Diffusion Tensor Imaging: Is It Ready For The Clinic ?
eEdE:14
Tushar Chandra, MD1
Mohit Agarwal, MD1
Ibrahim Tuna, MD1
Laura Kohl, MD1
Andrew Klein, MD1
Leighton Mark, MD1
Mohit Maheshwari, MD1
Suyash Mohan, MD2
Sumei Wang, MD2
John Ulmer, MD1
Medical College of Wisconsin, Milwaukee1
Perelman School of Medicine, University of Pennsylvania2
Disclosures
Nothing to disclose
Educational
Educational Objectives
Objectives
 Succinct overview of the fundamental principles and techniques of
diffusion imaging, Diffusion tensor imaging (DTI), fiber tractography
and Diffusion kurtosis imaging (DKI)
 Simplified interpretation of DTI metrics
 Discuss clinical application of DTI in neuropathology
 Overview technical limitations and pitfalls
Introduction
Introduction
Diffusion Tensor Imaging (DTI) is a novel method which has various
applications in clinical neuroimaging and research
Within the central nervous system, water diffusion is more anisotropic in
white matter and isotropic in gray matter and CSF
This property can be exploited to highlight white matter changes in various
pathological processes
DTI is a powerful tool for assessment of microstructural integrity of the
white matter qualitatively as well as quantitatively
Diffusion imaging - Principle
Water molecules in biological tissues are in
constant movement, governed by two major
principles:
a. Fick`s Law: Random diffusion due to
concentration differences
b. Temperature and ion-ion interactions
Random
Brownian Motion
Free Diffusion
Diffusion of water molecules can be restricted
in various pathological conditions
Restricted Diffusion
Diffusion imaging
Free Diffusion
Restricted Diffusion
Diffusion
imaging
Diffusion imaging - Technique
Detects the molecular motion of
water and allows for quantitative
assessement of the freedom of
diffusion
The addition of 2 strong, symmetric
gradients to a EPI SE sequence helps
in differentiation of stationary from
mobile water molecules
If there is net movement of spins (i.e.
if diffusion occurs) between the 2
gradients, signal attenuation occurs
Radiographics 2006;26: S205-223
Diffusion
Signal
Diffusion imaging
Application of
gradients
Signal drop
Gradients cause a drop in signal
if diffusion is present
No Diffusion
Between
Gradients More signal
More Diffusion
Between
Gradients Less signal
‘b’ value
Represents the strength of ‘diffusion
sensitizing gradients’
Expressed in s/mm2
The larger the b value, the smaller
magnitudes of water motion detected.
b 0 image:
 No diffusion weighting
 Poor man’s gradient or T2
Apparent diffusion coefficient - ADC
Measures area of water molecular diffusion
in 1 second
Expressed in mm2/s
Reduced ADC - acute stroke, abscesses,
cellular neoplasms, recurrent tumors
Increased ADC – benign lesions, necrosis,
post radiation changes
Why Apparent?
Since MRI cannot distinguish molecular motion arising from differences
in concentration gradient from that resulting from temperature gradient
or other reasons, the coefficient is apparent and not a true value
Exponential Apparent diffusion coefficient -eADC
Derived from dividing DWI by T2 images
to remove effects of T2 shine through
True restricted diffusion – dark on ADC,
bright on eADC
ADC or eADC maps can be used
depending on whether we want contrast
to match, or be opposite to, the diffusion
weighted images
Exponential Apparent diffusion coefficient -eADC
DWI
ADC
eADC
An area of increased diffusion signal on DWI image in the left
parietal lobe in a 60 y/o male with treated astrocytoma is slightly
dark on ADC but not increased in signal on eADC, suggesting that
there is no ‘true’ restricted diffusion.
There was no recurrent tumor on pathology
Diffusion Tensor imaging
ISOTROPIC- Equal diffusion in
all directions
ANISOTROPIC – Diffusion preferentially
increased in some directions
Diffusion Tensor imaging
DTI requires obtaining data from diffusion acquisitions
with gradients in different directions in each acquisition
to provide directional information to the diffusion data
The information is provided by 3 eigen values which
represent the direction of 3 major axes of the ellipsoid
and 3 eigen vectors that represent the magnitude in
these directions
Isotropic Diffusion
In the white matter, diffusion is anisotropic and is
related to cell density and integrity, axonal integrity,
and myelination status
Anisotropic Diffusion
Physiological Principals of DTI
White
matter
H2O
H2O
H2O
H2O
Diffusion Gradients
Physiological Principals of DTI
White
matter
Voxel
H2O
H2O
Diffusion Ellipsoids
Commentaries: Mark, Ulmer. AJNR 2002, 2004
Diffusion
Tensor
Diffusion
Tensor imaging
Tensor is a mathematical model of directional anisotropy of
diffusion
Diffusion tensor describes Gaussian diffusion distribution - a
3D ellipsoid with lengths and orientations of the 3 axes
corresponding to the eigen vectors - λ1, λ2 and λ3
Acquisition in at least 6 directions is required, but clinically
up to 30 directions are used
 From the tensor, we can calculate:
a. Direction of greatest diffusion
b. Degree of anisotropy
c. Diffusion constant in any direction
λ1
λ2
λ3
Diffusion
Kurtosis
imaging
DTI
Metrics
and
Tensor
Diffusion Kurtosis imaging
Diffusion Kurtosis imaging
λ1
λ2
λ1
λ2
λ3
λ3
ISOTROPIC
ANISOTROPIC
Mean Diffusivity (MD) = (λ1+λ2+λ3)/3
Axial Diffusivity (Da) = λ1
Radial Diffusivity (Dr) = (λ2+λ3)/2
Fractional anisotropy - FA
Measures the degree of anisotropic
(unequal) diffusion in a voxel
Ranges from 0 to 1 (no units)
0 – isotropic (sphere-like)
1 – Purely anisotropic (straight line)
Color coded FA map
(Red –Higher FA, Blue – Lower FA)
Note thatWM tracts showing red
color have a higher FA
Can characterize demyelinating lesions, e.g.,
breakdown of myelin and axonal loss can
reduce FA and remyelination can increase FA
FA value of CSF is 0.
Mean Diffusivity - MD
Measure of directionally averaged
magnitude of diffusion (λ1+λ2+λ3)/3
 Higher MD values mean that the tissue
is more isotropic
MD is an inverse measure of membrane
density and tumor cellularity
Color coded MD map
(Red –lower MD
Purple – higher MD)
Sensitive to cellularity, edema and necrosis
Axial Diffusivity - Da
Da is the apparent diffusion parallel to
white matter tracts
Da = Prinicipal Eigen value = λ1
Da is variable in white matter pathologies
Color coded Da map
(Red –Higher Da Blue
– Lower Da)
Da decreases in axonal degeneration
Radial Diffusivity - Dr
Apparent diffusion perpendicular to the
white matter tracts
Dr = (λ2+λ3)/2
Dr generally increases in white matter
demyelination and dysmyelination
Color coded Dr map
(Red –Higher Dr
Green – Lower FA)
Change in axonal diameter and density
also affect Dr
Fiber
DTITractography
- Tractography
Technique to assess direction of white matter
tracts within the brain
Directional information from neighboring
voxels is combined to estimate 3D structure
of major white-matter pathways
 Voxels are connected together taking into
consideration both the direction of principle
Eigen vector and FA value
DTI - HARDI

DTI ellipsoid not accurate for
detecting white matter
tracts as it assumes one
direction of axons in each
voxel (in truth, there are
crossing fibers in each voxel)

HARDI – can assess crossing
tracts in the same voxel
Diffusion Kurtosis imaging
DKI is an extension of conventional DTI.
DTI assumes Gaussian distribution (bell shaped curve)
of diffusion (not accurate), as water diffusion in
biological tissues is non-Gaussian.
 Due to the effects of cellular microstructure e.g., cell membranes,
organelles & myelin in brain
Diffusion kurtosis – studies non-Gaussian diffusion
behavior.
Leptokurtic- K>0
Mesokurtic –K=0
Platykurtic –K<0
Kurtosis measures the "peakedness" of the
probability distribution.
Qualitatively, a large diffusional kurtosis suggests a
high degree of diffusional heterogeneity and
microstructural complexity.
Diffusion Kurtosis imaging
From the diffusion and diffusional kurtosis tensors several
rotationally invariant metrics such as the mean, axial, and radial
kurtoses can be computed
The extra information provided by DKI can also resolve intra-voxel
fiber crossings and thus be used to improve fiber tractography of
white matter
DKI protocols require at least 3 b-values (as compared to 2 b-values
for DTI) and at least 15 independent diffusion gradient directions (as
compared to 6 for DTI)
Typical protocols for brain have b-values of 0, 1000, 2000 s/mm2 with
30 diffusion directions
Functional MRI
BOLD – Blood Oxygen Level Dependent

Rest: Normal flow



Activity: High flow
- Deoxyhemoglobin
- Oxyhemoglobin

As neural activity increases, blood flow
increases
Deoxyhemoglobin (paramagnetic)
concentration decreases
Magnetic field homogeneity increases
And therefore gradient echo EPI signal
increases, rather than loss of signal
BOLD technique is used with DTI fiber
tractography in pre-surgical mapping.
Clinical Applications – Normal Brain
Fiber tracking provides critical information
about white matter anatomy and
connections
Regions with similar tractographic features
tend to be functionally co-activated “neurons that fire together, wire together”
IQ has been positively correlated with
anisotropy in white matter association areas
Reading ability has been correlated with
anisotropy of left temporoparietal areas
In the visual pathway, DTI has shown the
retinotopic organization of fibers
Clinical Applications - Tumors
MD decreases as tumor cellularity increases, due to
decreased ECF volume
Atypical and malignant meningiomas - lower MD than typical meningiomas
Flair hyperintense mass in
Right frontotemporal region
Primary CNS lymphoma and Medulloblastoma also have low MD
MD increases with tumor response with treatment and
can be used as a biomarker
Relationship of FA with tumor cellularity and treatment
response is unclear
In the peritumoral zone, DTI metrics do not reliably
differentiate edema from tumor infiltration
Increased MD
suggesting low cellularity
Gr II glioma at biopsy
Clinical Applications - Tumors
Intact WM tracts displaced
by tumor retain anisotropy
and remain identifiable
Edematous or tumor-infiltrated
tracts lose some anisotropy
but remain identifiable
Destroyed WM tracts lose directional organization
and diffusion anisotropy is lost completely
Jellinson et al. AJNR 2004
Diffusion-weighted imaging: Diffusion Image,
Apparent diffusion coefficient (ADC), eADC –
tumor cellularity
Diffusion tensor imaging: Fractional anisotropy,
diffusivity (mean, axial and radial) – tumor biology
Diffusion and
Functional
Imaging
For Tumors
Tractography: Accurate localization of white
matter tracts in relationship to the tumor margins
Functional MR Imaging: Depiction of eloquent
cortical areas in relationship to tumor margins
Clinical Applications - Presurgical Brain Mapping
Progression free survival is directly related to
the extent of resection
Motor
Area
However, benefits of cytoreduction must be
weighed against risk of damage to eloquent
structures and white matter tracts
Pre-surgical mapping with DTI and fMRI
results in more informed presurgical planning
and decreases the risk of post operative
neurological deficits
White Matter
Tracts
Tumor
Fused image with functional motor areas and white
matter tracts superimposed on FLAIR depict relationship
of tumor to eloquent cortex and white matter tracts
Fiber Tractography - Presurgical Brain Mapping
34-year-old, right-handed woman with a posterior
parasylvian low-grade glioma. SPGR gadolinium-enhanced
underlays with 50% faded Colorcoded fractional anisotropy
(CC-FA) diffusion tensor imaging (DTI) map
Track-ball filtering of whole brain fiber tracking DTI data reveals better detail
of spatial relationships between tumor and SLF HB, SLF IV, IFOF, ILF, and OR
IFOF = Inferior fronto-occipital fasciculus, ILF = Inferior longitudinal fasciculus,
SLF HB = Superior longitudinal fasciculus horizontal bundle,
SLF IV = Superior longitudinal fasciculus IV, OR = Optic radiation, UF =
Uncinate fasciculus
Ulmer et al Neuroradiology Clinics of North America 2014
Tumors - Which functional systems are at risk ?
Motor
(Corticospinal
Tract)
Vision
(ILF, IFOF
Optic Radiations)
Language
(SLF,ILF,IFOF)
Vision
(Optic Radiation)
Clinical Applications - Demyelination
MS lesions have higher ADC and lower FA
values than Normal Appearing White Matter
(NAWM)
Significantly increased ADC and lower FA
values are seen in acute (enhancing) MS
lesions than chronic (non enhancing) lesions
FLAIR : MS plaque
MD image: High MD
Color FA Map : low FA
Tractography:
Decreased WM fibers
Non enhancing TI hypointense lesions have
higher ADC and lower FA values than T1
isointense lesions
Clinical Applications - Epilepsy
Increased MD and lower FA values are seen
in hippocampi of patients with mesial
temporal sclerosis
Gray Matter
Heterotopia
In patients with malformations of cortical
development, increased MD and lower FA
values are seen in abnormal areas within
MCD and also in the normal appearing areas
on MR
Increased MD and low FA can be used to
localize lesions in MR negative cases of
epilepsy
Displaced WM Tracts
Decreased
Radial
Diffusivity
Clinical Applications – Congenital Anomalies
White matter abnormalities in congenital
brain malformations can be assessed
with DTI
Pertinent applications include callosal
agenesis, cortical dysplasia,
holoprosencephaly, schizencephaly,
Chiari II malformation etc
Schizencephaly
DTI
Disrupted
WM Tracts
Improved understanding of white matter
abnormalities in developmental lesions
fMRI –
Motor
Cortex
Along
the cleft
Clinical Applications – Traumatic Brain Injury
DTI is a useful technique to evaluate
microstructural injury to the white
matter fiber tracts in patients with TBI
Decreased FA and increased MD are
seen in areas afflicted by TBI, that are
occult on conventional MRI
Studies suggest some correlation
between findings on DTI with EEG and
neuropsychological testing
In the future, DTI may serve as a
surrogate marker for closed head
injury
Cingulum
Temporal White Matter
Interpretative Challenges of Clinical DTI
Tumor, edema and radiation-induced decrease in anisotropy.
Tumor-induced geometric distortions of fiber tracts.
Anatomic constraints
• Distinguishing functionally different pathways in the same white matter
bundle.
• Acute angulations and blending of white matter pathways.
DTI data are imperfect!
Conclusion
 DTI is a powerful tool to investigate microstructural white matter changes
and brain connectivity
DTI is currently being clinically used in conjunction with functional MRI for
presurgical brain mapping and is gradually becoming the standard of care
For indications such as demyelination, trauma, epilepsy and congenital
anomalies, DTI provides useful information that is clinically helpful and
often helps in diagnostic interpretation and clinical decision making
As the technique becomes more robust, it will be increasingly applied in
clinical practice for other indications
Thank You
Author:
Tushar Chandra
Clinical Instructor, Radiology
Medical College of Wisconsin
9200 W Wisconsin Avenue,
Milwaukee WI 53226
Email: drtusharchandra@gmail.com