assessment of normal myelination with magnetic resonance ... · assessment of normal myelination...

Assessment of Normal Myelination withMagnetic Resonance ImagingKirk M. Welker, M.D. 1 Alice Patton, M.D. 1

1Division of Neuroradiology, Department of Radiology, Mayo Clinic,Rochester, Minnesota

Semin Neurol 2012;32:15–28.

Address for correspondence and reprint requests Kirk M. Welker,M.D., Division of Neuroradiology, Department of Radiology, MayoClinic, 200 First Street SW, Rochester, MN 55905 (e-mail: [email protected]).

Magnetic resonance imaging (MRI) has revolutionized ourability to evaluate myelination in young children. Until theadvent of cross-sectional imaging, the in vivo status of myelindevelopment could only be evaluated through clinical history,neurologic exam, or by histology. By the early 1980s, com-puted tomography allowed gross assessment of myelinationthrough its depiction of white matter density in the pediatricbrain.1 However, it was not until the introduction of clinicalMRI in the late 1980s that regional or tract-specific myelinmaturation could be visualized.2Myelin assessment has sinceevolved to become a routine aspect of pediatric neuroimag-ing. By reviewing a combination of T1- and T2-weighted MRIseries, radiologists and clinicians can quickly and reliablydetermine whether a child's myelin development is normal,delayed, or abnormal. This capability has greatly enhancedour ability to detect childhood leukoencephalopathies andother disorders of myelin at younger ages, with the attendantbenefit 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 thisprocess. To that end, the MRI techniques that have evolvedfor 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 myelindevelopment. Finally, we conclude with a brief review ofnormal variants and imaging pitfalls.

MR Pulse Sequences

The core MRI techniques for myelin assessment in the infantare T1- and T2-weighted pulse sequences. These two forms ofMRI contrast are complimentary in that T1-weighting pro-vides information regarding the early stages of myelination,whereas T2-weighting provides insight into later stages ofmyelin 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 to600 milliseconds and an echo time (TE) of less than 20

Keywords

► myelination► development► brain► white matter► infants► magnetic resonance

imaging

Abstract White matter myelination is essential to postnatal neurologic maturation and can beaccurately evaluated by magnetic resonance imaging (MRI). Accordingly, MRI pulsesequences should be optimized for detection of myelin in young children. T1-weightedimages are most useful during the first year of life. These demonstrate myelin-relatedwhite matter hyperintensity consequent to increasing cholesterol and galactocerebro-side within myelin membranes. T2-weighted images are most useful in later stages ofmyelination, during which time elaboration of myelin leads to reduction in brain watercontent with associated T2 hypointensity. Additional information regarding the statusof myelination can be obtained from T2-weighted fluid attenuation inversion recovery(FLAIR) and diffusion tensor imaging (DTI) pulse sequences. Clinically useful milestonesfor assessment of myelination across all these MRI pulse sequences are available asguidelines to image interpretation. Evaluation ofmyelination status using a combinationof T1- and T2-weighted images should be routine in the interpretation of all pediatricbrain MRI exams.

Issue Theme InheritedLeukoencephalopathies; Guest Editor,Deborah L. Renaud, M.D.

Copyright © 2012 by Thieme MedicalPublishers, Inc., 333 Seventh Avenue,New York, NY 10001, USA.Tel: +1(212) 584-4662.

DOI http://dx.doi.org/10.1055/s-0032-1306382.ISSN 0271-8235.

15

Dow

nloa

ded

by: N

atio

nwid

e C

hild

rens

Hop

sita

l. C

opyr

ight

ed m

ater

ial.

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 asa means of improving T1 contrast. Typical 3.0-T T1-weightedFLAIR scan parameters include TR ¼ 2950 milliseconds, TE¼ full minimum, inversion time (TI) ¼ 890 milliseconds. Analternate means of obtaining excellent T1 contrast at 3.0-Tfield 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). Commonscan parameters would include TR ¼ 6.4 milliseconds, TE ¼full minimum, TI ¼ 900 milliseconds, flip angle ¼ 8 degrees.

T2-weighted images can be acquired using conventionalspin echo or fast spin echo (FSE) techniques. However, onemust understand that FSE T2 images demonstrate myelinmaturation at a slightly earlier age than conventional spinecho images due to increased magnetization transfer ef-fects.4,5 In comparison to similar scans in adults, a higherT2-weighting is applied when scanning the brains of infantsto 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 133milliseconds.

Although T2-weighted FLAIR images are among the mostcommonly used pulse sequences in contemporary MRI of thebrain, the white matter contrast created by these images hastraditionally been considered substandard for myelin stag-ing.7However, T2-weighted FLAIR images demonstrate signalchanges related to the completion of myelin maturation aftermyelin has already reached its adult appearance on T1- andT2-weighted images.5,8,9 Consequently, this pulse sequencemay be of use in assessing the final stages of myelination invarious regions of the brain. We employ the following T2-weighted FLAIR imaging parameters at both 1.5- and 3.0-Tfield strength: TR¼ 11000, TE ¼ 147 milliseconds, and TI¼ 2250 milliseconds.

A recently developed tool in the armamentarium formyelin evaluation is diffusion tensor imaging (DTI). Thistechnique uses echo planar pulse sequences to exploit theanisotropic diffusion of water molecules in cerebral tissueand create images that reflect increasing axonal organizationin the brain. As areas in the brain with increased axonalorganization differentially restrict the movement of watermolecules perpendicular to the axon bundles, the fractionalanisotropy (FA) of water can be used as a surrogate measurefor white matter organization.10 Several studies have docu-mented the relationship between FA and myelin maturity ininfants.11–13 In particular, FA values have been useful forassessing the maturation of functional neuronal networksin the brain.13 Pediatric diffusion tensor imaging may besuccessfully obtained using the following parameters on a 3-Tscanner: echo planar SE pulse sequence, 26 diffusion direc-tions, TR ¼ 8000 milliseconds, TE ¼ minimum b-value¼ 1000 sec/mm2. For the purposes of myelin assessment,raw DTI images can be postprocessed into grayscale FA maps

or three-color directionally encoded FA maps where the red,green, or blue color corresponds to the principle axis ofanisotropy.

Other advanced MRI techniques have been applied togauging myelin maturation. These include magnetizationtransfer,14,15 quantitative T2measurement,16 functional con-nectivitymapping,17 andmultiparametric mapping of myelinwater fraction.18 Although none of these methods has yetseen widespread clinical use, they may provide importantfuture contributions to clinical assessment of myelindevelopment.

Finally, it should be stated that appropriate selection ofMRI planes can improve one's ability to appreciate age-related changes in myelination.6 As myelination is mostlycentered in the brainstem in neonates, the sagittal plane isparticularly useful in that group. During the intermediatestages of myelination, the axial plane is preferred due to itsability to demonstrate major tracts within the brain, such asthe corticospinal tracts and optic radiations with bilateralsymmetry. In the terminal stages of myelination, coronalimages are useful for clear depiction of subcortical U-fibersin the frontal lobes.

General Signal Patterns in BrainMyelination

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 signalcharacteristics and neuroanatomic distribution. An understand-ingof these patterns is critical to image interpretation, both fromthe standpoint of confirming normal development and foridentifying 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 tocortex on T2-weighted images. In the unmyelinated portionsof the neonatal brain, this pattern is reversed with the whitematter demonstrating T1 hypointensity and T2 hyperinten-sity relative to cortex. The first of the MR signal changes tooccur during myelination is an increase in white matter T1signal. This alteration of T1 signal is believed to be due toincreasing cholesterol19 and galactocerebroside20 within thecell membranes of the oligodendrocyte myelin processes. It isthought that these molecules create T1 shortening throughtheir interaction with adjacent free water with associatedmagnetization transfer effects.21

Unlike the previously described T1 signal change, T2 signalalteration during myelination is not solely contingent uponspecific biochemical changes in the composition of myelin.Rather, growing T2 hypointensity during myelination islargely consequent to generalized reduction in free watercontent in maturing white matter.2,22 As myelin sheaths areelaborated by oligodendrocytes and packed into tight spiralsaround axons, the increasing volume of myelin simply re-placeswater in the interstitial space.6,23Additionally, increas-ing length of hydrocarbon chains in the myelin membranesalong with increasing numbers of hydrocarbon double

Seminars in Neurology Vol. 32 No. 1/2012

Assessment of Normal Myelination with Magnetic Resonance Imaging Welker, Patton16

Dow

nloa

ded

by: N

atio

nwid

e C

hild

rens

Hop

sita

l. C

opyr

ight

ed m

ater

ial.

bonds24 contributes to a decrease in T2 times due to resultantincreasing hydrophobic properties of the myelin mem-branes.25 Such T2 changes occur days to months after whitematter has become hyperintense on the complimentary T1-weighted images26 and thus coincide with a later stage inmyelin development. Consequently, although T1-weightedimages provide the most useful information in the earlier

stages ofmyelination, T2-weighted images are superior in thelater stages of the process.

Of the standard MR pulse sequences, T2-weighted FLAIRimages demonstrate the most complex signal changes inresponse to myelination. In general, these images behave asconventional T2-weighted images, with the exception thatthe conversion from high T2 signal to low T2 signal generally

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 "Dorsal pons "Brachium pontis "I/S CBL peduncles "Midbrain "VL Thalamus"Posterior limb IC"Perirolandic centrumsemiovale and gyri"Optic nerves, tracts,and radiations"

Medulla ↓Dorsal pons ↓Midbrain ↓Perirolandic gyri↓I/S CBL peduncles↓VL Thalamus ↓

Deep occipital WM ↓Deep frontal WM ↓Deep temporal WM ↓

Central WM tracts"Peripheral WM ↓All CBL peduncles"ML and MLF"Corticospinal tracts"Cerebral peduncles"IC and corona radiata"Cingulum", Fornix "Corpus callosum"Anterior commissure ",UF"

2 Deep cerebellar WM"Anterior limb IC"

Brachium pontis ↓Posterior limb IC ↓Perirolandic centrumsemiovale ↓Optic tracts↓

Deep occipital WM "Deep frontal WM "Deep temporal WM "

FA in peripheral whitematter dramaticallyincreasing

4 Entire cerebellum"CC (splenium) "

Optic radiations↓Calcarine fissure ↓

Dorsal pons ↓Brachium pontis ↓Posterior limb IC ↓

Peripheral WM "IFOF "ILF "Subcortical U-fibers"Forceps minor "Forceps major "(inverted V shape)

6 CC (entire) " CC (splenium) ↓Ventral pons ↓

Optic radiations ↓Perirolandic centrumsemiovale↓CC (entire) ↓

Increasing definitionof forceps major andforceps minor

8 Subcortical U-fibersoccipital "

Anterior limb IC ↓CC (entire) ↓

Anterior limb IC ↓ Forceps majorobtaining invertedU shape

12 Subcortical U-fibersfrontal and temporal"Brain achieves adultappearance on T1.

Deep WM cerebellum↓Early occipital subcorticalU-fibers ↓Temporal central WM↓

Deep occipital WM ↓ SLF"Fiber crossing areas "

18 Minimal change Subcortical U-fibersoccipital poles↓Entire posterior fossa↓

Deep frontal WM ↓Subcortical occipitalWM ↓

Increasing FA andtract thicknessthroughout brain

24 Minimal change Subcortical U-fibers frontaland temporal poles↓

Deep temporal WM ↓Subcortical frontal WM↓

Increasing FA andtract thicknessthroughout brain

Other T1 provides littleinformation after 1st yearof life.

Periatrial terminal zonesmay remain hyperintenseinto 2nd decade.

Subcortical U-fibers intemporal poles remainhyperintense after24 months.

FA color mapsachieve adultappearance by48 months.

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


Assessment of Normal Myelination with Magnetic Resonance Imaging Welker, Patton 17

Dow

nloa

ded

by: N

atio

nwid

e C

hild

rens

Hop

sita

l. C

opyr

ight

ed m

ater

ial.

lags behind standard T2-weighted sequences.5,9 This delay isfelt to be secondary to partial T1-weighting within the FLAIRpulse sequence8 that partially mitigates the T2 effects. How-ever, unlike the remainder of the brain, the deep hemisphericcerebral white matter demonstrates an unusual triphasicpatternonT2-weighted FLAIR sequences.9Thispattern consistsof initial neonatal deep white matter hypointensity, followedby gradual signal conversion to hyperintensity. This is eventu-ally followed by reversion to a hypointense appearance duringthe final stages of myelin development. It is believed that theinitial hypointense phase of this FLAIR signal sequence is theresult of exceptionally prominent free water in the deepcerebral white matter during the early neonatal period.27

This water lowers the T1 signal to the point that white mattersignal is selectively suppressed by the T2 FLAIR pulse sequencein a manner similar to that seen with cerebrospinal fluid.9 Asthe white matter matures, free water decreases, raising theassociated T1 signal to the point that the FLAIR signal suppres-sion is lost, resulting in T2 hyperintense white matter.5,9

Finally, asmyelin undergoes further maturation, the freewaterconcentration further declines consequent to increasing vol-umes of hydrophobic myelin. Eventually, this free water lossleads to the third and final phase of signal change in the deephemispheric white matter, namely renewed T2 hypointensity.Despite occurring at a later time point, this final phase isentirely 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 morerecently 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 forincreasing white matter organization. However, even moreinteresting is the fact that FA values in the developing infantbrain increase in two different distinct phases.28 The first FArise actually precedes myelination. Consequently, authorshave suggested that this may be related to a premyelinationstate.29 The increase in anisotropy during this early phase isthought to be caused by elaboration of microtubule proteinsin the axonal cytoskeleton, increasing axon caliber, increasingactivity of sodium ion channels, and proliferation of oligo-dendrocytes as precursors to myelination.12,21,28,29 The sec-ond phase of FA growth coincideswith increasing elaborationof myelin28 and reduction in the size of the extracellularspace.21Myelinated axons restrict nonparallelwater diffusionleading to a local increase in FA values. Of note, this gradualrise in anisotropy continues beyond the second year of life,30

suggesting that FA values may eventually provide insight intothe subtle changes in brain maturation that occur betweenthe second year of life and adulthood.

General Anatomic Patterns in BrainMyelination

Myelination of the brain closely parallels pediatric neurologicfunctional maturity as measured through neurodevelopmen-tal testing.31 Hence, anatomic brain regions responsible forprimitive functions myelinate earlier than anatomic sites

corresponding to phylogenetically advanced function.32 Ad-ditionally, autopsy studies in infants have confirmed severalgeneral neuroanatomic rules regarding myelination.33,34

First, visual and auditory sensory regions myelinate, on thewhole, faster than motor regions. Second, the proximalportions of a neuroanatomic subsystem myelinate soonerthan the more distal components. For example, the optictracts myelinate before the optic radiations. These proximalelements of a functional neuroanatomic unit alsomyelinate ata faster rate than their more distal counterparts.34 Third,projection tracts within the brain generally myelinate earlierthan association tracts. Finally, the telencephalon beginsmyelination about the central sulcus region. Myelinationthen concurrently extends peripherally toward the variouspoles 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 intosimplified anatomic axioms of myelination: (1) myelinationproceeds from caudal to rostral; (2) myelination proceedsfrom posterior to anterior regions; and (3) myelinationproceeds from central to peripheral locations.5,8,26,35 Al-though these general rules provide a useful construct forthe practical review of pediatric MRI scans, one shouldunderstand that they are not inviolate. Important exceptionsdo exist within the normal developmental process.35 Forexample, the fact that the frontal poles myelinate beforethe temporal poles violates the posterior to anterior rule.Similarly, the more rostrally located perirolandic cortexmyelinates before the more caudally located internal capsuleanterior limb. The existence of such exceptions requires thatassessment of myelin be based on careful evaluation ofspecific neuroanatomic landmarks rather than a simple ge-stalt of the overall myelination pattern.

Contrast Specific Temporal Sequences ofMyelination

►Table 1 is a composite outline of normal myelinationchronology during the first 2 years of life as described bymultiple authors.5,6,9,13,25,36 This table presents the expectedappearance of T1- and T2-weighted MRI, T2-weighted FLAIR,and DTI images at specific time points during infancy. There issome inconsistency between authors regarding the timing ofsomemilestones of myelin maturation. This likely exists basedon variations in scan technique and image interpretationcriteria. Regarding this variability, ►Table 1 provides a rela-tively conservative reference in the sense that most authorsagree that myelination of the specific white matter structureshould be complete by the ages referenced in the table. Clinicalconfidence in myelin assessment is increased by employingmultipleMRI contrasts.►Figures 1 through 6 illustrate severalsignificant age-related myelination milestones in developingbrains. These will be revisited in the following discussion ofcontrast-specific myelination patterns.

T1-Weighted ImagesFrom birth through 12 months, T1-weighted images providean excellent window into myelin development. In the



Dow

nloa

ded

by: N

atio

nwid

e C

hild

rens

Hop

sita

l. C

opyr

ight

ed m

ater

ial.

newborn, there is extensive brainstem myelination (►Fig. 1).Myelin-associated T1 signal hyperintensity is noted in themedulla, dorsal pons, brachium pontis, and both the inferiorand superior cerebellar peduncles.5,25,37 More superiorly, my-elinatedwhitematter is visible in the cerebral peduncles of themidbrain, the ventral lateral thalami, and theposterior limbs ofthe internal capsules. Additional T1 hyperintense myelin canbe identified in the corticospinal tracts extending superiorly inthe perirolandic centrum semiovale.5 The cortex along thecentral sulci is similarly T1 hyperintense. In the visual path-ways, myelin is seen in the optic nerves, optic tracts, and opticradiations.25

By 2 to 3months of age,myelination in the internal capsulehas extended to involve the anterior limb (►Fig. 2).25 Be-tween 2 and 3 months of age, T1 hyperintense myelinprogresses peripherally from the deep cerebellar white mat-ter to involve the entire cerebellum.6,25 At 4 months, thesplenium of the corpus callosum has myelinated. Callosalmyelination proceeds in an anterior to posterior direction toinvolve the genu by 6 months of age (►Fig. 3).6

Outside the central sulcus region, initiation of myelinationin the subcortical white matter begins at �3 months of age.7

Progression of T1 hyperintensity in the supratentorial whitematter evolves peripherally from the perirolandic region to

Figure 1 A newborn boy imaged at 1.5 Tesla field strength. (A) Sagittal T1-weighted image demonstrating high-signal myelin within the dorsalmedulla, 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 internalcapsules and the superior cerebellar peduncles. (C) Axial T2-weighted fast spin echo inversion recovery image demonstrating low signal myelin inthe bilateral ventral lateral thalami. (D) Axial T2-weighted fluid attenuation inversion recovery image demonstrates patchy low signal in the deepfrontal and parietal white matter due to high water content with signal suppression.



Dow

nloa

ded

by: N

atio

nwid

e C

hild

rens

Hop

sita

l. C

opyr

ight

ed m

ater

ial.

involve the subcortical U-fibers in the occipital pole by7 months of age.5,6,25 On the other hand, T1 hyperintensityin the frontal and temporal lobes proceeds more slowly anddoes not reach the most anterior subcortical U-fibers in theselobes until �1 year (►Fig. 4).5,25 Despite the fact that there isstill active, ongoing cerebral myelination, the brain at thisstage has achieved a typical adult T1 contrast pattern. Conse-quently, T1-weighted images are of little use for myelinassessment beyond the first year.

T2-Weighted ImagesIn the newborn, myelination, as demonstrated by low T2signal, is anatomically less extensive than the signal changes

contemporaneously demonstrated by T1 images. Sites ofmyelination include the medulla, dorsal pons, superior andinferior cerebellar peduncles, midbrain, and ventral lateralthalamus (►Fig. 1).25,37 The cortex surrounding the centralsulcus also demonstrates low signal at the time of birth orshortly thereafter.37 By 2 months, low T2-signal myelin hasextended to involve thebrachiumpontis, posterior limb of theinternal capsule, and the perirolandic component of thecentrum 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 opticradiations and subcortical white matter about the calcarinefissure by 4 months of age.25

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



Dow

nloa

ded

by: N

atio

nwid

e C

hild

rens

Hop

sita

l. C

opyr

ight

ed m

ater

ial.

T2-signal changes in the corpus callosum lag 1 to 2monthsbehind the T1-signal changes at this site.7 Notably, at6 months, while the entire corpus callosum is hyperintenseon T1, the T2-signal changes are just beginning in thesplenium (►Fig. 3). The genu of the corpus callosum willnot demonstrate T2 hypointensity until 8 months.25 Concur-rent with these callosal signal changes, the anterior limb ofthe internal capsule achieves T2 hypointensity by 8 months.6

Within the posterior fossa, the ventral pons demonstratesT2 hypointense myelin by 6 months and the deep cerebellarwhite matter becomes hypointense by 12 months (►Fig. 4).6

The entire posterior fossa white matter is T2 hypointense by18 months.6,7

With respect to the hemispheric white matter, signalchanges commence in the central occipital white matter by7months, with progressive involvement of the central frontal

white matter by 11 months and the central temporal whitematter 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 occipitallobes around the 1-year mark. Occipital subcortical whitematter signal changes should be complete by 15 months(►Fig. 5).7 However, the anterior aspect of the frontal andtemporal lobes will not achieve a similar state of myelinationuntil around 24 months (►Fig. 6).5–7

T2-Weighted FLAIR ImagesAssessing myelination on the basis of T2-weighted FLAIRimaging is controversial with some authors advocating thispulse sequence,5,8 and other authors considering it to be ofminimal utility.3 Regardless of one's opinion on the matter,familiarity with the appearance of myelination on FLAIR

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



Dow

nloa

ded

by: N

atio

nwid

e C

hild

rens

Hop

sita

l. C

opyr

ight

ed m

ater

ial.

images is important as this pulse sequence is frequentlyencountered in clinical imaging.

At birth, areas of low T2 signal are noted in the deepwhitematter of the occipital, frontal, and temporal lobes (►Figs. 1

and 7).5,9 As previously discussed, this is the result of a largeamount of free water in these regions with consequent FLAIRsignal suppression. By 1 month of age, this low FLAIR signalwill have converted to high signal in the occipital lobe. By2 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 theposterior limb of the internal capsule and brachium pontisfirst demonstrating low T2 signal �3 months.9 Low myelin-related signal in the dorsal pons is not seen on FLAIR imagesuntil �4 months of age,5 a site that appears myelinated atbirth on both T1- and T2-weighted images. Visualization ofmyelin in the supratentorial motor and visual systems issimilarly delayed, with the perirolandic centrum semiovaledemonstratingmyelin by�5months and the optic radiationsdemonstrating myelin by �6 months (►Fig. 3).5

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



Dow

nloa

ded

by: N

atio

nwid

e C

hild

rens

Hop

sita

l. C

opyr

ight

ed m

ater

ial.

Of interest, there is minimal, if any, delay inmyelin-relatedsignal changes in the corpus callosum with respect to T2-weighted images. Authors describe callosal myelination to becomplete 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 mayslightly precede the time of callosal myelination as reportedby conventional spin echo T2-weighted images.25 Similarly,the appearance of myelin in the anterior limb of the internalcapsule at 8 months on FLAIR imaging5,9 is contemporarywith similar signal changes reported on conventional spinecho T2-weighted images, but apparently lags behind thoseseen on FSE T2 pulse sequences.

In the second year, the deep white matter completes itstriphasic FLAIR signal progression by reverting again to lowsignal asmyelinmatures (►Fig. 7). This occurs first in the deepoccipital white matter at 12 months (►Fig. 4), followed by thedeep frontal white matter at �14 months (►Fig. 5), and thedeep temporal white matter at �22 to 25 months (►Fig. 6).5,9

Low FLAIR signal in the peripheralwhitematter of the cerebralhemipheres occurs later than thedeepwhitematter changes ateach respective location. Subcortical low FLAIR signal is pres-ent in the occipital lobes at 14 months and in the frontal lobesat 20months.5OnT2-weighted FLAIR sequences, whitematterin the subcortical U-fibers of the temporal lobes commonlyremains hyperintense beyond 24 months (►Fig. 6).9

Figure 5 An 18-month-old girl imaged at 1.5 Tesla field strength. (A) Axial T2-weighted fluid attenuation inversion recovery (FLAIR) image showsearly low-signal myelin in the subcortical white matter of the occipital lobes (arrows). (B) Coronal axial T2-weighted FLAIR image demonstratinglow-signal myelin in the deep white matter of the frontal lobes. (C) Axial T2-weighted fast spin echo inversion recovery (FSE-IR) imagedemonstrates 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.



Dow

nloa

ded

by: N

atio

nwid

e C

hild

rens

Hop

sita

l. C

opyr

ight

ed m

ater

ial.

Diffusion Tensor ImagingIn 2006, Hermoye and colleagues published an analysis of DTIobtained from30 infants and children ranging in age from0 to54 months using a 1.5-T MRI scanner.13 Their qualitativeanalysis of the associated FA maps and color-encoded FAdirectional maps provide guidelines for assessment of suchimages in the clinical setting. The following is an abbreviatedsummary of their findings.

In contrast toT1- and T2-weighted imaging, themajority ofthemajorwhitematter tracts in thebrain arevisible at birth onFA maps. However, while the central portions of these tractsdemonstrate increased anisotropy, the peripheral portions of

these tracts have relatively lowFA that is difficult to distinguishfrom graymatter. Structures that arewell seen at birth includethe superior and inferior cerebellar peduncles, as well as thebrachium pontis. In the brainstem, a composite dorsal tractthat includes the medial longitudinal fasciculus, medial lem-niscus, and reticular formation is evident. Visible componentsof the motor system include the corticospinal tracts, cerebralpeduncles, internal capsules, and corona radiata. Within thelimbic system, the cingulum and fornix are discernible. Inaddition, several association tracts demonstrate increasedanisotropy, including the corpus callosum, anterior commis-sure, and uncinate fascicules.13

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



Dow

nloa

ded

by: N

atio

nwid

e C

hild

rens

Hop

sita

l. C

opyr

ight

ed m

ater

ial.

By the fourth month, the peripheral portions of thepreviously demonstrated tracts demonstrate increasing an-isotropy. Increased FA is also visible in subcortical U-fibers.Newly visible white matter tracts include the inferior frontaloccipital fasciculus and the inferior longitudinal fasciculus.The forceps minor and forceps major can now be identified.However, the forceps major demonstrates an immatureinverted V shape at 4 months that will convert to aninverted U shape by 6 months.13

At 1 year of age, the superior longitudinal fasciculusbecomes 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 whitematter locations where the forceps minor and forceps majormeet with the internal capsules along the lateral aspect of thecorpus callosum. Prior to 12months, these are low anisotropystructures.13

Beyond thefirst year, there is gradual, progressive increasein FA aswell as tract thickness throughout thebrain. However,unlike T1- and T2-weighted images that have a relativelymature appearance by 2 years, color-encoded directional FAmaps do not achieve a mature appearance until about 4 yearsof 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 ZONESA point of confusion that frequently arises in reviewing theT2-weighted conventional images and T2-weighted FLAIRimages in the brains of children and young adults are the

presence of small, bilaterally symmetric foci of high signaloccurring in the white matter dorsolateral to the atria of thelateral ventricles. These most commonly represent so-calledterminal zones of incompletely myelinated brain.25 Thesesmall areas of signal hyperintensity are considered to be anormal developmental variant and at times are even identi-fiable in the young adult population.6 Although early histo-pathologic studies have documented unmyelinated brain inthese regions, more recent literature has suggested thatprominent perivascular spaces may also be contributing tothis signal hyperintensity (►Fig. 9).7,38When these periatrialhyperintensities are seen in a young child, it is important todifferentiate normal terminal zones from pathologic periven-tricular leukomalacia associated with prematurity. The twoconditions can be distinguished from each other by lookingfor small bands of low signal, normally myelinated brainseparating the high signal regions from the ventricles.39 Thisfinding will be present with terminal zones of myelination,but will be absent in periventricular leukomalacia where thehigh signal intensity will commonly extend all the way to theventricular ependyma. Another helpful clue is that terminalzones have a triangular appearance in the coronal plane withthe tip of the triangle oriented superiorly.6,39 Finally, peri-ventricular leukomalacia typically occursmore inferolaterallyalong the atria, near the optic radiations.7

In addition to the periventricular regions, persistent un-myelinated areas of white matter are occasionally seen in theanterior frontal lobes and anterior temporal lobes beyond2 years of age.9,38 Consequently, when bilaterally symmetricwhite matter T2 signal hyperintensities are identified in thefrontotemporal regions in young children, considerationshould be given to this developmental variant. Generally,these sites of terminal myelination will convert to a normalmyelinated appearance by the age of 40 months.38

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



Dow

nloa

ded

by: N

atio

nwid

e C

hild

rens

Hop

sita

l. C

opyr

ight

ed m

ater

ial.

MYELINATION IN THE PRETERM INFANTFrequently, brain imaging is performed on children that havea history of premature birth, and the question arises as towhether assessment of myelination should be based on thechild'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 duringthe first 2 postnatal months due to endogenous steroidsecretion eliminates the need for such an adjustment after2 months of age.6 Finally, it should be noted that research hasbeen performed on normal myelination in fetuses and very

preterm infants.42,43 This literature can be used to guidemyelination assessment for infants imaged at less than40 weeks gestational age.

Conclusion

In the young infant, brain myelination is a crucial componentof neurologic development that correlates with increasingsensory, motor, and cognitive ability.31 Consequently, a direct-ed evaluation of myelination should be conducted on eachpediatric brain MRI. Both supratentorial and infratentorial

Figure 8 Diffusion tensor imaging with 26 diffusion directions. Directionally encoded fractional anisotropy (FA) maps from four different agedchildren: 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 FAin the so-called anterior crossing area between the genu of the corpus callosum and the anterior limb of the internal capsule (arrows) with ageprogression as indicated by increasing color in this region. The thickness of corpus callosum is seen to gradually progress with age.



Dow

nloa

ded

by: N

atio

nwid

e C

hild

rens

Hop

sita

l. C

opyr

ight

ed m

ater

ial.

white matter should be scrutinized for signal changes ofmyelination and compared against age-appropriate mile-stones. At the present time, T1- and T2-weighted imagescontinue to provide themost important information regardingcerebral myelination.7 T1-weighted images are most usefulduring thefirst year. As T1-weighted images approach amatureappearance, T2-weighted images become superior for contin-ued surveillance of ongoingmyelination. As our understandingof the later stages ofmyelination increases, particularly beyondthe first two years of life, other techniques, such as FLAIR andDTI, are gaining increasing clinical relevance. Additionally,quantitative MRI techniques16,18 for evaluation of myelinmay become clinically useful in the near future. As knowledgeof normal myelination advances, our ability to both recognizeand address conditions of abnormal myelination is enhanced.

References1 Brant-Zawadzki M, Enzmann DR. Using computed tomography of

the brain to correlate low white-matter attenuation with earlygestational 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 pediatricneuroimaging. In: Barkovich AJ, Raybaud C, eds. PediatricNeuroimaging. 5th ed. Philadelphia: Wolters Kluwer Health/Lip-pincott Williams & Wilkins; 2011;1–19

4 Shaw DW, Weinberger E, Astley SJ, Tsuruda JS. Quantitativecomparison of conventional spin echo and fast spin echo duringbrain myelination. J Comput Assist Tomogr 1997;21(6):867–871

5 Kizildağ B, Düşünceli E, Fitoz S, Erden I. The role of classic spin echoand FLAIR sequences for the evaluation of myelination in MRimaging. Diagn Interv Radiol 2005;11(3):130–136

6 Ruggieri PM. Metabolic and neurodegenerative disorders anddisorders with abnormal myelination. In: Ball WS, ed. PediatricNeuroradiology. Philadelphia: Lippincott-Raven; 1997;175–237

7 Barkovich AJ, Mukherjee P. Normal development of the neonataland infant brain, skull, and spine. In: Barkovich AJ, Raybaud C, eds.Pediatric Neuroimaging. 5th ed. Philadelphia: Wolters KluwerHealth/Lippincott Williams & Wilkins; 2011;20–80

8 Ashikaga R, Araki Y, Ono Y, Nishimura Y, Ishida O. Appearance ofnormal 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 ofthe pediatric brain imagedwith 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 pictorialreview 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 asshown by diffusion tensor imaging. AJR Am J Roentgenol 2002;179(6):1515–1522

12 Mukherjee P, Miller JH, Shimony JS, et al. Diffusion-tensor MRimaging of gray and white matter development during normalhuman brain maturation. AJNR Am J Neuroradiol 2002;23(9):1445–1456

13 Hermoye L, Saint-Martin C, Cosnard G, et al. Pediatric diffusiontensor imaging: normal database and observation of the whitematter maturation in early childhood. Neuroimage 2006;29(2):493–504

14 van BuchemMA, Steens SCA, Vrooman HA, et al. Global estimationof myelination in the developing brain on the basis of magnetiza-tion transfer imaging: a preliminary study. AJNR Am J Neuroradiol2001;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 tractswith magnetization transfer MR. Neuroimage 1999;9(4):393–406

Figure 9 Terminal zones of myelination in a 6-year-old girl. (A) Axial T2-weighted fluid attenuation inversion recovery image demonstratesfocally increased periatrial white matter signal (arrows) consistent with terminal zones of myelination. Notice the normal-appearing low-signalwhite 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 ofterminal myelination zones.



Dow

nloa

ded

by: N

atio

nwid

e C

hild

rens

Hop

sita

l. C

opyr

ight

ed m

ater

ial.

16 Ding X-Q, Kucinski T, Wittkugel O, et al. Normal brain maturationcharacterized with age-related T2 relaxation times: an attempt todevelop a quantitative imaging measure for clinical use. InvestRadiol 2004;39(12):740–746

17 Hagmann P, Sporns O, Madan N, et al. White matter maturationreshapes structural connectivity in the late developing humanbrain. 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 ofbrain: why white matter appears bright in MRI. Magn Reson Med1990;14(3):482–495

20 Kucharczyk W, Macdonald PM, Stanisz GJ, Henkelman RM. Relax-ivity and magnetization transfer of white matter lipids at MRimaging: 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 ofearly 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 ofhuman cerebral myelin during development. Adv Exp Med Biol1978;100:27–41

25 Barkovich AJ, Kjos BO, JacksonDE Jr, NormanD. Normalmaturationof the neonatal and infant brain: MR imaging at 1.5 T. Radiology1988;166(1 Pt 1):173–180

26 Martin E, Kikinis R, Zuerrer M, et al. Developmental stages ofhuman 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. JNeuroradiol 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

30 Mukherjee P, Miller JH, Shimony JS, et al. Normal brain maturationduring 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 anexpression of the functional maturity of the brain. Dev Med ChildNeurol 1991;33(10):849–857

32 Pujol J, Soriano-Mas C, Ortiz H, Sebastián-Gallés N, Losilla JM, DeusJ. 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 centralnervous systemmyelination in human infancy. I. An autopsy studyof myelination. J Neuropathol Exp Neurol 1987;46(3):283–301

34 Kinney HC, Brody BA, Kloman AS, Gilles FH. Sequence of centralnervous system myelination in human infancy. II. Patterns ofmyelination in autopsied infants. J Neuropathol Exp Neurol1988;47(3):217–234

35 van der Knaap MS, Valk J, Barkhof F. Magnetic resonance ofmyelination and myelin disorders. 3rd ed. Berlin, New York:Springer; 2005:12

36 Girard N, Gouny SC, Viola A, et al. Assessment of normal fetal brainmaturation in utero by proton magnetic resonance spectroscopy.Magn Reson Med 2006;56(4):768–775

37 Girard N, Confort-Gouny S, Schneider J, et al. MR imaging of brainmaturation. J Neuroradiol 2007;34(5):290–310

38 Parazzini C, Baldoli C, Scotti G, Triulzi F. Terminal zones ofmyelination: 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 periventricularleukomalacia: MR evaluation. Radiology 1988;168(3):809–815

40 Skranes JS, NilsenG, SmevikO, Vik T, Rinck P, BrubakkAM. Cerebralmagnetic resonance imaging (MRI) of very low birth weightinfants 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 assessmentof myelination in the very preterm brain. AJNR Am J Neuroradiol2002;23(5):872–881

43 GirardN, RaybaudC, PoncetM. InvivoMR studyof brainmaturationin normal fetuses. AJNR Am J Neuroradiol 1995;16(2):407–413



Dow

nloa

ded

by: N

atio

nwid

e C

hild

rens

Hop

sita

l. C

opyr

ight

ed m

ater

ial.

assessment of normal myelination with magnetic resonance ... · assessment of normal myelination...

Documents