Diffusion Tensor ImagingBiomarkers of BrainDevelopment and DiseaseEvan Calabrese
Outline1. Introduction and Background2. Optimization of DT-MRH for the rat brain3. DT-MRH of rat postnatal neurodevelopmen...
Introduction and Background
Postnatal neurodevelopmentChanges:• Functional• Behavioral• Macrostructural• Microstructural
Neurodevelopmental disorders• Genetic– Down syndrome– Fragile X syndrome• Infectious– Congenital toxoplasmosis– Congenital...
Animal modelsChanges:• Functional• Behavioral• Macrostructural• Microstructural
Animal models
Magnetic Resonance HistologyThe use of high-resolution MRI tostudymicrostructure infixed tissues
Magnetic Resonance HistologyHistology:the microscopicstructure of tissuesMicroscopic:too small to beseen by theunaided eye
Magnetic Resonance HistologyPros• Non-destructive• Non-deforming• 3D and isotropic• Many H1 contrasts• Quantitative contra...
Developmental Brain Atlasing• Neurodevelopmental diseases are difficult to studyin the dynamic background of neurodevelopm...
Developmental Brain Atlasing1970 2008 2011
Developmental Brain Atlases
An MRH Atlas of Rat PostnatalNeurodevelopment• Will reveal thespatiotemporal trajectory ofnormal postnatalneurodevelopment...
Diffusion Tensor MagneticResonance Histology• DT-MRH is the combination of DiffusionTensor Imaging (DTI) with MagneticReso...
Diffusion Weighted ContrastSdiff = Se-b·Db = diffusion weighting factorD = diffusion coefficient of tissue
Diffusion Weighted ContrastNo diffusion gradient
Diffusion Tensor ImagingTensorEstimation
Diffusion Tensor Imaging
FractionAnisoColorFADiffusionCoefDiffusion Tensor Imaging
Diffusion Tensor Imaging
Barriers to High-Resolution DT-MRH• Small voxel volume• Large data matrices• Long echo time from diffusionencoding• Diffus...
Optimization Points• Pulse sequence design• Specimen preparation• Radio frequency coil design
Diffusion Pulse Sequence Designb =g2d2G2 4D -dp2æèçöø÷S = M0(1-e-TR /T1)e-TE /T 2e-b·D
Specimen Preparation50 mM5 mM for 3-5 days
Specimen Preparation• For stained brains T2 ≈ ¼ T1• Optimal T1 for our pulsesequence = 107 ms• We achieved comparable T1si...
Radio Frequency Coil Design30 mm ID25 mm ID20 mm ID
Optimization Results• 25 µm anatomic (~1 billion voxels)• 50 µm DTI (~128 million voxels)• SNR > 30
DT-MRH of rat postnatalneurodevelopment
• 50 micron isotropic spatialresolution• The atlas includes 9 differenttime points between birth (p0)and adulthood (p80)• ...
Paxinos & Watson Paxinos & Ashwell• Data were oriented towards the relevant histology atlas• p0-p12: Paxinos and Ashwell, ...
Atlas Orientation
An Ontology-Based Segmentation for thePostnatal Rat Brain
The Developmental Ontology
The Developmental Ontology
The Developmental Ontology
Regional Volume Changes ThroughoutPostnatal Neurodevelopment
Regional Postnatal Volume Changes
Regional Postnatal Volume Changes
Regional Postnatal Volume Changesa = estimated adult volumeb = days until inflection pointc = relative growth rate
Voxelwise Estimates of Variability
Diffusion Parameter Changes ThroughoutPostnatal Neurodevelopment
Postnatal Diffusion Tensor Changes
White Matter Diffusion Changes
White Matter Diffusion Changes
Gray Matter Diffusion Changes
Gray Matter Diffusion Changes
Quantifying Neurodevelopmental Changes in aRat Model of FASD
Fetal Alcohol Spectrum Disorders• Caused by maternaldrinking during pregnancy• Leading preventable causeof mental retardat...
Rodent Models of FASD
Rodent Models of FASD• The spatiotemporal trajectory of FASDassociated brain injury is not known• Understanding the time-c...
Research Strategy• Model of 3rd trimester maternal binge drinking• Ethanol gavage on postnatal days 4-9(human 3rd trimeste...
Research StrategyVoxelwise analysisROI analysis
Expected Results and Interpretation
Expected Results and Interpretation
Expected Results and Interpretation
Potential Problems and Alternative Approaches• Model produces consistent injury• Alcohol gavage is technically challenging...
Acknowledgements• Lab– Al Johnson– Alexandra Badea– Yi Qi– Gary Cofer– James Cook– Matt Sherrier• Duke– Chunlei Liu– John ...
Thanks!
Prelim3
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Prelim3

  1. 1. Diffusion Tensor ImagingBiomarkers of BrainDevelopment and DiseaseEvan Calabrese
  2. 2. Outline1. Introduction and Background2. Optimization of DT-MRH for the rat brain3. DT-MRH of rat postnatal neurodevelopment4. Ontology-based segmentation of the postnatal ratbrain5. Analysis of regional volume changes6. Analysis of diffusion tensor changes7. Future directions: application to FASD
  3. 3. Introduction and Background
  4. 4. Postnatal neurodevelopmentChanges:• Functional• Behavioral• Macrostructural• Microstructural
  5. 5. Neurodevelopmental disorders• Genetic– Down syndrome– Fragile X syndrome• Infectious– Congenital toxoplasmosis– Congenital syphilis• Metabolic– Phenylketonuria– Mucopolysaccharidoses• Toxic/nutritional– Neural tube defects– Fetal Alcohol Spectrum Disorders (FASD)• Traumatic– Shaken baby syndrome– Perinatal asphyxia• Unknown/multifactorial– Autism spectrum disorders– Attention deficit hyperactivity disorder– SchizophreniaAberrant postnatal neurodevelopment
  6. 6. Animal modelsChanges:• Functional• Behavioral• Macrostructural• Microstructural
  7. 7. Animal models
  8. 8. Magnetic Resonance HistologyThe use of high-resolution MRI tostudymicrostructure infixed tissues
  9. 9. Magnetic Resonance HistologyHistology:the microscopicstructure of tissuesMicroscopic:too small to beseen by theunaided eye
  10. 10. Magnetic Resonance HistologyPros• Non-destructive• Non-deforming• 3D and isotropic• Many H1 contrasts• Quantitative contrast(Diffusion Tensor MRH)Cons• Resolution (10 μm?)• Expensive equipment• Contrasts mechanismsnot alwaysstraightforward
  11. 11. Developmental Brain Atlasing• Neurodevelopmental diseases are difficult to studyin the dynamic background of neurodevelopment• A well defined normal is necessary fordistinguishing normal from pathologic changes• A quantitative normative atlas of ratneurodevelopment would be helpful for studyingrat models of neurodevelopmental diseases
  12. 12. Developmental Brain Atlasing1970 2008 2011
  13. 13. Developmental Brain Atlases
  14. 14. An MRH Atlas of Rat PostnatalNeurodevelopment• Will reveal thespatiotemporal trajectory ofnormal postnatalneurodevelopment• Will serve as a quantitativereference and database forstudying rat models ofneurodevelopmental disease
  15. 15. Diffusion Tensor MagneticResonance Histology• DT-MRH is the combination of DiffusionTensor Imaging (DTI) with MagneticResonance Histology (MRH)• DT-MRH provides quantitativemeasurements of water diffusionmagnitude and directionality at every voxel
  16. 16. Diffusion Weighted ContrastSdiff = Se-b·Db = diffusion weighting factorD = diffusion coefficient of tissue
  17. 17. Diffusion Weighted ContrastNo diffusion gradient
  18. 18. Diffusion Tensor ImagingTensorEstimation
  19. 19. Diffusion Tensor Imaging
  20. 20. FractionAnisoColorFADiffusionCoefDiffusion Tensor Imaging
  21. 21. Diffusion Tensor Imaging
  22. 22. Barriers to High-Resolution DT-MRH• Small voxel volume• Large data matrices• Long echo time from diffusionencoding• Diffusion contrast = signal loss
  23. 23. Optimization Points• Pulse sequence design• Specimen preparation• Radio frequency coil design
  24. 24. Diffusion Pulse Sequence Designb =g2d2G2 4D -dp2æèçöø÷S = M0(1-e-TR /T1)e-TE /T 2e-b·D
  25. 25. Specimen Preparation50 mM5 mM for 3-5 days
  26. 26. Specimen Preparation• For stained brains T2 ≈ ¼ T1• Optimal T1 for our pulsesequence = 107 ms• We achieved comparable T1sin rat brains throughoutpostnatal neurodevelopmentS = M0(1-e-100/T1)e-16.2/T 2Mean T1 ≈ 110 ms
  27. 27. Radio Frequency Coil Design30 mm ID25 mm ID20 mm ID
  28. 28. Optimization Results• 25 µm anatomic (~1 billion voxels)• 50 µm DTI (~128 million voxels)• SNR > 30
  29. 29. DT-MRH of rat postnatalneurodevelopment
  30. 30. • 50 micron isotropic spatialresolution• The atlas includes 9 differenttime points between birth (p0)and adulthood (p80)• Each time point features 9distinct image contrasts, plustractographyGRE = gradient recalledechoFAC = FA colorAD = axial diffusivityDWI = diffusion-weightedimageX = magnetic susceptibilityRD = radial diffusivityT2 = T2-weighted contrastFA = Fractional anisotropyADC = apparent diffusioncoefficientAtlas Dimensionality
  31. 31. Paxinos & Watson Paxinos & Ashwell• Data were oriented towards the relevant histology atlas• p0-p12: Paxinos and Ashwell, Atlas of the Developing Rat Brain• p18-p80: Paxinos and Watson, The Rat Brain in Stereotaxic CoordinatesAtlas Orientation
  32. 32. Atlas Orientation
  33. 33. An Ontology-Based Segmentation for thePostnatal Rat Brain
  34. 34. The Developmental Ontology
  35. 35. The Developmental Ontology
  36. 36. The Developmental Ontology
  37. 37. Regional Volume Changes ThroughoutPostnatal Neurodevelopment
  38. 38. Regional Postnatal Volume Changes
  39. 39. Regional Postnatal Volume Changes
  40. 40. Regional Postnatal Volume Changesa = estimated adult volumeb = days until inflection pointc = relative growth rate
  41. 41. Voxelwise Estimates of Variability
  42. 42. Diffusion Parameter Changes ThroughoutPostnatal Neurodevelopment
  43. 43. Postnatal Diffusion Tensor Changes
  44. 44. White Matter Diffusion Changes
  45. 45. White Matter Diffusion Changes
  46. 46. Gray Matter Diffusion Changes
  47. 47. Gray Matter Diffusion Changes
  48. 48. Quantifying Neurodevelopmental Changes in aRat Model of FASD
  49. 49. Fetal Alcohol Spectrum Disorders• Caused by maternaldrinking during pregnancy• Leading preventable causeof mental retardation andbirth defects• Prevalence ≈1% in USA• At its most severe (FAS)retardation and craniofacialabnormalities
  50. 50. Rodent Models of FASD
  51. 51. Rodent Models of FASD• The spatiotemporal trajectory of FASDassociated brain injury is not known• Understanding the time-course of the injurywill be important for planning interventions• Specific Aim: Quantify the spatiotemporalcourse of brain injury in a rat model of FASD
  52. 52. Research Strategy• Model of 3rd trimester maternal binge drinking• Ethanol gavage on postnatal days 4-9(human 3rd trimester equivalent)• Imaging time points: p12, p18, p24, p40, p80• 8 ethanol exposed and 8 sham controls ateach time point
  53. 53. Research StrategyVoxelwise analysisROI analysis
  54. 54. Expected Results and Interpretation
  55. 55. Expected Results and Interpretation
  56. 56. Expected Results and Interpretation
  57. 57. Potential Problems and Alternative Approaches• Model produces consistent injury• Alcohol gavage is technically challenging(Sulik lab collaboration)• Lots of scan time required• Analysis will be computationally demanding• Results may require conventional histologicvalidation
  58. 58. Acknowledgements• Lab– Al Johnson– Alexandra Badea– Yi Qi– Gary Cofer– James Cook– Matt Sherrier• Duke– Chunlei Liu– John Lee– David Lee– Neil Medvitz– Sara Miller• Committee– Al Johnson– Charles Watson– Chunlei Liu– Gregg Trahey– James Provenzale• External– Charles Watson– George Paxinos– Kathleen Sulik– Shonagh O’Leary-Moore
  59. 59. Thanks!

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