1. (Pre-)Clinical and Applications with DTI
Guido Gerig
UNC Chapel Hill

2. DTI Applications Normal brain development and aging
Congenital anomalies and diseases of white matter
Traumatic brain injury
Encephalopathies – toxic, metabolic, infectious
Demyelinating and neurodegenerative diseases
Ischemia and stroke
Neoplasm, preoperative planning
Epilepsy
Dementia, schizophrenia, depression
Developmental disorders - fragile X, autism
Spinal Cord
ASNR 2003 –Washington,DC
DT-MRI Alexander

3. Normal Brain Development
Significant changes in anisotropy values of the white matter of the centrum semiovale take place well before changes in T1 and T2 relaxation detected by standard imaging methods. Cerebral cortex in infants less than 32 weeks gestational age (GA) has nonzero anisotropy values. Cortical A values decrease with increasing GA (r = 0.81, p < 0.05) and are consistent with zero after 35 weeks GA. The major axis of the diffusion ellipsoid is oriented radially, as would be expected if anisotropy were due to the radial orientation of apical dendrites of pyramidal cells.
Courtesy J. Neil Washington Univ., St. Louis
ASNR 2003 –Washington,DC
DT-MRI Alexander

4. WM Anisotropy Changes with Age
Pfefferbaum et al.
MRM 2000
genu
frontal
pericallosal
centrum
semiovale
Genu
Left pericallosal
Right pericallosal .3 .4 .5 .6 .7 .8 20 30 40 50 60 70 80
Age
Anterior FA
Splenium
Posterior
.34
.36
.38
.40
.42
.44
.46
.48
Centrum Semiovale
parietal
splenium
Courtesy K. Lim, Univ. Minn.
ASNR 2003 –Washington,DC
DT-MRI Alexander

5. Multiple Sclerosis ASNR 2003 –Washington,DC DT-MRI Alexander
R. Bammer, F. Fazekas, Neuroim Clinics N Am, Feb
S T A N F O R D
S C H O O L OF M E D I C I N E
Lucas MRS/I Center
ASNR 2003 –Washington,DC
DT-MRI Alexander

6. (Lim et al., Arch Gen Psychiatry 1999)
Schizophrenia
Structural Volume (FSE)
100
200
300
400
500
CSF
Gray
White
Fractional Anisotropy **
Median FA
SZ (N=10)
NC (N=10)
** p < .005
20000
40000
60000
80000
Number of pixels
CSF
Gray
White
This is a summary of the structural and FA data.
On the left are the pixel counts for the CSF, gray and white matter.
There was a slight but not significant increase in CSF, no difference in WM and a significant deficit in GM.
On the right are the FA values for each of the three compartments.
For FA, no difference in CSF or Gray, but a significant difference in WM.
(Lim et al., Arch Gen Psychiatry 1999)
ASNR 2003 –Washington,DC
DT-MRI Alexander

7. Negative Symptoms in Schizophrenia
No significant correlations found with mean diffusivity
Only significant correlations for FA found at AC-5
Courtesy K. Lim
Univ. Minnesota
ASNR 2003 –Washington,DC
DT-MRI Alexander
Wolkin et al., AJP, in press

8. DTI in Cerebral Neoplasms
Deviated
Infiltrated
Edematous
Destroyed
ASNR 2003 –Washington,DC
DT-MRI Alexander

9. Tract Displacement T2W ADC FA FA  1 ASNR 2003 –Washington,DC
Anaplastic astrocytoma
ASNR 2003 –Washington,DC
DT-MRI Alexander

10. Tract Infiltration Edema Oligo T2W ADC FA FA  1 T2W ADC FA FA  1
Grade 3 astro
ASNR 2003 –Washington,DC
DT-MRI Alexander

11. Pilocytic Astrocytoma
Preop
Postop
T2W
ADC
T2W
ADC FA
FA  1 FA
FA  1
ASNR 2003 –Washington,DC
DT-MRI Alexander

12. Cerebral Palsy
Courtesy of Susumu Mori

13. PNL Schizophrenia Study
Martha Shenton, PNL Harvard
Guido Gerig, UNC Chapel Hill

14. Atlas: Average + Set of transformed tensor fields
ROIs and tracts in atlas space transferred to every image.

15. Tractography in PNL Atlas
Cingulum full
Corpus Callosum middle part
Cingulum “spine”

16. Tractography per Group
Cingulum SZ Group
Cingulum Control Group
Tractography applied to tensor fields of the set of controls mapped to the atlas (left) ad the set of SZ mapped to the atlas (right).

17. Very, very preliminary tests …
SZ seems to have lower FA in middle portion of cingulum.
What does it mean w.r.t. diffusion properties?

18. ctd.
SZ group seems to have lower lambda1 and slightly higher radial diffusion (average lambda2 + lambda3) in middle region.

19. ctd. MD seems very similar for both groups.
GA shows same pattern as FA but much higher values.

20. DTI Population Atlases
Related work:
Alexander, D., Pierpaoli, C., Basser, P., Gee, J.: Spatial transformations of diffusion tensor magnetic resonance images. IEEE Transactions on Medical Imaging 20(11) (2001)
Zhang, H., Yushkevich, P., Gee, J.: Registration of diffusion tensor images. In: CVPR. (2004)

21. DTI Population Atlases
Neonates (N=50)
1yr olds (N=25)
2yr olds (N=15)

22. Fiber Tractography in Atlases
cingulate
fornix and uncinate
motor tracts
uncinate
genu, splenium, motor
Neonate atlas DTI
1yr atlas DTI

23. Krabbe Disease Maria Luisa Escolar, M.D.
Director, Program for the Study of Neurodevelopmental Function in Rare Disorders
Center for the Study of Development and Learning
University of North Carolina at Chapel Hill

24. Krabbe Disease Disease Lysosomal storage disorder Rare disease
Demyelination and dysmyelination in CNS and PNS
Progressive neurological deterioration
Symptoms occur before 6 months of age
Irritability, dysphagia,
progressive spasticity,
mental deterioration,
blindness, deafness,
seizures
Death within 1 to 2 years
Treatment:
Umbilic Cord Blood Transplantation (UCBT)
Marrow and immunoablation
Replacement with donor leukocytes produce enzyme
Problems:
UCBT improves survival and preserves neurological function only in Stage 1 early infantile patients treated before symptoms develop
Later onset motor disability:
Researching cause
Other therapeutic interventions to supplement UCB

25. Developmental Trajectory
Behavioral Phenotypes
Description of behavioral phenotypes are instrumental in understanding the disease’s process and its impact in neurological function.
Gross Motor ?
In medicine, a disease is symptomatic when it is at a stage when the patient is experiencing symptoms. It is generally used in counterdistinction of asymptomatic (when the disease is inapparent).
Symptomatic treatment is the practice of treating a patient's symptoms, rather than the disease or injury itself.
In medicine, a disease is asymptomatic while the patient does not experience symptoms. Asymptomatic diseases may not be discovered until the patient undergoes medical tests (X-rays or other investigations).
Some diseases remain asymptomatic for a remarkably long time, including some forms of cancer.
A patient's individual genetic makeup may delay or prevent the onset of symptoms.
Notion of normative atlas: Describe patients relative to population statistics of healthy development.

26. Neuroimaging for Phenotyping
Motor Tract
Motor Circuitry
UCBT
Cerebellar Peduncles

27. Neuroimaging for Phenotyping: Atlas-based white matter analysis
Normative Atlas (50 neonates), DTI: Average and statistics
Z-scores indicating regions with significant differences
Patient DTI
Please note absence of wm structuring (high FA) in right external capsule

28. DTI Fiber Tracts through Left Hemispheric Internal Capsule
Krabbe
Control
DTI fiber tracts through the left hemispheric internal capsule with Fractional Anisotry (FA) coloring of the fibers. Top row: Krabbe subjects, Bottom row: control subjects. Despite the large variability in FA values within the controls, the Krabbe subject K5 is clearly displaying lower FA values across the whole DTI fiber bundle.
FA color map

29. Bundles obtained from 50case atlas by tractography
Full tracts
Selection of center and off-center regions of interest

30. Early postnatal development of white matter: Joint analysis of sMRI and DTI
Analysis of white matter in healthy controls (N=47)
Co-registration of sMRI and DTI (deformable)
Fibertract-based segmentation of ROIs
Quantitative analysis of FA, MD, T1w, T2w
FA MD T1w T2w

31. Early postnatal development of white matter
Analysis of white matter in healthy controls (N=47)
Myelination and axon elimination:
FA center >> peripheral
FA splenium > genu
MD splenium & genu > intcaps
T1w splenium & genu < intcaps
Gilmore/Lin/Gerig , submitted AJNR

32. Early postnatal development of white matter
Joint analysis of structural MRI and DTI:
Genu at center (non myelinated) versus internal capsule (myelinated)
FA genu ≈ FA intcaps
T1w genu >> T1w intcaps
Analysis detects differences between dense structuring and early myelination
Procedure to be used to measure maturation process

33. Maturation shown via DTI/sMRI analysis
DTI neonate
DTI 1year
sMRI neonate
sMRI 1year

34. White matter maturation shown by DTI
Side by side comparison of the neonate DTI FA atlas (left) co-registered to the 1 years DTI FA atlas (right) by affine registration.
neo
1 yr
neo
1 yr
neo
1 yr
neo
1 yr

35. Longitudinal Follow-up
Neonate
1 year old

36. Corpus Callosum Tracts: Study of Early Development
Neonate (2 wks)
Adult
Corpus callosum: Commissural bundles, color coding of FA (0=blue, 1=red)
Infant (1 year)

37. “Maturation” of white matter tracts

38. Tensor Statistics Genu/Splenium: Neonate to 1yearsMD MD
Neo FA FA
1yr
Neonate
1year

39. Conclusions
Diffusion Imaging adds a measurement not obtained by other structural imaging sequences.
Invaluable for studying white matter disease, lesions, neurodevelopment and neurodegeneration.
MR-DTI made huge progress to provide high resolution with isotropic voxels.
Tools for comprehensive analysis available.