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

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

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

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

Multiple Sclerosis ASNR 2003 –Washington,DC DT-MRI Alexander R. Bammer, F. Fazekas, Neuroim Clinics N Am, Feb. 2002. 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

(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

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

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

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

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

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

Cerebral Palsy Courtesy of Susumu Mori

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

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

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

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).

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

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

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

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)

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

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

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

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

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.

Neuroimaging for Phenotyping Motor Tract Motor Circuitry UCBT Cerebellar Peduncles

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

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 0.0 1.0

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

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

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

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

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

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

Longitudinal Follow-up Neonate 1 year old

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)

“Maturation” of white matter tracts

Tensor Statistics Genu/Splenium: Neonate to 1years MD MD Neo FA FA 1yr Neonate 1year

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.