DTI vs. HARDI methods in 

diffusion MRI: advantages and 

limitations in a clinical setting

Carlo Pierpaoli

Program in Pediatric Imaging & Tissue Sciences

NICHD
Gray matter

(Cortex)

White matter

(Corpus callosum)

~ microns

isotropic

diffusion

anisotropic

diffusion

mm
Poll question

Anisotropy is related to which feature of the water 

displacement profile:

1) SIZE

2) SHAPE

3) ORIENTATION
Diffusion Tensor MRI Flowchart 
Diffusion ellipsoids 

computed in each 

voxel

Diffusion Tensor MRI of the Human 

Brain. 

Pierpaoli, et al, Radiology, 1996 
HARDI (High Angular Resolution 

Diffusion Imaging)

Slide courtesy of Everen Ozarslan (DT-MAP ) 
Diffusion MRI 

Diffusion tensor Imaging: minimum 

6 directions, b-value = 800-1200.

Spatial resolution: 2x2x2 mm 

HARDI (High Angular Resolution 

Difusion Imaging): minimum 40-60 

directions, b-value: 3,000 and higher.

Spatial resolution: 3x3x3 mm 

 
HARDI reconstruction, 

longitudinal data, some subject

A B 
Poll question

What determined the difference between scan A and B:

1) In scan A the subject was younger and the immature brain 

had less connections 

2) Scan A was in the acute phase of trauma, scan B at a 

later time shows brain reorganization

3) Pattern compatible with all of the above

4) Some strange experimental artifact
DTI vs. HARDI 

1) Proper HARDI requires a larger amount of high quality 

data than DTI. In a clinical setting, artifacts can be easily 

mistaken for biologically meaningful findings

HARDI reconstruction from 

previous data
B = 30 s/mm2 

B = 900 s/mm2

B = 9000 s/mm2 

Registration of high b-value images. A standing challenge.
DTI vs. HARDI 

1) Proper HARDI requires a larger amount of high quality 

data than DTI. In a clinical setting, artifacts can be easily 

mistaken for biologically meaningful findings

2) HARDI is almost exclusively used for “tractography” and 

“connettivity”. Diffusion MRI is ill-suited to investigate 

brain structural connectivity.
Interdigitation occurs at a microscopic level 
DTI vs. HARDI 

1) Proper HARDI requires a larger amount of high quality 

data than DTI. In a clinical setting, artifacts can be easily 

mistaken for biologically meaningful findings

2) HARDI is almost exclusively used for “tractography” and 

“connettivity”. Diffusion MRI is ill-suited to investigate 

brain structural connectivity.

3) There is no free lunch. ... with HARDI one has to tradeoff resolution to characterize a more complex 

displacement profile.
Radial Diffusion MRI for sub-millimeter 

resolution DTI (Sarlls et al. Neuroimage 2009)
Standring, S. (Ed.), 2005. Gray’s Anatomy: The Anatomical Basis of Clinical Practise. 

39 ed. Elsevier Churchill Livingstone, Edinburgh, London.

DTI vs. HARDI 

1) Proper HARDI requires a larger amount of high quality 

data than DTI. In a clinical setting, artifacts can be easily 

mistaken for biologically meaningful findings

2) HARDI is almost exclusively used for “tractography” and 

“connettivity”. Diffusion MRI is ill-suited to investigate 

brain structural connectivity.

3) There is no free lunch. ... with HARDI one has to tradeoff resolution to characterize a more complex 

displacement profile.

4) Clinical usefulness: DTI ++, HARDI ??
T2 weighted image Trace(D) map (also called ADC or MD)

Trace(D) (averaged mean-squared displacement)

• Trace(D) is 

homogeneous in 

normal brain 

parenchyma

• Low inter-subject 

variability
7.5-month old boy who reportedly fell off the bed onto a 

carpeted floor. Scan performed 1 day after presentation.

T2WI Trace(D)

Suh DY et al Neurosurgery, Vol. 49, No. 2, August 2001, 309-20
Neurite beading is sufficient to decrease ADCintra by restricting 

water mobility along each neurite.

Approach

Derive a biophysical model of beading in neurites

Simulate diffusion MR experiment in 3D geometrical surfaces

Validate model in mammalian tissues

Hypothesis by Matt Budde, et 

al., PNAS, 2010

 
In vivo two-photon microscopy (Murphy T, et al. J Neurosci 2008)

Normal Rodent 

Cortex

What can we learn from other imaging modalities?
Neurite beading occurs abruptly after ischemia...

4 min after MCAO
17 min after reperfusion

...and resolves upon reperfusion.
Diffusion anisotropy (shape of displacement profile)

T2 weighted image Anisotropy map

• Diffusion anisotropy 

is highly variable in 

normal white matter

• Differences in 

anisotropy reflect 

differences in white 

matter architecture
Secondary degeneration in the Cerebral Peduncle

T2WI Trace(D) Anisotropy

Healthy 

Side 

Affected 

Side 

NeuroImage 13, 1174–1185 (2001)
Fiber orientation

T2 weighted image DEC fiber orientation map

Pajevic, Pierpaoli, MRM 1999
Pyramidal Tract

Transverse Pontine Fibers 

Transverse Pontine Fibers 

Degeneration of pontocerebellar pathways

in Multiple System Atrophy

Healthy subject

MSA patient
Time 

0 

Time 1

T0 + 34 

days

Time 2

T0 + 140 

days

Time 3

T0 + 363 

days

Time 4

T0 + 426 

days

Temporal evolution of a Pontine Glioma 

DEC MAp

Delta R1 map
CONCLUSIONS 

1) Proper HARDI requires a larger amount of of high quality 

data than DTI. In a clinical setting, artifacts can be easily 

mistaken for biologically meaningful findings

2) HARDI is almost exclusively used for “tractography” and 

“connettivity”. Diffusion MRI is ill-suited to investigate 

brain structural connectivity.

3) There is no free lunch. ... with HARDI one has to tradeoff resolution to characterize a more complex 

displacement profile.

4) Clinical usefulness: DTI ++, HARDI ??



Outlier Rejection Probability Map

Lindsay Walker et al Neuroimage 2011
Biological Psychiatry, 2013
Rajendra Morey, M.D.

Associate Professor

MIRECC

Mid-Atlantic

Mental Illness Research, Education & Clinical Center

White Matter Damage in Blast-exposed Veterans 

without Mild TBI
Background

• Exposure to explosive forces from bombs is common in Veterans of 

recent military conflicts

• Majority of traumatic brain injury (TBI) at forward deployed medical 

facilities involves exposure an improvised explosive device (IED), 

grenade, rocket-propelled grenade (RPG), or mortar fire.

• Damage to brain tissue (white matter) using Diffusion Tensor 

Imaging (DTI) is well established in cases that clinical symptoms of 

mild TBI.

• Recent studies of sports participants show compromised white 

matter integrity even in the absence of clear concussive symptoms.


Poll question #1

• How many of you are familiar with the 

Junior Seau case?

– Yes

– No

– Not sure

Poll Question #2

Is there prominent injury to brain tissue in 

Veterans with blast exposure without clinical 

symptoms of TBI ?

– Yes

– No

– Not sure
Subconcussive blast exposure

• 6 Veterans with pure primary blast mTBI

• 16 blast exposed without mTBI

• 23 blast unexposed

• All had DTI scans in the chronic stage
Figure1. Whole brain voxelwise comparison of FA between the blast-exposed 

and the blast-unexposed control group was covaried for age and severity of 

PTSD (CAPS score). These results show significantly lower FA in the blastexposed group compared to the blast-unexposed group in diffuse cortical and 

subcortical tracts based in the right hemisphere including the forceps major, 

superior and inferior longitudinal fasciculus, anterior thalamic radiations, 

inferior fronto-occipital fasciculus, and the corticospinal tract (p < .05; 

corrected). 
reference group 

mean FA

test-subject FA

0

0.2

0.4

0.6

0.8

test-subject reference

FA

sample voxel

whole brain Z-map

reference subjects’ FA

+ 2 SD

- 2 SD

FA

Figure 1. Following preprocessing of DTI data, the analytic approach was based on registration of FA maps as implemented in 

the FSL tract based spatial statistics (TBSS). The primary statistical approach used the standard deviation of fractional 

anisotropy for each voxel in the reference group. Using the mean and standard deviation of FA for the reference group, the testsubject’s voxels were compared to the skeleton voxels (green highlight) that were generated for the reference group. For the 

test-subject, we computed a statistical map that reflects the number of standard deviations below the mean of the reference 

group, which is effectively a z- map. The whole brain z-map shows voxels (in red) where FA of the test-subject was found to be 

greater than two standard deviations below the mean FA of the reference group.
Figure 2. There was a significant main effect of group [F(2,42)=4.4, p=.02] on 

the number of small (25-50 voxel), medium (50-75 voxel), and large (75-100 

voxel) potholes, which were defined by low FA values (z < -2). The blastunexposed control group had significantly fewer potholes than the blast-mTBI 

group (p = .009) and the blast-exposed group (p = .036). Based on the number 

of potholes, the blast-exposed group resembled the blast-mTBI group when 

considered in relation to the blast-unexposed control group
Radial and Axial Diffusivity
Figure 4. There was a significant main effect of group [F(2,42)=3.7, p=.034] 

on the number of small (25-50 voxel), medium (50-75 voxel), and large (75-

100 voxel) potholes, which were defined by low radial diffusivity (z < -2). The 

blast-unexposed control group had significantly fewer radial diffusivity potholes 

than the blast-mTBI group (p = .032) and the blast-exposed group (p = .025). 

Based on the number of potholes, the blast-exposed group resembled the 

blast-mTBI group when considered in relation to the blast-unexposed control 

group.
Figure 4. There was a non-significant main effect of group [F(2,42)=2.0, 

p=.15] on the number of small (25-50 voxel), medium (50-75 voxel), and large 

(75-100 voxel) potholes, which were defined by voxels with low axial diffusivity 

values (z < -2). 
Figure 5. A whole brain voxelwise histogram of potholes over 25 voxels in size demonstrates that potholes in blast-exposed (top 

panel) and blast-mTBI (lower panel) veterans were distributed in a scattershot spatial distribution. In the voxelwise histogram overlay, 

lime-green indicates voxel locations where only 1 veteran had a pothole, violet indicates voxel locations were 2 veterans had a 

pothole, and dark blue indicates voxel locations where 3 veterans had a pothole. Rare instances of voxels had 4-7 subjects (data not 

shown).

Y=0

Y=0
Figure 6. Grey matter potholes with VBM
Conclusions

• Blast-exposed Veterans experience white matter 

damage that is comparable to mild TBI even in the 

absence of clinical symptoms. 

• The lack of clinically observable TBI symptoms following 

blast exposure may lead to the erroneous conclusion 

that little or no damage has occurred to brain tissue and 

consequently may go unnoticed. 

• If confirmed, our findings would argue for an overhaul of 

the established approach for making diagnoses based 

on clinically observable symptoms of mild TBI in favor of 

novel imaging based diagnostic criteria that “look below 

the surface” for pathology. 
References

• Davenport ND, Lim KO, Armstrong MT et al: Diffuse and spatially variable white 

matter disruptions are associated with blast-related mild traumatic brain injury. 

Neuroimage 2012; 59:2017-2024 

• Jorge RE, Acion L, White T et al: White matter abnormalities in veterans with mild 

traumatic brain injury. Am J Psychiat 2012; 169:1284-1291 

• Koerte IK, Ertl-Wagner B, Reiser M et al: White matter integrity in the brains of 

professional soccer players without a symptomatic concussion. JAMA 2012; 

308:1859-1861

• Koerte IK, Kaufmann D, Hartl E et al: A prospective study of physician-observed 

concussion during a varsity university hockey season: white matter integrity in ice 

hockey players. Part 3 of 4. Neurosurg Focus 2012; 33:E3-

• Bazarian JJ, Donnelly K, Peterson DR et al: The relation between posttraumatic 

stress disorder and mild traumatic brain injury acquired during Operations Enduring 

Freedom and Iraqi Freedom. J Head Trauma Rehabil 2013; 28:1-12 

• Morey RA, Haswell C, Selgrade E, Massoglia D, Liu C, Weiner J, Marx C, Workgroup 

M-AM, Cernak I, McCarthy G. Effects of chronic mild traumatic brain injury on white 

matter integrity in Iraq and Afghanistan Veterans. Human Brain Mapping. June 2012 
Q & A

Rajendra Morey, M.D., M.S.

Associate Professor

Psychiatry and Behavioral Sciences, 

and Duke-UNC Brain Imaging and Analysis Center

Duke University School of Medicine

Director, Neuroimaging Lab

Mental Illness Research Education and Clinical Center

Durham VA Medical Center

Phone: 919-286-0411 x 6425

Fax: 919-416-5892

email: rajendra.morey@duke.edu 

web: www.duke.edu/web/moreylab

Carlo Pierpaoli, M.D., Ph.D.

Program on Pediatric Imaging and Tissue Sciences,

National Institute of Child Health and Human 

Development (NICHD), National Institutes of Health

(NIH)

13 South Drive, MSC 5772

Bldg. 13, Rm. 3W16

Bethesda, MD 20892-5772

(301) 402-2289

Email: cp1a@nih.gov