What is DTI, its use in research and clinical practice, and its future potential
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1 NA-MIC What is DTI, its use in research and clinical practice, and its future potential Martin Styner with thanks to many, many people Departments of Computer Science and Psychiatry UNC Neurodevelopmental Disorders Research Center UNC Neuro Image Research and Analysis Lab
2 TOC Interpretation/validation of DTI properties!rat spinal cord studies Validation of tractography What can DTI be used for? Many different applications!main part of the talk Future of DTI: looks bright 2
3 DTI Properties (again) Fractional Anisotropy (Tensor shape), 0..1 Mean Diffusion (Tensor volume) WM/GM CSF Axial Diffusion In WM: Diffusion parallel to axon! 1 " Radial Diffusion! 2 " = λ 1 = λ (λ 2 + λ 3 ) =! 3 " = λ 2 In WM: Diffusion orthogonal to axon
4 Spinal Cord Degeneration DTI (AD/RD) & immunohistochemistry of Wallerian degeneration Unilateral L2 L4 dorsal axotomy in rat spine column DTI revealed dorsal lesion extending from lumbar to cervical cord 3D AD RD 4
5 Spinal Cord Degeneration AD RD Lesion at Day 3 Day 30 AD RD 5
6 Immunohistochemistry LFB: Myelin SMI : neurofilaments! 31: hyper-phosphylated! 32: hypo-phosphylated 6
7 Spinal Cord Degeneration Day 3 (as compared to unlesioned side)! DTI: significantly reduced AD and increased RD.! Immuno: Reduced phosphorylated, increased nonphosphorylated neurofilaments, swollen axons, myelin ovoids, no loss of myelin. Day 30 (as compared to day 3)! DTI: no reduction in AD but increase in RD! Immuno: Gradual clearance of myelin, no changes in neurofilament Conclusion:! DTI, AD/RD sensitive to axon degeneration! FA captures all effects, but cannot differentiate! Correlation of RD with myelin degeneration! Correlation of AD with loss of phosphorylated neurofilaments 7
8 Demyelinating Lesions Rat model of autoimmune encephalomyelitis/ms Injection of cytokines (TNF-!, IFN-") or lipopolysaccharides => spinal cord lesions DTI & Immunohistochemistry FA, AD and RD correlate with axon counts and degenerating axon counts FA and T2-w intensity correspond to changes in myelin loss and axon phosphorylation 8
9 Validation of Tractography Are results of DTI tractography anatomically correct? Yes and No Many studies using synthetic ground truth & MRI phantoms show convincingly positive results In/Ex vivo: stimulation mapping, manganese imaging, tracer studies! Several performed in primates, Dauguet 2007 (NeuroImage) Tracer 9 DTI Tracts
10 Validation of Tractography Good agreement for major fiber bundles Sensitivities to fiber crossings and small fiber bundles! Higher models of diffusion (Qball, DSI)! Anatomical knowledge via source and target selection! Novel tractography on DTI: multi-tensor or probabilistic tracking Overall convincing evidence for DTI tractography! Major fiber tracts are valid! #fibers highly variable!! Size of tracts variable! Number of fibers Scans' Comparison:Fibers (ROI: essai3-th69) Second Method without Interpolation Second Method with Interpolation Scan 1 Scan 2 Scan 3 Scan 4 Scan 5 Scan 6 Average
11 Intermezzo PhDcomics: Brain on a stick 11
12 Applications of DTI General:! Atlases! Parcellation of striatum, thalamus! Segmentation of MS lesions Neoplasm, preoperative planning Demyelinating and neurodegenerative diseases Normal brain development and aging Congenital anomalies and diseases of white matter Traumatic brain injury Ischemia and stroke Epilepsy Dementia, schizophrenia, depression, autism 12
13 DTI is Translational Humans Large Variability Translational Research Mouse, Rat Genetic control, small variability Monkey Reduced complexity and variability 13
14 DTI Population Atlases Definition of standard space SNR increase Better tractography Neonate 1 year Rhesus (15mo) 2 year Adult
15 Fiber tracts in Atlas fornix and uncinate genu, splenium, motor uncinate 15
16 Brain Evolution Arcuate fasciculus, associated with language/ expression! Temporal lobe projection absent/smaller in nonhuman primates Rilling, 2008 Nature Neuroscience Probabilistic tractography 16
17 DTI based Segmentation Tuch 2003 DTI based clustering of thalamus Striatal subdivision Via cortical connectivity Draganski, 08 J Neuroscience Ziyan and Westin, MICCAI 08 17
18 DTI: Cerebral Neoplasms Deviated Infiltrated Edematous Destroyed 18 Courtesy of AL Alexander
19 T2W Pilocytic Astrocytoma Preop ADC T2W Postop ADC FA FA # $ 1 FA FA # $ 1 Courtesy of AL Alexander
20 Tract Infiltration T2W ADC T2W ADC Oligo Edema FA FA # $ 1 FA FA # $ 1 Courtesy of AL Alexander
21 Cerebral Palsy Courtesy of Susumu Mori
22 Multiple Sclerosis
23 Fetal Alcohol Syndrome Control Rodent model of FAS 3D MRI reconstruction DTI & Histology Fiber Tracking Acute EtOH GD7 Absent fornix columns 23 Thickened, dysplastic fimbria
24 Normal Brain Development Courtesy P Hueppi Univ Geneva Courtesy J. Neil Washington Univ., St. Louis
25 WM Anisotropy Changes with Age frontal pericallosal genu FA!.8".7".6".5".4" Anterior Genu" Left pericallosal" Right pericallosal" centrum semiovale.3" splenium FA! parietal pericallosal 20" 30" 40" 50" 60" 70" 80" Age!.8".7".6".5".4".3" Posterior 20" 30" 40" 50" 60" 70" 80" Splenium" Left pericallosal" Right pericallosal".48".46".44".42".40".38".36" Centrum Semiovale.34" 20" 30" 40" 50" 60" 70" 80" Age! Courtesy K. Lim, Univ. Minn.
26 Corpus Callosum Tracts: Study of Early Development Neonate (2 wks) Infant (1 year) Adult Corpus callosum: Commissural bundles, color coding of FA (0=blue, 1=red)
27 Early postnatal development of white matter on neonates 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!"#$%&'()**+(,-./(
28 1-2 year old: CC Tracts 28 Goodlett 2009 NeuroImage
29 Left Motor Tract 29 Goodlett 2009 NeuroImage
30 Monkey Brain Studies Harlow Primate UWisc / Emory Studies: Intrauterine exposure (Flu, LPS), abuse Understanding brain development & environment Regression with age 30
31 DTI Comparison %FA vs %MD Y 1 Y %Fractional Anisotropy %Mean Diffusivity 31
32 How the brain of a toddler really looks like 32
33 Krabbe Leukodystrophy Rare, lethal genetic leukodystrophy! Autosomal recessive pattern (not X-linked)! Worldwide: 1 in 80,000 births.! Isolated communities: 6 per 1,000 births Deficiency in galactosylceramidase enzyme! Buildup of undigested fats affects myelin sheath! Imperfect growth and development of myelin! Severe degeneration of mental and motor skills Lorenzo s Oil featured similar leukodystrophy Normal at birth, symptoms usually start 2-6 mts Fever, uncontrollable crying, seizures, vomiting, spasticity, paralysis, blind, finally death within 2y Juvenile- and adult-onset cases rare Escolar 2009 AJNR
34 Krabbe: Treatment Therapy (Maria Escolar, UNC), Duke! Myeloablative chemotherapy followed by stem cell transplantation from umbilical-cord blood! Treatment at Birth, no effect at symptomatic stage! Treated kids show differences in motor abilities! Survival rate depends on survival of therapy (15 of 17 ~ 88%) New Krabbe s screening with enzyme test! New York started August 2006! Parents often wait DTI: Assessing damage at birth via DTI! Illustration of damage to parents? Diagnosis?! Prediction of developmental outcome for motor abilities Here: Prelim data of project
35 Motor Related Fibertracts Prefrontal cortex Premotor cortex Motor cortex VL thalamus superior cerebellar peduncle corona radiata internal capsule cerebral peduncle Pontine nuclei Deep cerebellar nuc-dentate Cerebellar cortex middle cerebellar peduncle Courtesy of Jim Fallon Left and right hemispheric Cortico-spinal tracts
36 Controls - Left Internal Capsule Tracts Krabbe s - Left Internal Capsule Tracts P1 P2 P3 P4 Worst motor development FA = 0 FA = 1
37 FA Statistics along Fibers FA along Left CorticoSpinal Tract Healthy Krabbe P FA Statistics over 6 Krabbe, 53 Healthy neonate babies
38 FA Stats Center Region Left Corticospinal Tract Left FA Controls Krabbe Left FA Ratio Controls Krabbe FA Value FA ratio (actual FA/Expected FA) FA Distance Along the Corticospinal Tract Gestational Age at Scan (days) Gestational Age at Scan (days) Center region selection => Mean FA computation FA ratio = FA divided by expected FA given gestational age at birth, at scan, birth weight, gender
39 Outcome Correlation FA Ratio at Baseline Cognition Developmental Age Gross motor Calendar Age (months) Fine Motor
40 Conclusion Krabbe Correlation of DTI with outcome after treatment Current investigation:! Natural history of development with DTI! Can DTI predict, when symptoms will arise if untreated? 40
41 Future of DTI Highly valuable MR based modality! Many applications! Considerable validation (though more is needed) What s next?! Higher order of diffusion representation! Improved tractography algorithms! Network analyses! Need for automatic, blackbox processing 41
42 Higher Order Diffusion Representations Active field of research since 2003! Qball, Tuch! DSI, Van Wedeen No real clinical tools yet! Next evolutionary stage for DTI? 42
43 Network Analyses Structural network using diffusion spectral imaging Combination with functional imaging (resting state, event driven) Main issue: stability, clinical application Hagmann 2008 PLOS Biology 43
44 Blackbox Processing DTI property images (FA, MD, AD, RD) clinically useful But tractography application lag behind in clinical use Current processing is! Mostly interactive! Significant training in DTI necessary Need for automatic blackbox tools! No technical training needed! Adequate in presence of pathology! Includes analysis framework 44
45 The last slide We love DTI! And there are many reasons why, as shown in this talk Thanks! 45
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