Membranes, water and diffusion: Potential for brain imaging

Transcription

1 Membranes, water and diffusion: Potential for brain imaging Denis Le Bihan NeuroSpin Director,, CEA-Saclay, France Kyoto University, Japan Institut de France, Academy of Sciences

2 Functional neuroimaging (PET, fmri): A Water Story Coupling between blood flow, metabolism and activation (Roy & Sherrington, 1894) Iron Do we need better? BOLD fmri H2015* PET Hemoglobin Rest Activation Òblood flow Òquantity of radioactive water in activated tissues Radioactive water Seiji Ogawa Òblood flow & oxygenation Ômagnetized water relaxation in/near vessels Magnetized water

3 BOLD fmri: Hemodynamic events Coupling between CBF, metabolism and activation (Roy & Sherrington, 1894) Rationale & mechanism? metabolism (glucose) vs neurogenic? activation of glial cells by glutamate arachidonic acid > vasodilation/vasoconstriction (Gordon et al. Nature. 456, 745, 2008) po 2? large increase in blood flow but small increase in O 2 consumption AVM embolization Biochemistry Lehericy et al. Neurology, 2002 Biophysics fmri BOLD not always coupled to neuronal activity or metabolism! Anticipatory signals (Sirotin et al. Nature 457, 475, 2009), pathology, drugs: indomethacin, antihistamin, 5.9% 4.9% 3.9% 2.9% 1.9% 0.9% -0.1% Time (s) T monkey Logothetis et al Nature Functional hyperhemia & local field potentials Other more direct mechanisms? Small induced electric axonal currents ( EEG/MEG) Indirect reflect of neuronal activation No Neurotransmission: separation of neuron Ca 2+ inflow clusters as seen sharing with MnMRI vascularization Intrinsic Structural limitation events induced spatial/temporal in cortical cells resolution Water diffusion MRI [Darquie et al. PNAS 2001]

4 IRM IRM de DIFFUSION chelle macroscopique (millimètres) Cancer? chelle microscopique (micromètres) Free water: D C <x²> 1/2 17µm (T d = 50ms) 17 <x 2 > 1/2 D Eau (noyaux d hydrogène) Le Bihan & Breton, CRASS, 1985 Stroke Brain connectivity Functional MRI b 50 Td 1/2

5 IRM de Diffusion... Effet directionnel (anisotropie) Mangin, Poupon et al. MICCAI 1998, NI 2000 vers la connectivité cérébrale

6 Du mouvement brownien à la connectivité cérébrale: L imagerie du Tenseur de diffusion (Basser & Le Bihan, ) BrainVISA software Cointepas et al.

7 Diffusion-sensitized MRI: tissue events 1 - Cell swelling Ù Decreased water diffusion 9 9 Change in water diffusion coefficient with osmolality High osmolality Æ cell shrinking, increased diffusion Low osmolality Æ cell swelling, decreased diffusion Decreases water diffusion have been reported in - Stroke - Extra-physiological activation: status epilepticus induced by bicuculline and cortical electroshocks (Zhong), spreading depression (Sotak, Moseley) 2 - Physiological neuronal activation Ù cell swelling NIRS data, Grinwald et al. CA1 Hippocampal region Extracellular field potential OPTICAL IMAGING Infra-Red transmittance black: dendritic region gray: somatic region Tasaki, 1988 Neuron s Vasculature (Takagi et al. 2002) Optical imaging

8 Diffusion-sensitized 3T Diffusion fmri 2.20% % % BOLD fmri 0.70% 0.20% -0.30% Time (s) Early response (<vascular events) deoxyhb rcbf oxyhb rcbf-cmro² Total Hb rcbv Le Bihan et al. PNAS 103, , 2006 SIgnal intensity (raw) b time (s) Simultaneous measurement of NIRS, BOLD and DfMRI (Satoru Kohno et al. JCBFM in press)

9 Water diffusion model in the brain: Back to Einstein P ( R, t d ) = 4πDt R 4 Dt d <x²> 1/2 For MRI: S=exp (-b D) 1 d e 2 Free diffusion = Gaussian distribution of displacements <x²> = 2 Dt human brain cortex Clark CA & Le Bihan D, MRM, 2002 A d Restricted ln (S) b D Hindered Permeable Barriers B Displacement profil (q-space) : Gaussian 1 + Gaussian 2 Biexponential behavior: diffusion is not free 2 water pools?

10 3.2 Å The water molecule 'Water is H2O, hydrogen two parts, oxygen one, but there is also a third thing, that makes it water and nobody knows what it is. D H Lawrence ( ) Hydrogen bond Å (liquid) Water tetramer R = (+0.000, ) Å, α = 6 ± 20, β = 57 ± 10 Æ Liquid water: tetrahedral H-bond network with local defects Proton mobility (diffusion) decreases with increase degree of structuring (lower density of local defects) Marx et al. Nature 1999

11 Brain water diffusion model: structured water ln(signal) Visual cortex f fast = 65.9% f slow = 34.1% D fast = mm²/s D slow = mm²/s b value ln (S) b D 2 KINDS OF WATER IN CELLS: SLOW + FAST DIFFUSION POOLS Water Water-membrane diffusion in brain interface: is mainly hindered by cell membranes Long-range electrostatic trapping Diffusion behavior is well described by a biexponential model -Protein «trapping» effects: structured water Slow -Extend and fast to adherent diffusion water pools layers do not out coincide to 180nm with the intra- and extracellular (Xu & Yeung, volumes Science 1998, Vogler, 1998) - 30% of cell water (Pissis, 1987) but Slow variations diffusion in slow/fast pool: structured diffusion fractions water bound correlateto well membranes with those of the EC/IC volumes (cell size) (stroke, ADC changes osmotic with challenges, membrane statussurface epilepticus, interaction spreading depression ) (cell size, anisotropy, cellularity, ) Intra-cellular compartment Cell swelling: ADC, f slow Extra-cellular compartment - Extra Cellular (20%) =Fast? Intra Cellular (80%) =Slow? Fast Diffusion Pool Slow Diffusion Pool

12 2 KINDS OF WATER IN CELLS: SLOW + FAST DIFFUSION POOLS Slow diffusion pool :membrane interactions Le Bihan Phys. Med. Biol. 52 R57-R90, 2007 Fast pool: Bulk water and proteins-bound water Acute stroke Cell swelling Slow pool: Membrane-bound water (w/cytoskeleton ± 40 nm) Y Cell anisotropy Rest Activation Fast Diffusio n Pool Intra-cellular compartment Slow Diffusion Pool Membranes: ADC, f slow Extra-cellular compartment Cell proliferation (cancer) Z D xx D yy D zz <D> D slow D fast f slow Human brain white matter Clark & Le Bihan, MRM, 2002 Ross B. J. Natl. Cancer Inst, 92, , 2000 Day 0 Day 2 Day 4 Day 8 r=.78 Day 16 Day 20

13 Water BOLD diffusion fmri: Hemodynamic fmri: Cell membrane events events Fast Coupling coupling between between CBF, ion metabolism fluxes, membrane and activation depolarization ( PET-H 2 0, and PET-FDG, water structure NIRS) 2.20% % % % % S(t)={DRF,HRF} paradigm DRF HRF DRF: Tmax=1.65, alpha=0.5 HRF: Tmax=6, alpha= seconds -0.30% Time (s) Baseline Mechanism: fluxes of ions AND water Swelling Swelling of neurons (soma, dendrites) and glial cells Membrane surface scales with square of cell size Phase transition ( order) of water near polarized membranes AND attached polymer-gel matrix Stress and Fold Localization in Thin Elastic Membranes Pocivavsek et al. Science 230; , 2008 Diffusion and Hemodynamic Response Functions extracted from the MRI signal time courses (Aso et al. HBM06) Why and how do cell swell? A hypothesis - Action potentials Phase transition - Require cytoskeleton integrity (Matsumoto) - Cytoskeleton undergoes physical changes (Sato) -CA1 Calcium Hippocampal is critical (Tasaki, region 1988) - Transient cellular expansion (swelling) and water influx (Tasaki) Extracellular field potential - Transient liberation of heat (23µ C Tasaki) Hodgkin & Huxley model revisited: Not fast enough? Induction of hemodynamic response (Bold) Unique feature of action potential initiation in neocortical neurons Naundorf DLB (see March08 Naundorf G.H. et Pollack al. at Nature al. Nature 440;1060, 440:1060, ) OPTICAL (=Cold)?? IMAGING Infra-Red transmittance Water seems black: dendritic to play region a central role in cell activation gray: somatic physiology region (Takagi et al. 2002) Action potential, cell swelling, heat transfer Tasaki, 1988 Cytoskeleton density gradient from Tsukita & Matsumoto, 1986

14 Rest Water: the molecule of the mind? H * PET Le Bihan D. The wet mind Phys. Med. Biol. 52:557-90, 2007 BOLD fmri Active role of water in cell depolarization, action potential? -more water influx in cells than expected from ion transferts Role of blood water in heat transfert (increase in CBF)? -activation --> heat release -increase of CBF and metabolism (energy demand) more to restore baseline conditions after activation, housekeeping Role of cell structure changes (swelling) in information flow -neurons & glial cells as (reversible) piezo-electric transducers -faster than neurotransmission for local, intracotical networks 2.2% 1.7% Diffusion 1.2% 0.7% 0.2% % Time (s) DIFFUSION fmri BOLD Activation blood flow quantity of radioactive water in activated tissues Radioactive water blood flow & oxygenation magnetized water relaxation in/near vessels Magnetized water cell size and membrane surface diffusion of water near membranes Plain brain water