTI) pulse sequences. Clinically useful milestones
► white matter for assessment of myelination across all these MRI pulse sequences are available as
► infants guidelines to image interpretation. Evaluation of myelination status using a combination
► magnetic resonance of T1- and T2-weighted images should be routine in the interpretation of all pediatric
imaging brain MRI exams.

Magnetic resonance imaging (MRI) has revolutionized our
ability to evaluate myelination in young children. Until the
advent of cross-sectional imaging, the in vivo status of myelin
development could only be evaluated through clinical history,
neurologic exam, or by histology. By the early 1980s, com-
puted tomography allowed gross assessment of myelination
through its depiction of white matter density in the pediatric
brain.1 However, it was not until the introduction of clinical
MRI in the late 1980s that regional or tract-specific myelin
maturation could be visualized.2 Myelin assessment has since
evolved to become a routine aspect of pediatric neuroimag-
ing. By reviewing a combination of T1- and T2-weighted MRI
series, radiologists and clinicians can quickly and reliably
determine whether a child's myelin development is normal,
delayed, or abnormal. This capability has greatly enhanced
our ability to detect childhood leukoencephalopathies and
other disorders of myelin at younger ages, with the attendant
benefit of allowing for earlier prognostication and/or treat-
ment. However, effectively detecting abnormalities of myeli-
nation is dependent on both proper imaging technique and an
understanding of normal, age-related progression of this
process. To that end, the MRI techniques that have evolved
for the assessment of cerebral myelination will be reviewed.
This will be followed by a discussion of both general myeli-
nation patterns as well as age-related milestones in myelin
development. Finally, we conclude with a brief review of
normal variants and imaging pitfalls.
MR Pulse Sequences
The core MRI techniques for myelin assessment in the infant
are T1- and T2-weighted pulse sequences. These two forms of
MRI contrast are complimentary in that T1-weighting pro-
vides information regarding the early stages of myelination,
whereas T2-weighting provides insight into later stages of
myelin maturation.
For myelin assessment with a 1.5-Tesla (T) MRI scanner,
T1-weighted images are generally acquired using conven-
tional spin echo images with a repetition time (TR) of !500 to
600 milliseconds and an echo time (TE) of less than 20

Issue Theme Inherited Copyright © 2012 by Thieme Medical DOI http://dx.doi.org/

Leukoencephalopathies; Guest Editor, Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0032-1306382.
Deborah L. Renaud, M.D. New York, NY 10001, USA. ISSN 0271-8235.
Tel: +1(212) 584-4662.
16 Assessment of Normal Myelination with Magnetic Resonance Imaging
milliseconds.3 Due to the significant reduction in T1 relaxa-
tion times at 3.0-T field strength, T1-weighted fluid attenua-
tion inversion recovery images (FLAIR) are often employed as
a means of improving T1 contrast. Typical 3.0-T T1-weighted
FLAIR scan parameters include TR ¼ 2950 milliseconds, TE
¼ full minimum, inversion time (TI) ¼ 890 milliseconds. An
alternate means of obtaining excellent T1 contrast at 3.0-T
field strength is through the use of a three-dimensional (3D)
gradient echo T1-weighted pulse sequence, such as magneti-
zation prepared rapid gradient echo (MP-RAGE). Common
scan parameters would include TR ¼ 6.4 milliseconds, TE ¼
full minimum, TI ¼ 900 milliseconds, flip angle ¼ 8 degrees.
T2-weighted images can be acquired using conventional
spin echo or fast spin echo (FSE) techniques. However, one
must understand that FSE T2 images demonstrate myelin
maturation at a slightly earlier age than conventional spin
echo images due to increased magnetization transfer ef-
fects.4,5 In comparison to similar scans in adults, a higher
T2-weighting is applied when scanning the brains of infants
to compensate for the increased cerebral water content. 6
One means of accomplishing this is using a heavily T2-
weighted fast spin echo inversion recovery (FSE-IR) se-
quence. At our institution, we commonly employ the fol-
lowing parameters for this purpose at 1.5-T field strength:
TR ¼ 5000 milliseconds, TE ¼ 101 milliseconds, TI ¼ 133
milliseconds.
Although T2-weighted FLAIR images are among the most
commonly used pulse sequences in contemporary MRI of the
brain, the white matter contrast created by these images has
traditionally been considered substandard for myelin stag-
ing.7 However, T2-weighted FLAIR images demonstrate signal
changes related to the completion of myelin maturation after
myelin has already reached its adult appearance on T1- and
T2-weighted images.5,8,9 Consequently, this pulse sequence
may be of use in assessing the final stages of myelination in
various regions of the brain. We employ the following T2-
weighted FLAIR imaging parameters at both 1.5- and 3.0-T
field strength: TR¼ 11000, TE ¼ 147 milliseconds, and TI
¼ 2250 milliseconds.
A recently developed tool in the armamentarium for
myelin evaluation is diffusion tensor imaging (DTI). This
technique uses echo planar pulse sequences to exploit the
anisotropic diffusion of water molecules in cerebral tissue
and create images that reflect increasing axonal organization
in the brain. As areas in the brain with increased axonal
organization differentially restrict the movement of water
molecules perpendicular to the axon bundles, the fractional
anisotropy (FA) of water can be used as a surrogate measure
for white matter organization.10 Several studies have docu-
mented the relationship between FA and myelin maturity in
infants.11–13 In particular, FA values have been useful for
assessing the maturation of functional neuronal networks
in the brain.13 Pediatric diffusion tensor imaging may be
successfully obtained using the following parameters on a 3-T
scanner: echo planar SE pulse sequence, 26 diffusion direc-
tions, TR ¼ 8000 milliseconds, TE ¼ minimum b-value
¼ 1000 sec/mm2. For the purposes of myelin assessment,
raw DTI images can be postprocessed into grayscale FA maps
Seminars in Neurology Vol. 32 No. 1/2012
Welker, Patton
or three-color directionally encoded FA maps where the red,
green, or blue color corresponds to the principle axis of
anisotropy.
Other advanced MRI techniques have been applied to
gauging myelin maturation. These include magnetization
transfer,14,15 quantitative T2 measurement,16 functional con-
nectivity mapping,17 and multiparametric mapping of myelin
water fraction.18 Although none of these methods has yet
seen widespread clinical use, they may provide important
future contributions to clinical assessment of myelin
development.
Finally, it should be stated that appropriate selection of
MRI planes can improve one's ability to appreciate age-
related changes in myelination.6 As myelination is mostly
centered in the brainstem in neonates, the sagittal plane is
particularly useful in that group. During the intermediate
stages of myelination, the axial plane is preferred due to its
ability to demonstrate major tracts within the brain, such as
the corticospinal tracts and optic radiations with bilateral
Downloaded by: Nationwide Childrens Hopsital. Copyrighted material.
symmetry. In the terminal stages of myelination, coronal
images are useful for clear depiction of subcortical U-fibers
in the frontal lobes.
General Signal Patterns in Brain
Myelination
Despite region-related differences in the timing of myelin devel-
opment, normal myelination in the brain progresses in a pre-
dictable, orderly fashion, both in terms of MRI signal
characteristics and neuroanatomic distribution. An understand-
ing of these patterns is critical to image interpretation, both from
the standpoint of confirming normal development and for
identifying pathologic alterations in the myelination process.
First, consider the general pattern of MR signal progres-
sion. In the fully myelinated brain, white matter is hyperin-
tense to cortex on T1-weighted images and hypointense to
cortex on T2-weighted images. In the unmyelinated portions
of the neonatal brain, this pattern is reversed with the white
matter demonstrating T1 hypointensity and T2 hyperinten-
sity relative to cortex. The first of the MR signal changes to
occur during myelination is an increase in white matter T1
signal. This alteration of T1 signal is believed to be due to
increasing cholesterol19 and galactocerebroside20 within the
cell membranes of the oligodendrocyte myelin processes. It is
thought that these molecules create T1 shortening through
their interaction with adjacent free water with associated
magnetization transfer effects.21
Unlike the previously described T1 signal change, T2 signal
alteration during myelination is not solely contingent upon
specific biochemical changes in the composition of myelin.
Rather, growing T2 hypointensity during myelination is
largely consequent to generalized reduction in free water
content in maturing white matter.2,22 As myelin sheaths are
elaborated by oligodendrocytes and packed into tight spirals
around axons, the increasing volume of myelin simply re-
places water in the interstitial space.6,23 Additionally, increas-
ing length of hydrocarbon chains in the myelin membranes
along with increasing numbers of hydrocarbon double
 Assessment of Normal Myelination with Magnetic Resonance Imaging Welker, Patton 17

Table 1 Age Specific Progression of Myelination on MRI5,6,9,13,25,36

Age Specific Progression of Myelination on MRI

Age (Months) T1 (Signal) T2 (Signal) T2 FLAIR (Signal) DTI (Anisotropy)
Birth Medulla " Medulla ↓ Deep occipital WM ↓ Central WM tracts"
Dorsal pons " Dorsal pons ↓ Deep frontal WM ↓ Peripheral WM ↓
Brachium pontis " Midbrain ↓ Deep temporal WM ↓ All CBL peduncles"
I/S CBL peduncles " Perirolandic gyri↓ ML and MLF"
Midbrain " I/S CBL peduncles↓ Corticospinal tracts"
VL Thalamus" VL Thalamus ↓ Cerebral peduncles"
Posterior limb IC" IC and corona radiata"
Perirolandic centrum Cingulum", Fornix "
semiovale and gyri" Corpus callosum"
Optic nerves, tracts, Anterior commissure ",
and radiations" UF"
2 Deep cerebellar WM" Brachium pontis ↓ Deep occipital WM " FA in peripheral white
Anterior limb IC" Posterior limb IC ↓ Deep frontal WM " matter dramatically
Perirolandic centrum Deep temporal WM " increasing
semiovale ↓
Optic tracts↓

Downloaded by: Nationwide Childrens Hopsital. Copyrighted material.

4 Entire cerebellum" Optic radiations↓ Dorsal pons ↓ Peripheral WM "
CC (splenium) " Calcarine fissure ↓ Brachium pontis ↓ IFOF "
Posterior limb IC ↓ ILF "
Subcortical U-fibers"
Forceps minor "
Forceps major "
(inverted V shape)
6 CC (entire) " CC (splenium) ↓ Optic radiations ↓ Increasing definition
Ventral pons ↓ Perirolandic centrum of forceps major and
semiovale↓ forceps minor
CC (entire) ↓
8 Subcortical U-fibers Anterior limb IC ↓ Anterior limb IC ↓ Forceps major
occipital " CC (entire) ↓ obtaining inverted
U shape
12 Subcortical U-fibers Deep WM cerebellum↓ Deep occipital WM ↓ SLF"
frontal and temporal" Early occipital subcortical Fiber crossing areas "
Brain achieves adult U-fibers ↓
appearance on T1. Temporal central WM↓
18 Minimal change Subcortical U-fibers Deep frontal WM ↓ Increasing FA and
occipital poles↓ Subcortical occipital tract thickness
Entire posterior fossa↓ WM ↓ throughout brain
24 Minimal change Subcortical U-fibers frontal Deep temporal WM ↓ Increasing FA and
and temporal poles↓ Subcortical frontal WM↓ tract thickness
throughout brain
Other T1 provides little Periatrial terminal zones Subcortical U-fibers in FA color maps
information after 1st year may remain hyperintense temporal poles remain achieve adult
of life. into 2nd decade. hyperintense after appearance by
24 months. 48 months.

", increased signal or anisotropy; ↓, decreased signal or anisotropy; CBL, cerebellar; CC, corpus callosum; DTI, diffusion tensor imaging; FA, fractional
anisotropy; FLAIR, fluid attenuation inversion recovery; IC, internal capsule; IFOF, inferior frontal occipital fasciculus; ILF, inferior longitudinal
fasciculus; I/S, inferior and superior; ML, medial lemniscus; MLF, medial longitudinal fasciculus; MRI, magnetic resonance imaging; SLF, superior
longitudinal fasciculus; VL, ventral lateral; UF, uncinate fasciculus; WM, white matter.

bonds24 contributes to a decrease in T2 times due to resultant
increasing hydrophobic properties of the myelin mem-
branes.25 Such T2 changes occur days to months after white
matter has become hyperintense on the complimentary T1-
weighted images26 and thus coincide with a later stage in
myelin development. Consequently, although T1-weighted
images provide the most useful information in the earlier
stages of myelination, T2-weighted images are superior in the
later stages of the process.
Of the standard MR pulse sequences, T2-weighted FLAIR
images demonstrate the most complex signal changes in
response to myelination. In general, these images behave as
conventional T2-weighted images, with the exception that
the conversion from high T2 signal to low T2 signal generally

Seminars in Neurology Vol. 32 No. 1/2012

18 Assessment of Normal Myelination with Magnetic Resonance Imaging
lags behind standard T2-weighted sequences.5,9 This delay is
felt to be secondary to partial T1-weighting within the FLAIR
pulse sequence8 that partially mitigates the T2 effects. How-
ever, unlike the remainder of the brain, the deep hemispheric
cerebral white matter demonstrates an unusual triphasic
pattern on T2-weighted FLAIR sequences.9 This pattern consists
of initial neonatal deep white matter hypointensity, followed
by gradual signal conversion to hyperintensity. This is eventu-
ally followed by reversion to a hypointense appearance during
the final stages of myelin development. It is believed that the
initial hypointense phase of this FLAIR signal sequence is the
result of exceptionally prominent free water in the deep
cerebral white matter during the early neonatal period.27
This water lowers the T1 signal to the point that white matter
signal is selectively suppressed by the T2 FLAIR pulse sequence
in a manner similar to that seen with cerebrospinal fluid.9 As
the white matter matures, free water decreases, raising the
associated T1 signal to the point that the FLAIR signal suppres-
sion is lost, resulting in T2 hyperintense white matter.5,9
Finally, as myelin undergoes further maturation, the free water
concentration further declines consequent to increasing vol-
umes of hydrophobic myelin. Eventually, this free water loss
leads to the third and final phase of signal change in the deep
hemispheric white matter, namely renewed T2 hypointensity.
Despite occurring at a later time point, this final phase is
entirely analogous to the hypointensity observed on conven-
tional T2 images during the later stages of myelination.
Diffusion tensor imaging for measurement of FA is a more
recently introduced tool for the evaluation of myelin; how-
ever, this imaging technique is becoming increasingly wide-
spread in clinical practice. As previously mentioned,
increasing FA values can serve as a surrogate measure for
increasing white matter organization. However, even more
interesting is the fact that FA values in the developing infant
brain increase in two different distinct phases.28 The first FA
rise actually precedes myelination. Consequently, authors
have suggested that this may be related to a premyelination
state.29 The increase in anisotropy during this early phase is
thought to be caused by elaboration of microtubule proteins
in the axonal cytoskeleton, increasing axon caliber, increasing
activity of sodium ion channels, and proliferation of oligo-
dendrocytes as precursors to myelination.12,21,28,29 The sec-
ond phase of FA growth coincides with increasing elaboration
of myelin28 and reduction in the size of the extracellular
space.21 Myelinated axons restrict nonparallel water diffusion
leading to a local increase in FA values. Of note, this gradual
rise in anisotropy continues beyond the second year of life,30
suggesting that FA values may eventually provide insight into
the subtle changes in brain maturation that occur between
the second year of life and adulthood.
General Anatomic Patterns in Brain
Myelination
Myelination of the brain closely parallels pediatric neurologic
functional maturity as measured through neurodevelopmen-
tal testing.31 Hence, anatomic brain regions responsible for
primitive functions myelinate earlier than anatomic sites
Seminars in Neurology Vol. 32 No. 1/2012
Welker, Patton
corresponding to phylogenetically advanced function.32 Ad-
ditionally, autopsy studies in infants have confirmed several
general neuroanatomic rules regarding myelination.33,34
First, visual and auditory sensory regions myelinate, on the
whole, faster than motor regions. Second, the proximal
portions of a neuroanatomic subsystem myelinate sooner
than the more distal components. For example, the optic
tracts myelinate before the optic radiations. These proximal
elements of a functional neuroanatomic unit also myelinate at
a faster rate than their more distal counterparts.34 Third,
projection tracts within the brain generally myelinate earlier
than association tracts. Finally, the telencephalon begins
myelination about the central sulcus region. Myelination
then concurrently extends peripherally toward the various
poles of the brain, reaching them in the following order:
occipital pole, frontal pole, temporal pole.34 These neuro-
histologic patterns have been distilled by various authors into
simplified anatomic axioms of myelination: (1) myelination
proceeds from caudal to rostral; (2) myelination proceeds
Downloaded by: Nationwide Childrens Hopsital. Copyrighted material.
from posterior to anterior regions; and (3) myelination
proceeds from central to peripheral locations.5,8,26,35 Al-
though these general rules provide a useful construct for
the practical review of pediatric MRI scans, one should
understand that they are not inviolate. Important exceptions
do exist within the normal developmental process.35 For
example, the fact that the frontal poles myelinate before
the temporal poles violates the posterior to anterior rule.
Similarly, the more rostrally located perirolandic cortex
myelinates before the more caudally located internal capsule
anterior limb. The existence of such exceptions requires that
assessment of myelin be based on careful evaluation of
specific neuroanatomic landmarks rather than a simple ge-
stalt of the overall myelination pattern.
Contrast Specific Temporal Sequences of
Myelination
►Table 1 is a composite outline of normal myelination
chronology during the first 2 years of life as described by
multiple authors.5,6,9,13,25,36 This table presents the expected
appearance of T1- and T2-weighted MRI, T2-weighted FLAIR,
and DTI images at specific time points during infancy. There is
some inconsistency between authors regarding the timing of
some milestones of myelin maturation. This likely exists based
on variations in scan technique and image interpretation
criteria. Regarding this variability, ►Table 1 provides a rela-
tively conservative reference in the sense that most authors
agree that myelination of the specific white matter structure
should be complete by the ages referenced in the table. Clinical
confidence in myelin assessment is increased by employing
multiple MRI contrasts. ►Figures 1 through 6 illustrate several
significant age-related myelination milestones in developing
brains. These will be revisited in the following discussion of
contrast-specific myelination patterns.
T1-Weighted Images
From birth through 12 months, T1-weighted images provide
an excellent window into myelin development. In the
 Assessment of Normal Myelination with Magnetic Resonance Imaging Welker, Patton 19

Downloaded by: Nationwide Childrens Hopsital. Copyrighted material.

Figure 1 A newborn boy imaged at 1.5 Tesla field strength. (A) Sagittal T1-weighted image demonstrating high-signal myelin within the dorsal
medulla, pons, and midbrain. Compare with the unmyelinated low-signal white matter in the ventral pons and hemispheric white matter. (B)
Coronal T1-weighted three-dimensional gradient echo image demonstrates high signal myelin in the posterior limbs of the bilateral internal
capsules and the superior cerebellar peduncles. (C) Axial T2-weighted fast spin echo inversion recovery image demonstrating low signal myelin in
the bilateral ventral lateral thalami. (D) Axial T2-weighted fluid attenuation inversion recovery image demonstrates patchy low signal in the deep
frontal and parietal white matter due to high water content with signal suppression.

newborn, there is extensive brainstem myelination (►Fig. 1).
Myelin-associated T1 signal hyperintensity is noted in the
medulla, dorsal pons, brachium pontis, and both the inferior
and superior cerebellar peduncles.5,25,37 More superiorly, my-
elinated white matter is visible in the cerebral peduncles of the
midbrain, the ventral lateral thalami, and the posterior limbs of
the internal capsules. Additional T1 hyperintense myelin can
be identified in the corticospinal tracts extending superiorly in
the perirolandic centrum semiovale.5 The cortex along the
central sulci is similarly T1 hyperintense. In the visual path-
ways, myelin is seen in the optic nerves, optic tracts, and optic
radiations.25
By 2 to 3 months of age, myelination in the internal capsule
has extended to involve the anterior limb (►Fig. 2).25 Be-
tween 2 and 3 months of age, T1 hyperintense myelin
progresses peripherally from the deep cerebellar white mat-
ter to involve the entire cerebellum.6,25 At 4 months, the
splenium of the corpus callosum has myelinated. Callosal
myelination proceeds in an anterior to posterior direction to
involve the genu by 6 months of age (►Fig. 3).6
Outside the central sulcus region, initiation of myelination
in the subcortical white matter begins at !3 months of age.7
Progression of T1 hyperintensity in the supratentorial white
matter evolves peripherally from the perirolandic region to

Seminars in Neurology Vol. 32 No. 1/2012

20 Assessment of Normal Myelination with Magnetic Resonance Imaging Welker, Patton

Downloaded by: Nationwide Childrens Hopsital. Copyrighted material.

Figure 2 A 2-month-old girl imaged at 3 Tesla field strength. (A) Axial T1-weighted image demonstrates prominent high-signal myelination of
the posterior limbs of the internal capsules and early myelination within the anterior limbs. (B) Axial T2-weighted fluid attenuation inversion
recovery image shows uniform high signal throughout the deep hemispheric white matter. The low-signal regions characteristic of the newborn
have resolved by this age. (C) Axial T2-weighted fast spin echo inversion recovery (FSE-IR) image demonstrating low-signal myelin within the
posterior limbs of the internal capsules, the anterior thalami, and to a lesser extent, the bilateral optic radiations. (D) Axial T2-weighted FSE-IR
image displays myelin involving the brachium pontis bilaterally with early involvement of the deep cerebellar white matter.

involve the subcortical U-fibers in the occipital pole by
7 months of age.5,6,25 On the other hand, T1 hyperintensity
in the frontal and temporal lobes proceeds more slowly and
does not reach the most anterior subcortical U-fibers in these
lobes until !1 year (►Fig. 4).5,25 Despite the fact that there is
still active, ongoing cerebral myelination, the brain at this
stage has achieved a typical adult T1 contrast pattern. Conse-
quently, T1-weighted images are of little use for myelin
assessment beyond the first year.
T2-Weighted Images
In the newborn, myelination, as demonstrated by low T2
signal, is anatomically less extensive than the signal changes
contemporaneously demonstrated by T1 images. Sites of
myelination include the medulla, dorsal pons, superior and
inferior cerebellar peduncles, midbrain, and ventral lateral
thalamus (►Fig. 1).25,37 The cortex surrounding the central
sulcus also demonstrates low signal at the time of birth or
shortly thereafter.37 By 2 months, low T2-signal myelin has
extended to involve the brachium pontis, posterior limb of the
internal capsule, and the perirolandic component of the
centrum semiovale (►Fig. 2).5,25,37 Also, at about this time,
myelin becomes visible in the optic tracts. Progressive myeli-
nation of the visual system leads to low T2 signal in the optic
radiations and subcortical white matter about the calcarine
fissure by 4 months of age.25

Seminars in Neurology Vol. 32 No. 1/2012

 Assessment of Normal Myelination with Magnetic Resonance Imaging Welker, Patton 21

Downloaded by: Nationwide Childrens Hopsital. Copyrighted material.

Figure 3 A 6½-month-old boy imaged at 3 Tesla field strength. (A) Sagittal T1-weighted fluid attenuation inversion recovery (FLAIR) image
demonstrates high-signal myelin throughout the entire corpus callosum. (B) Axial T2-weighted FLAIR image showing low signal in the posterior
limbs of the internal capsules and optic radiations (arrows). (C) Axial T2-weighted fast spin echo (FSE) image confirms complete myelination of the
ventral pons. (D) Axial T2-weighted FSE image demonstrating low-signal myelin in the splenium of the corpus callosum and the posterior limbs of
the internal capsules.

T2-signal changes in the corpus callosum lag 1 to 2 months
behind the T1-signal changes at this site.7 Notably, at
6 months, while the entire corpus callosum is hyperintense
on T1, the T2-signal changes are just beginning in the
splenium (►Fig. 3). The genu of the corpus callosum will
not demonstrate T2 hypointensity until 8 months.25 Concur-
rent with these callosal signal changes, the anterior limb of
the internal capsule achieves T2 hypointensity by 8 months.6
Within the posterior fossa, the ventral pons demonstrates
T2 hypointense myelin by 6 months and the deep cerebellar
white matter becomes hypointense by 12 months (►Fig. 4).6
The entire posterior fossa white matter is T2 hypointense by
18 months.6,7
With respect to the hemispheric white matter, signal
changes commence in the central occipital white matter by
7 months, with progressive involvement of the central frontal
white matter by 11 months and the central temporal white
matter by 12 months.5 As this process is completing, periph-
eral extension of T2 hyperintensity into the subcortical U-
fibers is beginning with early involvement of the occipital
lobes around the 1-year mark. Occipital subcortical white
matter signal changes should be complete by 15 months
(►Fig. 5).7 However, the anterior aspect of the frontal and
temporal lobes will not achieve a similar state of myelination
until around 24 months (►Fig. 6).5–7
T2-Weighted FLAIR Images
Assessing myelination on the basis of T2-weighted FLAIR
imaging is controversial with some authors advocating this
pulse sequence,5,8 and other authors considering it to be of
minimal utility.3 Regardless of one's opinion on the matter,
familiarity with the appearance of myelination on FLAIR

Seminars in Neurology Vol. 32 No. 1/2012

22 Assessment of Normal Myelination with Magnetic Resonance Imaging Welker, Patton

Downloaded by: Nationwide Childrens Hopsital. Copyrighted material.

Figure 4 A 12-month-old boy imaged at 3 Tesla field strength. (A) Coronal T1-weighted three-dimensional gradient echo image demonstrates
an adult pattern of myelination with high-signal myelin extending into the subcortical U-fibers of the frontal and temporal lobes as well as
throughout the cerebellum. (B) Axial T2-weighted fluid attenuation inversion recovery image shows early low-signal myelin in the deep white
matter of the anteromedial occipital lobes best seen on the right (arrow). (C) Axial T2-weighted fast spin echo inversion recovery (FSE-IR) image
demonstrates low-signal myelin in the deep white matter of the cerebellar hemispheres. (D) Axial T2-weighted FSE-IR image at a more superior
level demonstrating early hypointense myelination of the occipital subcortical U-fibers. There is low-signal myelin in the deep temporal white
matter; however, the subcortical white matter of the temporal lobes demonstrates persistent high signal.

images is important as this pulse sequence is frequently
encountered in clinical imaging.
At birth, areas of low T2 signal are noted in the deep white
matter of the occipital, frontal, and temporal lobes (►Figs. 1
and 7).5,9 As previously discussed, this is the result of a large
amount of free water in these regions with consequent FLAIR
signal suppression. By 1 month of age, this low FLAIR signal
will have converted to high signal in the occipital lobe. By
2 months of age, this same deep white matter signal conver-
sion will be complete in the frontal and temporal lobes
(►Figs. 2 and 7).9
On FLAIR imaging, familiar myelination landmarks gener-
ally lag behind conventional T2-weighted images, with the
posterior limb of the internal capsule and brachium pontis
first demonstrating low T2 signal !3 months.9 Low myelin-
related signal in the dorsal pons is not seen on FLAIR images
until !4 months of age,5 a site that appears myelinated at
birth on both T1- and T2-weighted images. Visualization of
myelin in the supratentorial motor and visual systems is
similarly delayed, with the perirolandic centrum semiovale
demonstrating myelin by !5 months and the optic radiations
demonstrating myelin by !6 months (►Fig. 3).5

Seminars in Neurology Vol. 32 No. 1/2012

 Assessment of Normal Myelination with Magnetic Resonance Imaging Welker, Patton 23

Downloaded by: Nationwide Childrens Hopsital. Copyrighted material.

Figure 5 An 18-month-old girl imaged at 1.5 Tesla field strength. (A) Axial T2-weighted fluid attenuation inversion recovery (FLAIR) image shows
early low-signal myelin in the subcortical white matter of the occipital lobes (arrows). (B) Coronal axial T2-weighted FLAIR image demonstrating
low-signal myelin in the deep white matter of the frontal lobes. (C) Axial T2-weighted fast spin echo inversion recovery (FSE-IR) image
demonstrates prominent subcortical white matter myelination posteriorly and significantly less subcortical myelination in the frontal lobes. (D)
Axial T2-weighted FSE-IR image demonstrates complete peripheral myelination in the cerebellum.

Of interest, there is minimal, if any, delay in myelin-related
signal changes in the corpus callosum with respect to T2-
weighted images. Authors describe callosal myelination to be
complete on FLAIR between 5 and 7 months,5,9 which mini-
mally lags behind reported callosal myelination on FSE T2-
weighted images.5 However, this FLAIR signal change may
slightly precede the time of callosal myelination as reported
by conventional spin echo T2-weighted images.25 Similarly,
the appearance of myelin in the anterior limb of the internal
capsule at 8 months on FLAIR imaging5,9 is contemporary
with similar signal changes reported on conventional spin
echo T2-weighted images, but apparently lags behind those
seen on FSE T2 pulse sequences.
In the second year, the deep white matter completes its
triphasic FLAIR signal progression by reverting again to low
signal as myelin matures (►Fig. 7). This occurs first in the deep
occipital white matter at 12 months (►Fig. 4), followed by the
deep frontal white matter at !14 months (►Fig. 5), and the
deep temporal white matter at !22 to 25 months (►Fig. 6).5,9
Low FLAIR signal in the peripheral white matter of the cerebral
hemipheres occurs later than the deep white matter changes at
each respective location. Subcortical low FLAIR signal is pres-
ent in the occipital lobes at 14 months and in the frontal lobes
at 20 months.5 On T2-weighted FLAIR sequences, white matter
in the subcortical U-fibers of the temporal lobes commonly
remains hyperintense beyond 24 months (►Fig. 6).9

Seminars in Neurology Vol. 32 No. 1/2012

24 Assessment of Normal Myelination with Magnetic Resonance Imaging Welker, Patton

Downloaded by: Nationwide Childrens Hopsital. Copyrighted material.

Figure 6 A 28-month-old boy imaged at 1.5 Tesla field strength. (A) Axial T2-weighted fluid attenuation inversion recovery (FLAIR) image
demonstrating near complete low signal white matter myelination with the exception of the anterior temporal poles. Persistent high signal in the
occipital lobes adjacent to the occipital horns of the lateral ventricles represents a normal FLAIR variant. (B) Axial T2-weighted FLAIR image
confirms complete low-signal myelination of the frontal and parietal lobes with terminal zones of high signal in the periatrial regions as a normal
variant. (C,D) Axial fast spin echo T2-weighted images demonstrate complete low-signal myelination throughout the brain with the exception of
the periatrial terminal zones.

Diffusion Tensor Imaging
In 2006, Hermoye and colleagues published an analysis of DTI
obtained from 30 infants and children ranging in age from 0 to
54 months using a 1.5-T MRI scanner.13 Their qualitative
analysis of the associated FA maps and color-encoded FA
directional maps provide guidelines for assessment of such
images in the clinical setting. The following is an abbreviated
summary of their findings.
In contrast to T1- and T2-weighted imaging, the majority of
the major white matter tracts in the brain are visible at birth on
FA maps. However, while the central portions of these tracts
demonstrate increased anisotropy, the peripheral portions of
these tracts have relatively low FA that is difficult to distinguish
from gray matter. Structures that are well seen at birth include
the superior and inferior cerebellar peduncles, as well as the
brachium pontis. In the brainstem, a composite dorsal tract
that includes the medial longitudinal fasciculus, medial lem-
niscus, and reticular formation is evident. Visible components
of the motor system include the corticospinal tracts, cerebral
peduncles, internal capsules, and corona radiata. Within the
limbic system, the cingulum and fornix are discernible. In
addition, several association tracts demonstrate increased
anisotropy, including the corpus callosum, anterior commis-
sure, and uncinate fascicules.13

Seminars in Neurology Vol. 32 No. 1/2012

 Assessment of Normal Myelination with Magnetic Resonance Imaging Welker, Patton 25

Figure 7 Triphasic evolution of myelin signal in the deep hemispheric white matter on T2-weighted fluid attenuation inversion recovery images.

Downloaded by: Nationwide Childrens Hopsital. Copyrighted material.

(A) In this 3-week-old boy, there is patchy low signal in the deep white matter due to high cerebrospinal fluid-like content with signal suppression.
(B) In this 4-month-old boy, deep white matter signal has converted to a uniformly hyperintense appearance. (C) In this 2½-year-old girl,
myelination has caused the deep white matter to again become hypointense with the exception of the periatrial terminal zones.

By the fourth month, the peripheral portions of the
previously demonstrated tracts demonstrate increasing an-
isotropy. Increased FA is also visible in subcortical U-fibers.
Newly visible white matter tracts include the inferior frontal
occipital fasciculus and the inferior longitudinal fasciculus.
The forceps minor and forceps major can now be identified.
However, the forceps major demonstrates an immature
inverted V shape at 4 months that will convert to an
inverted U shape by 6 months.13
At 1 year of age, the superior longitudinal fasciculus
becomes the last major white matter tract to become con-
spicuous. White matter landmarks unique to DTI, the so-
called crossing areas, demonstrate increased FA at this time
(►Fig. 8). The term “crossing areas” refers to the four white
matter locations where the forceps minor and forceps major
meet with the internal capsules along the lateral aspect of the
corpus callosum. Prior to 12 months, these are low anisotropy
structures.13
Beyond the first year, there is gradual, progressive increase
in FA as well as tract thickness throughout the brain. However,
unlike T1- and T2-weighted images that have a relatively
mature appearance by 2 years, color-encoded directional FA
maps do not achieve a mature appearance until about 4 years
of age.13 Despite the adult-like appearance of FA maps,
quantitative analysis demonstrates gradual increasing anisot-
ropy throughout the white matter throughout the first de-
cade of life.12
Normal Variants and Pitfalls
TERMINAL ZONES
A point of confusion that frequently arises in reviewing the
T2-weighted conventional images and T2-weighted FLAIR
images in the brains of children and young adults are the
presence of small, bilaterally symmetric foci of high signal
occurring in the white matter dorsolateral to the atria of the
lateral ventricles. These most commonly represent so-called
terminal zones of incompletely myelinated brain.25 These
small areas of signal hyperintensity are considered to be a
normal developmental variant and at times are even identi-
fiable in the young adult population.6 Although early histo-
pathologic studies have documented unmyelinated brain in
these regions, more recent literature has suggested that
prominent perivascular spaces may also be contributing to
this signal hyperintensity (►Fig. 9).7,38 When these periatrial
hyperintensities are seen in a young child, it is important to
differentiate normal terminal zones from pathologic periven-
tricular leukomalacia associated with prematurity. The two
conditions can be distinguished from each other by looking
for small bands of low signal, normally myelinated brain
separating the high signal regions from the ventricles.39 This
finding will be present with terminal zones of myelination,
but will be absent in periventricular leukomalacia where the
high signal intensity will commonly extend all the way to the
ventricular ependyma. Another helpful clue is that terminal
zones have a triangular appearance in the coronal plane with
the tip of the triangle oriented superiorly.6,39 Finally, peri-
ventricular leukomalacia typically occurs more inferolaterally
along the atria, near the optic radiations.7
In addition to the periventricular regions, persistent un-
myelinated areas of white matter are occasionally seen in the
anterior frontal lobes and anterior temporal lobes beyond
2 years of age.9,38 Consequently, when bilaterally symmetric
white matter T2 signal hyperintensities are identified in the
frontotemporal regions in young children, consideration
should be given to this developmental variant. Generally,
these sites of terminal myelination will convert to a normal
myelinated appearance by the age of 40 months.38

Seminars in Neurology Vol. 32 No. 1/2012

26 Assessment of Normal Myelination with Magnetic Resonance Imaging Welker, Patton

Downloaded by: Nationwide Childrens Hopsital. Copyrighted material.

Figure 8 Diffusion tensor imaging with 26 diffusion directions. Directionally encoded fractional anisotropy (FA) maps from four different aged
children: 9 months (A), 15 months (B), 2 years (C), and 3 years (D). Green indicates those white matter (WM) tracts oriented anterior to posterior.
Red indicates WM tracts oriented in a transverse direction. Blue indicates WM tracts oriented in the superoinferior direction. Notice increasing FA
in the so-called anterior crossing area between the genu of the corpus callosum and the anterior limb of the internal capsule (arrows) with age
progression as indicated by increasing color in this region. The thickness of corpus callosum is seen to gradually progress with age.

MYELINATION IN THE PRETERM INFANT
Frequently, brain imaging is performed on children that have
a history of premature birth, and the question arises as to
whether assessment of myelination should be based on the
child's birth age or an age adjusted to account for prematurity.
Although some authors advocate using the adjusted age,40,41
others argue that rapid acceleration of brain growth during
the first 2 postnatal months due to endogenous steroid
secretion eliminates the need for such an adjustment after
2 months of age.6 Finally, it should be noted that research has
been performed on normal myelination in fetuses and very
preterm infants.42,43 This literature can be used to guide
myelination assessment for infants imaged at less than
40 weeks gestational age.
Conclusion
In the young infant, brain myelination is a crucial component
of neurologic development that correlates with increasing
sensory, motor, and cognitive ability.31 Consequently, a direct-
ed evaluation of myelination should be conducted on each
pediatric brain MRI. Both supratentorial and infratentorial

Seminars in Neurology Vol. 32 No. 1/2012

 Assessment of Normal Myelination with Magnetic Resonance Imaging
Figure 9 Terminal zones of myelination in a 6-year-old girl. (A) Axial T2-weighted fluid attenuation inversion recovery image demonstrates
focally increased periatrial white matter signal (arrows) consistent with terminal zones of myelination. Notice the normal-appearing low-signal
white matter separating these zones from the ventricles. (B) T2-weighted image demonstrates small semilinear foci of cerebrospinal fluid signal
(arrows) in these same regions consistent with prominent perivascular spaces. These perivascular spaces may contribute to the appearance of
terminal myelination zones.
white matter should be scrutinized for signal changes of
myelination and compared against age-appropriate mile-
stones. At the present time, T1- and T2-weighted images
continue to provide the most important information regarding
cerebral myelination.7 T1-weighted images are most useful
during the first year. As T1-weighted images approach a mature
appearance, T2-weighted images become superior for contin-
ued surveillance of ongoing myelination. As our understanding
of the later stages of myelination increases, particularly beyond
the first two years of life, other techniques, such as FLAIR and
DTI, are gaining increasing clinical relevance. Additionally,
quantitative MRI techniques16,18 for evaluation of myelin
may become clinically useful in the near future. As knowledge
of normal myelination advances, our ability to both recognize
and address conditions of abnormal myelination is enhanced.
References
1 Brant-Zawadzki M, Enzmann DR. Using computed tomography of
the brain to correlate low white-matter attenuation with early
gestational age in neonates. Radiology 1981;139(1):105–108
2 Holland BA, Haas DK, Norman D, Brant-Zawadzki M, Newton TH.
MRI of normal brain maturation. AJNR Am J Neuroradiol 1986;7
(2):201–208
3 Hess CP, Barkovich AJ. Techniques and methods in pediatric
neuroimaging. In: Barkovich AJ, Raybaud C, eds. Pediatric
Neuroimaging. 5th ed. Philadelphia: Wolters Kluwer Health/Lip-
pincott Williams & Wilkins; 2011;1–19
4 Shaw DW, Weinberger E, Astley SJ, Tsuruda JS. Quantitative
comparison of conventional spin echo and fast spin echo during
brain myelination. J Comput Assist Tomogr 1997;21(6):867–871
5 Kizildağ B, Düşünceli E, Fitoz S, Erden I. The role of classic spin echo
and FLAIR sequences for the evaluation of myelination in MR
imaging. Diagn Interv Radiol 2005;11(3):130–136
Welker, Patton 27
Downloaded by: Nationwide Childrens Hopsital. Copyrighted material.
6 Ruggieri PM. Metabolic and neurodegenerative disorders and
disorders with abnormal myelination. In: Ball WS, ed. Pediatric
Neuroradiology. Philadelphia: Lippincott-Raven; 1997;175–237
7 Barkovich AJ, Mukherjee P. Normal development of the neonatal
and infant brain, skull, and spine. In: Barkovich AJ, Raybaud C, eds.
Pediatric Neuroimaging. 5th ed. Philadelphia: Wolters Kluwer
Health/Lippincott Williams & Wilkins; 2011;20–80
8 Ashikaga R, Araki Y, Ono Y, Nishimura Y, Ishida O. Appearance of
normal brain maturation on fluid-attenuated inversion-recovery
(FLAIR) MR images. AJNR Am J Neuroradiol 1999;20(3):427–431
9 Murakami JW, Weinberger E, Shaw DWW. Normal myelination of
the pediatric brain imaged with fluid-attenuated inversion-recov-
ery (FLAIR) MR imaging. AJNR Am J Neuroradiol 1999;20(8):
1406–1411
10 Jellison BJ, Field AS, Medow J, Lazar M, Salamat MS, Alexander AL.
Diffusion tensor imaging of cerebral white matter: a pictorial
review of physics, fiber tract anatomy, and tumor imaging pat-
terns. AJNR Am J Neuroradiol 2004;25(3):356–369
11 McGraw P, Liang L, Provenzale JM. Evaluation of normal age-
related changes in anisotropy during infancy and childhood as
shown by diffusion tensor imaging. AJR Am J Roentgenol 2002;179
(6):1515–1522
12 Mukherjee P, Miller JH, Shimony JS, et al. Diffusion-tensor MR
imaging of gray and white matter development during normal
human brain maturation. AJNR Am J Neuroradiol 2002;23
(9):1445–1456
13 Hermoye L, Saint-Martin C, Cosnard G, et al. Pediatric diffusion
tensor imaging: normal database and observation of the white
matter maturation in early childhood. Neuroimage 2006;29
(2):493–504
14 van Buchem MA, Steens SCA, Vrooman HA, et al. Global estimation
of myelination in the developing brain on the basis of magnetiza-
tion transfer imaging: a preliminary study. AJNR Am J Neuroradiol
2001;22(4):762–766
15 Rademacher J, Engelbrecht V, Bürgel U, Freund H, Zilles K. Mea-
suring in vivo myelination of human white matter fiber tracts
with magnetization transfer MR. Neuroimage 1999;9(4):
393–406
Seminars in Neurology Vol. 32 No. 1/2012
28 Assessment of Normal Myelination with Magnetic Resonance Imaging
16 Ding X-Q, Kucinski T, Wittkugel O, et al. Normal brain maturation
characterized with age-related T2 relaxation times: an attempt to
develop a quantitative imaging measure for clinical use. Invest
Radiol 2004;39(12):740–746
17 Hagmann P, Sporns O, Madan N, et al. White matter maturation
reshapes structural connectivity in the late developing human
brain. Proc Natl Acad Sci U S A 2010;107(44):19067–19072
18 Deoni SC, Mercure E, Blasi A, et al. Mapping infant brain myelina-
tion with magnetic resonance imaging. J Neurosci 2011;31
(2):784–791
19 Koenig SH, Brown RD III, Spiller M, Lundbom N. Relaxometry of
brain: why white matter appears bright in MRI. Magn Reson Med
1990;14(3):482–495
20 Kucharczyk W, Macdonald PM, Stanisz GJ, Henkelman RM. Relax-
ivity and magnetization transfer of white matter lipids at MR
imaging: importance of cerebrosides and pH. Radiology 1994;192
(2):521–529
21 Barkovich AJ. Concepts of myelin and myelination in neuroradiol-
ogy. AJNR Am J Neuroradiol 2000;21(6):1099–1109
22 Dietrich RB, Bradley WG, Zaragoza EJ IV, et al. MR evaluation of
early myelination patterns in normal and developmentally de-
layed infants. AJR Am J Roentgenol 1988;150(4):889–896
23 Barkovich AJ, Lyon G, Evrard P. Formation, maturation, and dis-
orders of white matter. AJNR Am J Neuroradiol 1992;13(2):
447–461
24 Svennerholm L, Vanier MT. Lipid and fatty acid composition of
human cerebral myelin during development. Adv Exp Med Biol
1978;100:27–41
25 Barkovich AJ, Kjos BO, Jackson DE Jr, Norman D. Normal maturation
of the neonatal and infant brain: MR imaging at 1.5 T. Radiology
1988;166(1 Pt 1):173–180
26 Martin E, Kikinis R, Zuerrer M, et al. Developmental stages of
human brain: an MR study. J Comput Assist Tomogr 1988;12
(6):917–922
27 Girard N, Raybaud C, du Lac P. MRI study of brain myelination. J
Neuroradiol 1991;18(4):291–307
28 Hüppi PS, Dubois J. Diffusion tensor imaging of brain development.
Semin Fetal Neonatal Med 2006;11(6):489–497
29 Wimberger DM, Roberts TP, Barkovich AJ, Prayer LM, Moseley ME,
Kucharczyk J. Identification of “premyelination” by diffusion-
weighted MRI. J Comput Assist Tomogr 1995;19(1):28–33
Seminars in Neurology Vol. 32 No. 1/2012
Welker, Patton
30 Mukherjee P, Miller JH, Shimony JS, et al. Normal brain maturation
during childhood: developmental trends characterized with dif-
fusion-tensor MR imaging. Radiology 2001;221(2):349–358
31 van der Knaap MS, Valk J, Bakker CJ, et al. Myelination as an
expression of the functional maturity of the brain. Dev Med Child
Neurol 1991;33(10):849–857
32 Pujol J, Soriano-Mas C, Ortiz H, Sebastián-Gallés N, Losilla JM, Deus
J. Myelination of language-related areas in the developing brain.
Neurology 2006;66(3):339–343
33 Brody BA, Kinney HC, Kloman AS, Gilles FH. Sequence of central
nervous system myelination in human infancy. I. An autopsy study
of myelination. J Neuropathol Exp Neurol 1987;46(3):283–301
34 Kinney HC, Brody BA, Kloman AS, Gilles FH. Sequence of central
nervous system myelination in human infancy. II. Patterns of
myelination in autopsied infants. J Neuropathol Exp Neurol
1988;47(3):217–234
35 van der Knaap MS, Valk J, Barkhof F. Magnetic resonance of
myelination and myelin disorders. 3rd ed. Berlin, New York:
Springer; 2005:12
36 Girard N, Gouny SC, Viola A, et al. Assessment of normal fetal brain
maturation in utero by proton magnetic resonance spectroscopy.
Magn Reson Med 2006;56(4):768–775
Downloaded by: Nationwide Childrens Hopsital. Copyrighted material.
37 Girard N, Confort-Gouny S, Schneider J, et al. MR imaging of brain
maturation. J Neuroradiol 2007;34(5):290–310
38 Parazzini C, Baldoli C, Scotti G, Triulzi F. Terminal zones of
myelination: MR evaluation of children aged 20-40 months.
AJNR Am J Neuroradiol 2002;23(10):1669–1673
39 Baker LL, Stevenson DK, Enzmann DR. End-stage periventricular
leukomalacia: MR evaluation. Radiology 1988;168(3):809–815
40 Skranes JS, Nilsen G, Smevik O, Vik T, Rinck P, Brubakk AM. Cerebral
magnetic resonance imaging (MRI) of very low birth weight
infants at one year of corrected age. Pediatr Radiol 1992;22
(6):406–409
41 Valk J, van der Knaap MS. Magnetic resonance of myelin, myeli-
nation, and myelin disorders. Berlin, New York: Springer-Verlag;
1989:34
42 Counsell SJ, Maalouf EF, Fletcher AM, et al. MR imaging assessment
of myelination in the very preterm brain. AJNR Am J Neuroradiol
2002;23(5):872–881
43 Girard N, Raybaud C, Poncet M. In vivo MR study of brain maturation
in normal fetuses. AJNR Am J Neuroradiol 1995;16(2):407–413