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WaterWater: : thethe forgottenforgotten moleculemoleculeDiffusionDiffusion magneticmagnetic resonanceresonance imagingimagingand and fiberfiber trackingtrackingDr. András Jakab, MD, PhDDr.Berényi Ervin, MD, PhD

Multimodal Imaging in Neurosciences credit course, 2012

Diagnostic neuroimaging modalities

CT – Computed TomographyBrain anatomyStereotactic reference frame

Structural MRIFine brain anatomyVascular structure

Diffusion, perfusion MRIFine pathologicalinformation

Intra-operative imagingmodalities, open MRI, low-field

Multi-modal imagingspectrum for

MR SpectroscopyBrain metabolismBiochemical mapping

Positron EmissionTomography PETBrain metabolismBrain function

Functional MR imaging fMRIBrain function

Electro encephalography, LORETTA, Magnetoencephalography

1.Diagnostic imaging2.Research

3.Neurosurgery

KEY LEARNING POINTS TODAY

1. What is the biological diffusion in thehuman brain like?

2. How does diffusion weighted MRI work? (DWI)

3. How does diffusion tensor MRI work? (DTI)4. What is fiber tractography?5. What are the clinical applications of DWI?6. What are the research applications of DTI

and tractographies?

CHAPTER I. – BIOLOGICALDIFFUSION

MeasuringMeasuring tissuetissue propertiesproperties withwith MRIMRI

T1 relaxation

T2 relaxation

Proton density

Ti diff i

Structural MRI

Diffusion-weightedTissue diffusion

Diffusion direction

Diffusion anisotropy

Diffusion maps

Metabolites

weightedimaging

Diffusion tensorimaging

Diffusion spectralimaging, HARDI

MR spectroscopy

„The „The forgottenforgotten moleculemolecule””

Water has special properties:

•H-bonds

• Favours polar molecules

• Topologically binds to proteins?

• High surface friction

• High heat capacity

• Soluble oxygen

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„The „The forgottenforgotten moleculemolecule””Water in biological tissues

Kémiai Nobel –díj 2003: Peter Agre (aquaporins), Roderick MacKinnon (K-csat.)

DiffusionDiffusion: : thethe biologicalbiological basicsbasics

1827, Robert BrownVis vitalis? Or sometingelse?Random motionRandom motion„Thermal motion” F.M.Exner, 1900

DiffusionDiffusion: : basicbasic physicsphysics1905: „the miraculous year”

“On a Heuristic Point of View on the Creation and Conversion of Light”(17 March 1905)(Photo-Electric Effect) Nobel prize in physics, 1921

“On the Electrodynamics of Moving Bodies” (30 June 1905)

“Does the inertia of a body depend on its energy content?”(27 September 1905)(Theory of Special Relativity) E = mc²

“Investigation on the Theory of the Brownian Movement: On the motion of small particles suspended in liquids at rest …”(11 May 1905)

Albert Einstein, 1905

Einstein, Einstein, 19051905The molecular-kinetic theory of temperature : Brownian motion = molecular diffusion

0

RANDOM WALK

?

SourceSource Karla Miller, FMRIB, University of OxfordKarla Miller, FMRIB, University of Oxford

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Image source: Brian Wandell, Stanford

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End of part I. - any questions? CHAPTER II. – DIFFUSION MRI

THE MRI RECIPE

Human, made of

1. Patient (water + fat = lot of spins)

2. Excite (Shout at the patient with a radiofrequency coil)

3. Wait until the excited spins „relax”

4. During relaxation, the spins (water + fat =patient) shout back at you, theysend an ECHO

5. You listen to the echo and record it(this is the k-space acquisition)

Repeat this! This is called SEQUENCE

6 D d th i l t i !,excitable spins

(H proton spins)ECH

O6. Decode the signal, get image!

DiffusionDiffusion--weightedweighted MR MR imagingimaging (DWI)(DWI)

Le Bihan & Breton, CRASS, 1985Intravoxel incoherent motionMovement during imaging = the MRI signal is affectedS ti ll i t ti di tSpatially variant magnetic gradientencodes the location of spinsStationary vs. Moving molecules arecoded

Forrás: Karla Miller, FMRIB, University of OxfordForrás: Karla Miller, FMRIB, University of Oxford Forrás: Karla Miller, FMRIB, University of OxfordForrás: Karla Miller, FMRIB, University of Oxford

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The image The image contrastcontrast formationformation duringduringDWIDWI

If particles move during the imaging time, the signal is attenuatedIf diffusion is slower, the signal is higher(more particles „stay in place”)( p „ y p )

StejskalStejskal--TannerTanner sequencesequenceDiffusion-weighting in the MRI sequence◦ Apply a gradient for delta time (-> DTI!)◦ Apply in many directions (at least 3)

◦ So what does DWI tells us?

◦ = the diffusion magnitude = diffusion coefficient

SoSo whatwhat doesdoes diffusiondiffusion MRI MRI measuremeasure??1. How fast is diffusion in tissues?2. Is there a pathology, where diffusion is

restricted (cells are dead)?

…. WHAT ELSE??

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WhyWhy tissuetissue diffusiondiffusion is is specialspecial??It has directional preference = anisotropic!!

Forrás: Karla Miller, FMRIB, University of OxfordForrás: Karla Miller, FMRIB, University of Oxford

WhatWhat typestypes of of diffusiondiffusion areare therethere??

Free diffusion (isotropic)Restricted diffusionHindered diffusion (barriers)

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Diffusion ImagingDiffusion Imaging

S. Maier and M. Kubicki

In an isotropic medium (inside a glass of water for example) water molecules naturally move according to Brownian motion.

In biological tissues however the diffusion is very often anisotropic. For example a molecule inside the axon of a neuron has a low probability to cross a myelin membrane.

Apply gradient in a given direction dark regions correspond to where non Brownian motion has occured.

Displaying Displaying thethe diffusion’sdiffusion’s directiondirectionBiological diffusion shows various magnitudes in different directions.

Herpes encephalitisforrás: emedicine.medscape.com

Healthy brain

ACA strokeforrás: RADsounds Wiki

DTI allows researchers to quantify the diffusion of water in brain tissue

Diffusion for each image voxel is described by 3 perpendicular vectors

λ1λ2

λ1

Diffusion Tensors & AnisotropyDiffusion Tensors & Anisotropy

λ3λ2

λ3

Isotropic diffusion occurs when there is no restriction to water movement (e.g., ventricles, CSF)

Anisotropic diffusionoccurs when water movement is restricted to one primary direction (e.g., myelinated fibers)

DiffusionDiffusion tensorstensors (?)(?)Examining diffusion from many directions = direction encoding

Peter Basser (NIH)

TENSORS: the keyto display directiondependency

MappingMapping diffusiondiffusion

Diffusion weighted image acquisition

Spatial representation of diffusion magnitudes

Calculating tensors for eachimage point

Displaying tensorial information on scalarimages

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Image source: Brian Wandell, Stanford

So what is needed for diffusiontensor imaging?

- Many diffusion weightingdirections during a scan

-At least 6 directions

- Suggested: 24-64 directions

- Processing of images- Processing of images

- Special display modes

WhatWhat cancan wewe measuremeasure withwith DTI?DTI?Diffusion MAGNITUDE: APPARENT DIFFUSION COEFFICIENTThe orderedness of diffusion: DIFFUSION ANISOTROPY

Diffusion direction (color coded maps)

Diffusion magnitudes parallel and perpendicular to fibers

End of part II. - any questions? CHAPTER III. – TRACTOGRAPHY

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DiffusionDiffusion tractographytractographyTract = brain pathway, axonal pathwaysTractography = displaying white matter pathways through post-procesisng of diffusion tensor imagesBrain connections?Computerized data and image processing

DiffusionDiffusion tractography: tractography: examplesexamplesDisplaying the cortico-spinal tract

DiffusionDiffusion tractography: tractography: examplesexamples

Displaying language pathways

Right handed Left handed

NeuroImage 35 (2007) 1064–1076

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Konnektivity (c) Jakab A.

BeyondBeyond tensorstensors……Making the resolution of axons betterQ-ball imaging, High angular diffusionimaging (HARDI)

End of part III. - any questions?

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CHAPTER IV. – PRACTICAL USE OFDIFFUSION MRI (DWI, DTI)

SummarySummary soso far:far:T1, T2-weighted MRI: relaxation time of tissue waterprotons (i.e. in „watery” of „fatty” environment)

Diffusion weighted MRI (DWI) : the magnitude of diffusion, restricted diffusion

Diffusion tensor MRI (DTI): the orientation of diffusion

Tractography: displaying white matter pathways

Diffusion spectrum imaging (DSI): the precise spatialcharacteristics of diffusion with high angular resolution

DWI, DTI and tractography can be combinedwith oter imaging modalities (CT, MRI, PET…)

Post-contrast Axial T1-wtd image

T1-wtd imageFLAIR ImageDiffusion weighted image (DWI)

Diffusion weighted image (DWI)

9.1a 9.1b 9.1c 9.1d

Q9.1. Diagnosis Please Post-contrast coronal T1 wtd image

MRA Circle of Willis

Diffusion weighted image (DWI)9.1e 9.1f

47 year-old left handed gentleman with one day history of somnolence, left facial droop and slurred speech.

11. DWI . DWI inin ischaemicischaemic strokestrokeStroke: ischaemiaCells are dying, Na/K pump disfunction, cells swell, extracellular spaces are reduced (cytotoxic edema!)Diffusion becomes restricted in 15-30 minutesIschaemic stroke is the single best clinical application of DWI so far!

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2. DWI 2. DWI differentiatesdifferentiates abscessesabscesses and and tumorstumors

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AbscessNecrotic high-gradetumor

Content of an abscess = „soup”, dense pusContent of a necrotic tumor center = liquid

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33. DWI . DWI differentiatesdifferentiates epidermoidepidermoid cystcystfromfrom arachnoidarachnoid cystscysts

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Content of an epidermoid tumor = dense cellsContent of a arachnoid cyst = liquid

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White White mattermatter characterizationcharacterization withwith DTI?DTI?

Anizotrópia ++ Anizotrópia +Anizotrópia -Diffúzió -

Anizotrópia - -Diffúzió ? / n

Anizotrópia - -Diffúzió - -

DTI DTI applicationsapplications 11..

Structure, anatomy of white matter◦ Development, anatomy of white matter◦ Disrupted anatomy of white matter (i.e. for

neurosurgeons)

Tissue integrity◦ Demyelinisation (Multiple sclerosis)◦ Axonal damage, Wallerian degeneration◦ Edemea◦ Characterizing pathological tissues

DTI DTI inin neuroneuro--oncologyoncology• DTI can characterize brain tumors

preoperatively– FA is reduced: vasogenic edema or infiltration?– Tumor FA: cellularity, proliferation activity

current literature”:– „current literature :• Frakcionális anizotrópia: Cellularitás és proliferációs aktivitás (MIB-2)• MRS és DTI: Proliferációs aktivitás (Ki-67)• FA: Low grade vs. Anaplasticus glioma• ADC hisztogramok: 1p/19q l.o.h. oligodendrogliomákban• „Oligo-like” és „astro-like” komponens megjelenítése• ADC hisztogram: Terápiás válasz (Bevacizumab), progressziómentes időtartam becslése

– Displaying white matter tract’s relation to tumors

mean FA: 0.1887

mean ADC(x1k): 1.4791

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DTI DTI inin neuroneuro--oncologyoncologyA. Jakab, M. Emri, P. Molnár, E. Berényi. Glioma grade assessment by using histogram analysis of diffusion tensor imaging-derived maps. Neuroradiology. 2010 Sep 21.

What is the tumor’sgrade?Low? (WHO I-II) High? (WHO III-IV)

DTI: DTI: clinicalclinical examplesexamples

• Forrás: Nucifora et al. (2007) Diffusion-Tensor MR Imaging and Tractography: Exploring BrainMicrostructure and Connectivity. Radiology. 245, 367-384.

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Theodor Meynert (1833-1892)• Role of the frontal lobe• White matter connections

underlie intelligence?• Disconnection in syndromes

• Forrás: Nucifora et al. (2007) Diffusion-Tensor MR Imaging and Tractography: Exploring BrainMicrostructure and Connectivity. Radiology. 245, 367-384.

• Forrás: Nucifora et al. (2007) Diffusion-Tensor MR Imaging and Tractography: Exploring BrainMicrostructure and Connectivity. Radiology. 245, 367-384.

• Forrás: Nucifora et al. (2007) Diffusion-Tensor MR Imaging and Tractography: Exploring BrainMicrostructure and Connectivity. Radiology. 245, 367-384.

• Forrás: Lee et al. Diffusion-Tensor MR Imaging and Fiber Tractography: A New Method of Describing Aberrant Fiber Connections in Developmental CNS Anomalies

Cerebral palsy in a 20-month-old girl with spastic hemiplegia.

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• Source: Berényi E, Jakab ASmall girl, epileptic seizures

Ohdo syndromaOhdo syndroma

DTI and DTI and neuroscienceneuroscience researchresearch

UnderstandingUnderstanding brainbrain developmentdevelopment ininuteroutero

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FiberFiber trackingtracking of a of a livingliving fetusfetus ininuteroutero

Image credits: Gregor Kasprian, University of Vienna

Language pathways

Jakab A, Béres M, Spisák T, Kis SA, Emri M, Berényi E, Handedness and interhemispheric differences in the anatomical connectivity of perisylvian language areas: a network-based approach, Magn. Reson. Mat. Phys. Biol. Med. 24 (S1):276, 2011.

Left sideRight side

Right dominance!

Displaying the arcuate fasciculus

Normal anatomy vs. Aphasia!

Malformations• The anatomy of the arcuate in severe

brain developmental diseases inchildren

• Schizencephaly, polymicrogyria, lissencephaly, …

• Jakab A M Paldino – Harvard MedicalJakab A, M.Paldino Harvard MedicalSchool, Children’s Hospital

Parcellating grey matter from connectivity• Visualizing the connections from subcortex to cortex• Thalamus

• Specific cortical connections

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Behrens et al. Non-invasive mapping of connections between human thalamus and cortex using diffusion imaging Nature Neuroscience 6, 750 - 757 (2003)

Segmenting the thalamus

New type of image contrast

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Biological correspondence: regions defined by Atlas vs. connectivity

Biological correspondence: regions defined by Atlas vs. connectivity

Biological correspondence: regions defined by Atlas vs. connectivity

Cortico-thalamic connections depicted using probabilistic tractography. Points represent the center-of-gravities of each connectivity map. Axial (top) view, isometric 3d display.

Connections of the precentral and postcentral gyrus and the spatial relationship between connectivity-based landmarks and the MNI152-transformed Morel Atlas data (VLpv, VPLa, VPLp nuclei). Points represent the center-of-gravities of each connectivity map. Superior view, isometric 3d display.

Applications: neurosurgical planning(thalamotomies)Kincses ZT et al. (2012) Target Identification for Stereotactic ThalamotomyUsing Diffusion Tractography- PloS One.7(1): e29969. doi:10.1371/journal.pone.0029969

Jakab A et al. (2012) Generation of Individualized Thalamus Target Maps by Using Statistical Shape Models and Thalamocortical Tractography. AJNR American Journal of Neuroradiology. doi: 10.3174/ajnr.A3140

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Any questions?