ASL Methods and Poten/al for pHMRI Michael Kelly, PhD Layout •  Introduc/on to cerebral perfusion •  Arterial spin labelling •
•
•
•
•
Basics Techniques (con/nuous ASL, pulsed ASL, pseudo-­‐con/nuous ASL) Quan/fica/on of CBF (Buxton model, alterna/ves) Typical setup for pCASL experiment Current applica/ons (at FMRIB) •  Poten/al of ASL for pHMRI •  Advantages •  Confounds •  Recent pHMRI ASL studies Introduc/on •  Cerebral perfusion – “the process involved in the delivery of nutri/ve blood to the brain /ssue capillary bed” •  Various modali/es: PET, SPECT, CeCT, Doppler ultrasound…. •  Many parameters: CBF (ml/100g /ssue/min), CBV (ml/100g), MTT (s), blood velocity (cm/s)….. •  Two main quan/ta/ve MRI techniques: DSC-­‐MRI & ASL Introduc/on •  Why might we want to measure / quan/fy cerebral perfusion? •  Altered in various disease states… •  Stroke -­‐ possible to iden/fy ischaemic core and penumbra of possibly salvageable /ssue: (1) CBF map from stroke survivor shows ischaemic region (measured by ASL) •  Hyperperfusion in tumours: (2) CBF map of glioblastoma. Hyper-­‐ perfusion within periphery (measured by ASL) (1) Brumm et al, Neuroimage, (2010) 51(3):995-­‐1005. (2) Deibler et al, AJNR, (2008) 29:1428-­‐1435. Introduc/on •
Func/onal MRI… •
•
•
BOLD signal is a combina/on of changes in CBF, CBV and CMRO2 BOLD signal % -­‐ not a quan/ta/ve physiological parameter Direct measures of CBF and CBV may be more closely localised at the site of neuronal ac/vity Combined BOLD & ASL  CMRO2 (and more…) •
www.fmrib.ox.ac.uk/educa/on/fmri MRI perfusion techniques DSC-­‐MRI •  Capture first pass of intravenously injected bolus of paramagne/c contrast agent (Gadolinium) •  Contrast is either relaxivity (T1) / suscep/bility (T2 and T2*) based Østergaard, JMRI, (2005) 22:710-­‐717 MRI perfusion techniques Note the units of the perfusion parameters! Drawbacks: •  Requires injec/on of exogenous contrast agent •  Quan/fica/on requires accurate measurement of arterial input func/on •  Not suitable for longitudinal experiments / mul/ple measurements •  Not suitable in certain disease states Non-­‐invasive quan/ta/ve MRI method?? – ASL (1) Ohtonari et al, Neurol Med Chir, (2008) 48:331-­‐336. ASL -­‐ Basics Arterial Spin Labelling (ASL) •  Acquire tag image  inflowing arterial blood water labelled by magne/c inversion: Time delay between 1 and 2: Labelled water reaches capillary bed and is exchanged with water molecules in the /ssue  signal change •  Acquire control image  inflowing blood is not labelled: •  Difference between control and tag image is perfusion-­‐weighted: www.umich.edu/~fmri/asl.html Arterial Spin Labelling: Tag Imaging slice Inflowing arterial blood water Arterial Spin Labelling: Tag Imaging slice
Inflowing arterial blood water Inversion
Arterial Spin Labelling: Tag CBF (inverted spins) arteries veins capillaries Arterial Spin Labelling: Tag CBF arteries veins capillaries Arterial Spin Labelling: Tag CBF arteries veins capillaries Arterial Spin Labelling: Control Imaging slice Inflowing arterial blood water Arterial Spin Labelling: Control Imaging slice
Inflowing arterial blood water Inversion
Arterial Spin Labelling: Control CBF arteries veins capillaries Arterial Spin Labelling: Control CBF arteries veins capillaries Arterial Spin Labelling: Control CBF arteries veins capillaries Arrival of labelled blood Flow Arterial Arrival Time Whole-­‐brain CBF maps CBF (ml / 100 g /ssue / min) Whole-­‐brain AAT maps AAT (seconds) ASL -­‐ Techniques (Con/nuous ASL, Pulsed ASL, Velocity-­‐selec/ve ASL) Con/nuous Arterial Spin Labelling (CASL)
•  First ASL technique (2) Control •  3 – 4 sec RF pulse with magne/c field gradient in direc/on of arterial flow: Label Δr Mcontrol Mlabel ∆M •  Label: inflowing spins inverted by principle of flow-­‐driven adiaba/c inversion •  Control: fl -­‐fl (or G -­‐G): inflowing spins are unaffected Adapted from (1) •  Host sequence (e.g. EPI, GRASE) played arer /me delay (“post labelling delay”) •  ΔM=Mc-­‐Ml perfusion weighted image (1) Petersen et al, Br J Radiol, (2006) 79:688-­‐701 (2) Williams et al, Proc Natl Acad Sci, (1992) 89:212-­‐216 Adiaba/c inversion RF pulses •  Before understanding how flowing spins are inverted in CASL, we need to look briefly at adiaba/c inversion pulses… •  Amplitude and frequency of adiaba/c inversion pulses depends on /me: A(t) and ωrf(t) •  The net magne/za/on vector, M, precesses around Beff in the rota/ng frame •  Principle of adiaba/c fast passage  M follows Beff provided direc/on of Beff does not vary too much during one precession of M about Beff •  By modula/ng A(t) and ωrf(t), Beff can be swept from +z to –z and if adiaba/c condi/on is sa/sfied, M will follow and be inverted (1) M.A. Bernstein. Handbook of MRI Pulse Sequences. Oxford: Academic Press, 2004 Adiaba/c inversion RF pulses (Used to invert large volume of spins in PASL) Flow-­‐driven Adiaba/c Inversion •  Back to CASL…apply fixed RF (no amplitude or frequency modula/on) for 2 -­‐ 4 secs: No /me-­‐dependency on either A or ω •  We know this pulse cannot adiaba/cally invert sta/onary (/ssue) spins (Why?) •  Recall that a gradient G=Gz is applied along with the RF: Gz z •  For flowing spins, B0 is swept due to Gz  Spins flowing with constant velocity along z experience a linearly varying magne/c field and a resultant sweep of the resonant frequency (1) M.A. Bernstein. Handbook of MRI Pulse Sequences. Oxford: Academic Press, 2004 Flow-­‐driven Adiaba/c Inversion v •  Spins moving towards r0 from r(t)<<r0 experience a /me-­‐varying frequency offset: r >> r0 r > r0 Labeling plane r < r0 r = r0 •  And an effec/ve magne/c field given by: r << r0 •  If velocity of flowing spins is within the correct range, this frequency offset acts on flowing spins like an adiaba/c pulse as Beff is swept by changing Δω: (1) M.A. Bernstein. Handbook of MRI Pulse Sequences. Oxford: Academic Press, 2004 Flow-­‐driven Adiaba/c Inversion (1) v z r >> r0 r > r0 Labeling plane r = r0 y r < r0 r << r0 x Spins far from labeling plane  Δω is large (propor/onal to r(t) – r0) Flow-­‐driven Adiaba/c Inversion (2) z y x Spins approaching labeling plane  Δω decreasing (propor/onal to r(t) – r0) Flow-­‐driven Adiaba/c Inversion (3) z y x Spins at the labeling plane  Δω goes to zero (propor/onal to r(t) – r0) Flow-­‐driven Adiaba/c Inversion (4) z y x Spins moving away from labeling plane  Δω starts to increase but is now posi/ve (propor/onal to r(t) – r0) Flow-­‐driven Adiaba/c Inversion (5) z y x Spins flowing into brain  Δω is large (propor/onal to r(t) – r0) and flowing spins are inverted! Magne/za/on Transfer Effects •
CASL – apply long off-­‐resonance RF pulse •
Schema/c diagram of absorp/on spectra of free water and macromolecule protons(1): At the imaging plane ASL labelling pulse •
Free water protons at the imaging plane are largely unaffected (due to narrow RF absorp/on spectrum) •
Protons bound to macromolecules at imaging plane are inverted by the off-­‐
resonance labelling pulse (due to broad spectrum of immobile protons) •
Chemical exchange between the two proton pools  magne/za/on transfer •
Used as a posi/ve contrast mechanism (MTI – magne/za/on transfer imaging) but problema/c in ASL….why? (1) Grossman et al, Radiographics, (1994) 14:279-­‐290 Magne/za/on Transfer Effects •  Water in sta/c /ssue appears to be inverted due to magne/za/on transfer •  This adds to the blood water signal that we want to measure with ASL but is not true perfusion signal •  Overes/mate ASL difference signal Magne/za/on Transfer Effects Label off-­‐ resonance pulse (fL) Control off-­‐ resonance pulse (-­‐fL) •
To compensate for MT effect in ASL control image acquired with frequency offset fc = -­‐fL •
ΔM=Mc-­‐Ml  MT contribu/on should be the same in both the tag and control image removed by subtrac/on BUT •
Assumes MT effect is symmetrical about ω0 •
ΔM/M0 is the frac/onal signal difference between an image acquired with frequency offset +δω2 and one acquired with with frequency offset -­‐δω2 •
MT effect is not symmetrical  this label / control scheme (+/-­‐ fl) s/ll leads to an error in subsequent perfusion es/ma/on (1) Pekar et al, MRM, (1996) 35:70-­‐79 Magne/za/on Transfer Effects •  Best solu/ons to MT problem -­‐ use dedicated labelling coil(1) •  Small sensi/ve region of coil  no satura/on of macromolecules at the imaging region •  Can be used to easily selec/vely label main feeding arteries(2): (1) Zhang et al, MRM, (1995) 33:370-­‐376 (2) Werner et al, MRM, (2004) 52:1443-­‐1447 Pseudo-­‐con/nuous ASL •  CASL drawbacks: –  Magne/za/on transfer (as we have just described) –  Inversion efficiency (<< 100%) –  Requires applica/on of long RF pulse (“con/nuous mode opera/on”) •  Pseudo-­‐conJnuous ASL (pCASL) (a)  Label: B1ave≠0, Gave≠0 (b)  Control: B1ave=0, Gave=0 –  Magne/za/on transfer is matched between tag and control –  High inversion efficiency (typically 90%  increased SNR) –  Can be implemented on clinical systems that do not support con/nuous RF (1) Dai et al, MRM, (2008) 60:1488-­‐1497 Pseudo-­‐con/nuous ASL Sweeping the phase shir accumulated between RF pulses results in an inversion of flowing spins •  Control (doKed line): 1800 phase shir for all posi/ons (alternate sign of RF pulse + zero net gradient) •  Label: Imbalance in gradients  Posi/on dependent phase shir •  Changing gradient imbalance  sweep ϕ from -­‐1800 to +1800 causes inversion of flowing spins (1) Garcia et al, Proc ISMRM, (2005) 13:37 (2) Dai et al, MRM, (2008) 60:1488-­‐1497 Pseudo-­‐con/nuous ASL Mul/slice perfusion weighted images from pCASL experiment Vessel-­‐encoded pCASL Perfusion territory image •
pCASL labelling scheme (RF and Gz) •
Add transverse gradient blips (Gxy)  can label selec/vely (e.g. along line A) •
RF pulse phase cycled such that spins in the tag vessel (e.g. A) are inverted while spins along control vessel (e.g. B) are unaffected •
Different tag / ctrl vessel combina/ons are possible Vessel-­‐encoded dynamic angio (1) (1) Okell et al, MRM,(2010) 64:698-­‐706 Pulsed Arterial Spin Labelling ConJnuous and pseudo-­‐conJnuous ASL (CASL and pCASL): •  Label for a given /me at a specific loca/on (i.e. in the neck) Pulsed ASL (PASL): •  Label a large volume of blood with short RF pulse •  Typically use adiaba/c RF pulse (described earlier) •  Wait for labeled volume (or bolus) to flow into capillary bed and exchange with /ssue •  Two “families” of PASL sequence: –  Echo planar and signal targe/ng with alterna/ng RF (EPISTAR) –  Flow sensi/ve alterna/ng inversion recovery (FAIR) •  Quan/ta/ve imaging of perfusion using a single subtrac/on (QUIPSS) EPISTAR(1) Saturate spins at the imaging loca/on fl Dephase transverse magne/za/on prior to labeling fc=-­‐fl Spa/ally selec/ve adiaba/c inversion pulse •  ΔMEPISTAR=MC -­‐ ML •  Doesn’t account for MT asymmetry problem •  PICORE  drop the slab selec/on gradient in the control phase (problem with this?) •  Other EPISTAR–type sequences: STAR, STAR-­‐HASTE, TILT…. (1) Edelmann et al, Radiology,(1994) 192:513-­‐520 FAIR(1) Slice selec/ve gradient: 1800 pulse only inverts spins at the imaging loca/on No slice selec/ve gradient: 1800 pulse inverts spins in the en/re sensi/ve region •  ΔMFAIR=ML – MC •  No off resonance RF  not sensi/ve to MT effects •  Other FAIR-­‐type sequences: UNFAIR, FAIRER (1) Kwong et al, Radiology,(1994) 192:513-­‐520 Quan/fica/on? •
In order to quan/fy, generally vary post labelling delay and image mul/ple /me-­‐
points (usually called inversion /me (TI)= labelling dura/on + post labelling delay) •
Track /me-­‐course of flowing spins at the imaging loca/on (more on this in quan/fica/on sec/on…) Voxel with arrival Time of ~200ms Voxel with arrival Time of ~500ms ? •
•
Transit /me sensi/vity: ΔM depends on what TI is used (in a single TI experiment) CBF quan/fica/on from single TI? Are rela/ve perfusion values between regions valid? (1) Petersen et al, Br J Radiol,(2006) 79:688-­‐701 QUIPSS •  Reduces the transit /me sensi/vity of single-­‐TI PASL techniques(1) •  Inplane satura/on applied arer TI1 removes contribu/on to the final difference image of spins that arrived before TI1 •  Only labelled blood that arrives at the imaging loca/on between TI1 and TI2contributes to the perfusion weighted signal •  Reduces transit /me sensi/vity  more confidence in quan/fica/on •  QUIPSS2  apply satura/on pulse at the labeling plane instead (1) Wong et al, MRM,(1998) 39:702-­‐708 Velocity Selec/ve ASL(1) •  CASL and PASL label spins based on their loca/on (spa/al selec/vity) •  VS-­‐ASL modulates longitudinal magne/za/on of flowing spins based on their velocity •  Uses a velocity selec/ve scheme •  Gradients induce a velocity-­‐dependent phase shir between each pair or RF pulse train elements: •  These parameters define a cut-­‐off velocity, Vc •  Only spins with V > Vc are labeled •  Image acquisi/on only includes spins with V < Vc •  Only decelera/ng spins are included  arteriole / capillary specific (excludes venous blood) (1) Wong et al, MRM,(2006) 55:1334-­‐1341 ASL -­‐ Quan/fica/on ASL Quan/fica/on •
Mul/-­‐TI ASL experiment  ΔM(t) (ASL difference signal is measured as a func/on of /me) pCASL data: Labelling dura/on=1.4s, 6 x PLDs •  Mathema/cal model for ΔM(t), containing flow term, T1, describing exchange of labelled water between blood and /ssue, etc.  QuanJfy CBF •  Fit model to data  Quan/fy physiological parameters (i.e. CBF, AAT) ASL Quan/fica/on •
Typically use the Buxton(1) general kine/c ASL model •
ΔM(t) constructed as a sum over /me of the delivery of magne/za/on to the /ssue ΔM(t) = difference signal measured by ASL α = inversion efficiency (between 0 and 1) M0b = equilibrium magne/za/on of blood f = cerebral blood flow (CBF) Integeral = convolu/on of delivery func/on, c(t), with product of residue func/on, r(t), and magne/za/on relaxa/on func/on, m(t) •
Fit to the solu/on to this equa/on for the type of ASL data you have acquired (i.e. CASL, PCASL or PASL) •
Get voxel-­‐by-­‐voxel map of CBF (and possibly arterial transit /me (ATT)) (1) Buxton et al, MRM,(1998) 40:383-­‐396 ASL Quan/fica/on pCASL data: Labelling dura/on=1.4s, 6 x PLDs Perform voxel-­‐wise fit of CASL solu/on to general kine/c model to data (need to assume / measure values for T1, α, M0b,λ) ASL Quan/fica/on pCASL data Model fit ASL Quan/fica/on Effect of varying CBF, arterial transit /me, T1 and labelling dura/on on the general kine/c model: (1) Buxton et al, MRM,(1998) 40:383-­‐396 M0,blood Calibra/on •
•
Look again at the the equa/on for ΔM(t): Before CBF can be obtained in absolute units (ml/100g /ssue/min), need to measure M0,blood and es/mate or measure α M0,blood Calibra/on Measuring M0b: •  Measure equilibrium magne/za/on of CSF and use this to calculate M0,blood •
Acquire iden/cal image (e.g. EPI / GRASE) to ASL acquisi/on, without labelling and with long TR •
Calculate mean CSF signal (i.e. within a CSF mask)  M0,csf •
Calculate M0,blood from the following rela/onship: •
Where λ = ρblood/ρcsf = 0.87 (ml/ml) and we also correct for T2* (for gradient echo) decay of the signal within the echo /me(1) (1) Hersovitch & Raichle, JCBFM,(1985) 5:65-­‐69 Inversion Efficiency •
Degree of inversion (α) achieved by labelling scheme: •
CASL ≈ 0.7 -­‐ 0.8 •
Can vary significantly as a func/on of velocity  studies involving hypercapnia challenge (CO2)? •
Aslan et al  Combine phase-­‐contrast and pCASL to measure αpCASL  decreased from 0.95 to 0.84 during inhala/on of 5% CO2 •
Cardiac cycle, intra-­‐subject variability in BP etc  need to measure on per-­‐subject basis? pCASL ≈ 0.9 – 0.95 (1) Aslan et al, MRM,(2010) 63:765-­‐771 Sources of error in General Kine/c Model (1) •  Assumes plug flow  no labelled spins arrive at the imaging region before Δt •
Range of transit /mes more likely  can lead to underesJmate of perfusion (especially with PASL)  should account for distribu/on of arrival /mes (2) •  Single-­‐compartment kine/cs  assumes rapid exchange of labelled spins between vessels and /ssue •
Some labelled spins may remain in vessels before being exchanged (some may even pass through the voxel without undergoing exchange(1)) •
This assump/on also leads to an underesJmaJon of perfusion (3) •  Labeled magne/za/on is assumed to decay with /ssue T1 on arrival at the imaging voxel •
This assump/on leads to an overesJmaJon of perfusion (1) Silva et al, MRM,(1997) 38:232-­‐237 Typical PCASL experiment setup (1) Run /me-­‐of-­‐flight angiography to visualise vessels in the neck: (2) Run ASL sequence: (3) Run calibra/on scan(s) for M0blood calcula/on: ÷ Head coil = Body coil Sensi/vity map ASL -­‐ Current applica/ons Current ASL applica/ons (1) Okell et al, MRM,(2010) 64:698-­‐706 Current ASL applica/ons (1) Okell et al, MRM (2010) Current ASL applica/ons Kelly et al, BRAIN (2011) Current ASL applica/ons ASL + BOLD weighting (TE) + gas challenges
Bulte et al, Neuroimage (2012) Current ASL applica/ons Whole-­‐brain PCASL acquisi/on, focal pain s/mulus What about 7T? •  T1 of blood changes from ~1600ms at 3T to ~2000ms at 7T •  Labeled signal will decay more slowly •  Improved CNR and ability to acquire more slices? But… •  B1 homogeneity in the neck?  need specific labeling coil? •  Specific absorp/on rate – more RF power needed? ASL – Poten/al for pHMRI Advantages of ASL for pHMRI •  Non-­‐invasive (compared to PET) – suitable for longitudinal studies •  CBF – single physiological parameter quan/fied in absolute units •  Don’t need to use s/mulus / task response to drug effects •  Quan/fy CBF at rest and during s/mulus: –  Separate effects of pharmacological agents on baseline and task-­‐
induced ac/va/on –  NB where task-­‐based studies may be affected by deteriora/ng performance (clinical popula/ons) Advantages of ASL for pHMRI •  Baseline CBF affects the func/onal CBF response (during visual s/mulus) but not the BOLD response (CMRO2 / CBF coupling) •  Ability to detect baseline CBF with ASL (versus BOLD) is advantageous Advantages of ASL for pHMRI •  Pairwise (control-­‐tag) subtrac/on in ASL acts as a high pass filter •  Frequency spectrum of ASL /me series is flat (“white noise”) -­‐ as opposed to BOLD which has elevated power at low frequency •  ASL is more suitable for studying slow changes in brain func/on (e.g. drug effects taking hours / days) Power
BOLD –high power
at low frequency
0
0.005
0.010
0.015
Ff 0.020
0.025
Frequency
Frequency
(Hz)
Aguirre et al, Int Rev Neurobiol (2005) Advantages of ASL for pHMRI •  BOLD – EPI suffers from distor/on and dropout •  ASL – can use alterna/ve sequences that are resistant to magne/c field inhomogeneity (suscep/bility) effects •  Improved visualiza/on of orbitofrontal, temporal and limbic regions (linked to neurotransmi…er systems) Advantages of ASL for pHMRI •  3D GRASE readout: •  Aside: data demonstrates importance of acquiring mul/-­‐TI ASL data MacIntosh et al, JCBFM (2008) Advantages of ASL for pHMRI •  Drug ac/on /mes range from seconds (intravenous) and hours (oral) to days and weeks (treatment cycle) •  Need high test-­‐retest reliability (precision) reliability
accuracy
•  Within-­‐subject coefficient of varia/on ~10% for global CBF and ~15% for regional measures •  To detect a 15% change in CBF with 90% power and 15% varia/on between repeated measures requires ~20 subjects Wu et al, MRM (2007), Wang et al, JPET (2011) Recent important technical advances •
•
•
•
•
Increased field strength Parallel imaging (increased SNR and temporal stability) Recent progress in commercialisa/on pCASL – increased labelling efficiency and SNR Background suppression to suppress background /ssue –  reduces physiological noise and sensi/vity to mo/on –  improves sensi/vity and temporal stability –  whole brain coverage, 4mm isotropic in a few minutes Fernandez-­‐Seara et al, MRM (2008) Challenges for ASL •  CBF measured by ASL – s/ll an indirect measure of regional brain func/on •  Vascular confounds -­‐ Some agents may directly alter CBF (or mediators or neurovascular coupling) rather than brain func/on itself •  e.g. Caffeine: •  But….no change significant change in CMRO2 (measured by calibrated BOLD/ASL)  coupling between CBF and CMRO2 is altered Wang et al, JPET (2011) and Perthen et al, Neuroimage (2008) Challenges for ASL •  4 doses of remifentanil  PaCO2 increases with increased seda/on  global CBF increase (global systemic CBF increase -­‐ A) •  Need to normalize regional CBF by global CBF to iden/fy remi-­‐induced regional CBF varia/on (limbic CBF effect – B) Ko‡e et al, Anesth Analg (2007) Future direc/ons •  Con/nued improvement in hardware and sequence development •  Further move towards calibrated ASL or ASL/BOLD  CBF, AAT, CMRO2, OEF, CBV •  Perfusion-­‐based fMRI / pHMRI  long behavioural tasks (stress, craving, pain…) Ques/ons?