IRM fonctionnelle cérébrale:Bases physiques et biologiques

Denis Le BihanService Hospitalier Frédéric Joliot, UNAF/CEA, Orsay

Magnetic Resonance Imaging…

Signa LX, SHFJ/CEA, Orsay

Strong magnet

The Magnets…

Signa 3.0T

Signa Infinity 1.5T

Ovation 0.35T

Signa SP 0.5T

Refrigerator door magnets 0.005T=50G!

• Magnetic field strength measured in units of Gauss or Tesla:

• 1 tesla = 10,000 gauss• Earth’s magnetic field: 0.5 gauss• Superconducting magnets: filled

with liquid Helium (-269°C)

Profile 0.2T

Magnex 7.0T

OpenSpeed 0.7T

Magnetizing tissues …• Not all nuclei are MRI friendly!

Hydrogen 1H (42.6 MHz/T) Body abondance (H20) +++Carbon 12C Carbon 13C (1% of natural carbon)Oxygen 16O Oxygen 17O (5.8 MHz/T)

Fluor 19F (40MHz/T)

Phosporus 31P (17.2 MHz/T)

No field Bo field (thermal equilibrium) (against thermal equilibrium)

Bo (T) 0.1 0.5 1.5 3 …E (MHz) 4.3 21 64 125 …

M = MH-MLMH-ML ≈ 1/106 (very weak effect!)MH-ML α Bo

1M$/T !

• Magnetization of atomic nuclei

Magnetic Resonance Imaging…

Signa LX, SHFJ/CEA, Orsay

Strong magnetic field

Water(hydrogen nuclei)

Radiofrequency field Tx/Rx

RF coils…• Must be as close as possible to the object to image

(filling factor)• 3 types of coils:

• Transmit/receive (linear, quadrature)(body, head quadrature coils, knee coil …)

• Receive only (surface coils)(all purpose coils, breast coils, …)

• Phased array coils(cardiac/torso, spine, vascular coils, …)

Ehigh

Elow

1-Transmission (short RF pulse on resonance frequency)

RF pulses

Free Induction Decay signals

Getting a signal:Magnetic Resonance…

2-Excitation (transient)

3-Relaxation

4-Reception (on resonance frequency)

T1

T2

T2 T2 ++Playing with basic contrast (T1, T2)

Magnetic Resonance Imaging…

Signa LX, SHFJ/CEA, Orsay

Strong magnet

Water(hydrogen nuclei)

Gradient coils

Radiofrequency field Tx/Rx

Bo

z-gradient y-gradient

z

y

FREQUENCY

POSITION

SIGNAL

FIELD GRADIENT:

ω = γ G z

t

Localizing the MR signal:Gradient coils…

SPECTRUM =PROJECTION

ω

(Slice selection)

ω = γ G y

ALL COLUMNS CENTRAL 50% OUTER 50%

ky

kx

GzSlice selection

Gx

Gy

The MRI slice in k-space

Image space k-space

K-space sampling strategies

• « OLD style »• Switch from Spin-Echo to Gradient-Echo• Partial k-space sampling

(Half or partial Nex, rectangular FOV,…)

• « MODERN tricks »• Several echoes (lines) per shot (EPI, FSE,…)• Fast gradient hardware

• RADIAL (back-projections)• LINES (single lines 2D-FT)• ZIG-ZAG (EPI)• SPIRAL• YOUR OWN ….

• ISSUES: GRADIENT PERFORMANCE+++• Speed/Resolution• Artifacts (motion, reconstruction)• Contrast, SNR

EPI: Practical issues

• Sensitive to field gradient artifacts (eddy currents, susceptibility interfaces)– geometric distortion (anatomical localization of activation foci)– signal drop-out (frontal and temporal poles)

5 mT/m 10 mT/m 16 mT/m 80 ms130 ms250 ms

New high resolutionMR detectors

SENSE reconstruction

Without SENSE, ETL=48

ETL=32Shorter acquisition time with SENSE

kx

ky

« NEW tricks »: Parallel Imaging (SMASH, SENSE,…)Simultaneous acquisition of k-space linesSpecial phased-array coils: RF hardware

The spatial information contained in the component detectors of an array are used to partially replace spatial encoding which would normally be performed using gradients

More SNR, higher spatial or temporal resolution, less distortion, better spatial coverage.

De l’anatomie à la fonction:Un peu de physiologie...

Brain of Mr. Leborgne, Broca’s patient

Anatomie Fonctionelle macroscopique:– correlation entre anatomie et fonction (Broca) +++

• Fonctionnement cérébral:– Cortex/Noyaux gris:

péricaryons, dendrites, synapses – Substance blanche:

axones myélinisés– Glie , vaisseaux, ....

Paramètres d’accès au fonctionnement cérébral• Biophysique

polarisation dendritique, potentiels d’action,échanges ioniques --> EEG/MEG

Neurochimie, neuropharmacologie(neurotransmetteurs, récepteurs--> ligands TEP)

Biologie moléculaire(canaux ioniques, expression gènes)

Biochimie: TEP, IRMf, NIRSmétabolisme (présynaptique)--> (CMRglu, CMRO2, ... ? CBF)

• Imagerie--> Choix des paramètres à mesurer/imager--> Limites de la résolution temporelle et spatiale--> Définit le caractère non invasif, simplicité, coût

FMRI (PET)Neuronal activation ⇐⇒ Metabolism ⇐⇒ Blood Flow

..."The brain possesses an intrinsic mechanism by which its vascular supply can be varied locally in correspondence with local variations of functional activity"...

Roy, C.W. & Sherrington, C.S. J Physiol 1890, 11: 85-108.

Sat O2CBF CBVArtery Capillaries Vein

ActivationRest

Functional MRI: The Hemodynamic Filter

• Indirect reflect of neuronal activity– neurovascular (un)coupling?

CMRO2 < CRMglu << CBF,CBV– Origin? Mechanism? Adapted from Magistratti et al.

IRM et Perfusion cérébrale• Traceurs diffusibles: 19F, D2O, H2

17O (effet direct)

• Agents intravasculaires (+++): – Origine:

Exogènes: Complexes de Gadolinium (Gd-DTPA)Endogènes: Déoxyhémoglobine (BOLD)

– UtilisationIRM de perfusion clinique (Gd)fMRI standard (BOLD)

– Mécanisme indirect: différence de susceptibilité magnétique sang/tissue

Blood Oxygen Level Dependent(BOLD)Contrast- Theory -

BOLD fMRI Physics

• Magnetic status of Hemoglobin in RBC: (O2)-Fe-HemeOxyHb: DiamagneticDeoxyHb: Paramagnetic ( Hb: Gd-chelate like)

DeoxyHb in Red Blood Cells induces a local susceptibility difference which results in local magnetic field gradients (Thulborn1982)

Effect on nearby tissue water relaxation (amplification)

BOLD fMRI: A Historical Perspective ...

Ogawa et al. (rat), 1990 followed by Turner et al. (cat): 1991

Hypoxic brain

Effect of RBC DeoxyHb on tissue water relaxation

Hb

Hb

Hb

TISSUEVessel

• Dynamic effect: diffusion (α Bo²)– seen on both GE & SE sequences

Echo signal drop

MRI Signal(tissue water)

TE

DeoxyHb: T2*

• Static effect: intravoxel dephasing (α Bo) – seen on Gradient Echo sequences only

BOLD fMRI: A Historical Perspective ...

Kwong al. (human), followed by Bandettini et al. (cat), 1992

Visual stimulation

Sat O2CBF CBVArtery Capillaries Vein

ActivationRest

BOLD fMRI Biophysics: Summary ...

-0.1%0.9%1.9%2.9%3.9%4.9%5.9%

-4 -2 0 2 4 6 8 10 121416 1820Time (s)

BOLD signal4.4s stimulation BOLD effect

-is small-delayed with respect to stimulus onset-lasts a few seconds

BOLD (susceptibility) effect increases with Bo, better seen with gradient-echoes than spin-echoes

BOLD Imaging=vessel imaging!∆R2* = 4.3 γ∆χ(1-Y) B0 CBV

∆R2* = 0.04 {γ∆χ(1-Y)}2 B02 CBV

(venules, larger vessels)

(smaller capillaries)Ogawa et al., Biophys. J., 64:803-812, 1993

• Effets champ, séquence, taille vaisseaux(Weisskoff):

»composante ‘petits vaisseaux’(<30µm):diffusion ++, varie avec Bo², visible SE

(TEopt=T2)»composante ‘macrovaisseaux’

déphasage statique ++, varie avec Bo, visible GE>ASE>SE (TEopt=T2*)

High Resolution at 4 Tesla

0

1

2

3

4

0 4 8 12 16 20 24 28

Time (s)

Perc

ent s

igna

l cha

nge Corresponding eye

stimulation

Other eyestimulation

Ocular dominance columns

University of Western Ontario

Drive to Higher Field

• Conventional field strength: 1.5 Tesla• High field systems: 2 Tesla - 4.7 Tesla• Ultra high field systems: 7, 8, 9.4,… Tesla

Blood Oxygen Level Dependent(BOLD)Contrast

- Practical matters -

BOLD fMRI: …which MRI sequence?

• Requirement: Ultra-fast imaging +++– to follow the hemodynamic response (TR=2-3 s)– with whole brain coverage (30+ slices)– robust to motion artifacts (single shot sequence)

TR

BOLD responsemostly used sequence = Echo-Planar Imaging (EPI)

EPI: Practical issues (1)• Optimization of EPI sequence:

– TE ≈ brain tissue T2* (60ms @ 1.5T, 35ms @ 3T)– voxel size: isotropic (typically 2-4mm)– data echo train: as short as possible (half-Fourier, …)

• Artifacts +++ (distorsion, signal drop-out)• Gradient switching is extremely noisy (100+

dB)

– hear protection mandatory (ears plugs,…)

– interference with auditory stimuli (language,…)use of silent interval or insertion of ‘silent’ sequences

0 2 4 6 8 10 12 14

(silence) (silence) (silence) (silence)

1 volume (2.1 sec) 22 slices 1 TR (3.5 sec)

Time (seconds)

AuditoryStimuli

“BEEPS” (slices)

Patient set-up +++

• Stimulation hardware– vision, audition, taste, ….– Compatible by MRI equipement– Synchronization with MRI scanner

• Task performance control– Mouse/joystick (yes/no response, reaction times)– Eye motion recording, EEG,...

Le filtre hémodynamique

• Résolution limitée– Résolution spatiale (réseau vasculaire)

» Selon le compartiment vasculaire (mm3)(artériole, capillaire, vénule)

– Résolution temporelle limitée (régulation vasculaire)» Réponse hémodynamique (secondes)

Relation avec l’activation

– Linéarité? (stim. paramétriques, multiples ou rapprochés)

– Effets toniques/transitoires ? (stimuli longs)– Seuil? (stimuli brefs ou faibles)

Imagerie Neurofonctionnelle:Le filtre hémodynamique

• Réflexion indirecte de l’activité neuronale– Mécanisme?

recrutement capillaire, vitesse de circulation– Régulation?

neurogène, neuromédiateur, NO,...– Couplage réponse BOLD/ neurophysiologie: relation

complexe (biologie ET physique: résolution, Bo,…)

– Variations?Âgepathologie:MAV,..., pharmacologie: antihistaminiques?

Absence de réponse BOLD ???

Left prefrontal AVMStory ListeningWord repetition

Before embolization

After embolization

S. Lehéricy et al., Radiology

Interprétation des données IRMf

• Régions ‘silencieuses’?– seuils statistiques

• Régions ‘activatées’?– rôle réel dans une fonction cognitive

• Précision anatomique?– Position/extension des foyers activés– Corrélation avec l’électrophysiologie

(moteur, language, ...)

BONUS- Agents de contraste –

- IRM de diffusion -

IRM et Perfusion cérébrale• Traceurs diffusibles: 19F, D2O, H2

17O (effet direct)

• Agents intravasculaires (+++): – Origine:

Exogènes: Complexes de Gadolinium (Gd-DTPA)Endogènes: Déoxyhémoglobine (BOLD)

– UtilisationIRM de perfusion clinique (Gd)fMRI standard (BOLD)

– Mécanisme indirect: différence de susceptibilité magnétique sang/tissue

CBV Mapping Using MION

dextran coating

central mono-crystallinemagnetite-like single crystal core

iron oxide agentcrystal 3.94±0.3nmMION 17.1±0.9nm

Ralph WeisslederMGH Center forMolecular Imaging Research

Localizationforepaw stimulation cocaine

BOLD

CBV

J.B. Mandeville, MGH-NMR Center

Diffusion MRI…

… of water

Water (hydrogen protons)

Magnetic Resonance Imaging (MRI)Diffusion

• Free water: D ≈3 10-9m²/s @ 37°C <x²>1/2 ≈ 17µm (Td = 50ms)

<x2>1/2

Td1/2

D

50

17

Global scale

Meso scale architecture ?

b

S

b

ADC

Diffusion sensitized Half-Fourier Spin Echo EPI

sequence

RF

Gsel.Gph-enc.

Gread.

ADC map

Dw MRI

AnisotropicDiffusion

• 1990: Diffusion anisotropy in brain/spine white matter

• 1992-94: Diffusion Tensor MRI principles

Mapping cortex connectivity with MR diffusion(Mangin, Poupon, Cointepas)

Tracts + cortical gyri

Infering connectivity matrices

Functional networks

Grasping

Tensor imaging

Tracking main bundles

High angular resolutionBundle crossing

Spin glass models

Combining BOLD fMRI and DTI in the cat cortex. Kim and al., 2001

Combining fMRI + DTI

A BPrimary Auditory CortexReceptive Language AreaExpressive Language Area

• A: Fiber bundles originating from Wernicke• B: Fiber tract between Wernicke and Broca: fasciculus

arcuatusCourtesy S. Sunaert, Leuwen

Dysconnection (DTI)

Leftwords

Rightwords

Normal Subject

Combining fMRI + DTI

Alexic Patient

Leftwords

Rightwords

Molko, Cohen, Le Bihan, Dehaene et al. JoCN, 2002

For their contribution:(Lab. of Anatomical and Functional Neuroimaging, SHFJ/CEA, Orsay)– H. Chabriat , S. Pappata & N. Molko– C. Clark, N. Lori– A. Darquie, I. Klein– S. Chabert, C. Mecca– S. Dehaene and coll.– L. Hertz-Pannier & C. Chiron– F. Lethimmonier, E. Giacomini– J.F. Mangin, D. Papadopoulos, D.

Rivière, C. Poupon,Y. Cointepas– J.B. Poline, Ph. Ciuciu, F. Kherif &

A.L. Paradis