fMRI

1. fMRI Joe Mandeville Martinos Center for Biomedical Imaging Massachusetts General Hospital

2. What is fMRI • Many ways to measure “function” • Diffusion, flow, spectroscopy, BBB, T2, … • “fMRI” usually refers to • Task-induced changes in function • BOLD signal most common • Relatively rapid ON/OFF paradigms • Sensory, motor, cognitive • But also … • CBF, or CBV in animal models • Drug stimuli or other slow/non-averaged responses

3. History of fMRI (History really starts long before fMRI) • Brain activity is coupled to metabolism • Roy & Sherington, 1890 • Invasive “imaging” in animal brain • Bolus contrast material for CBF,CBV (1954) • Radiolabeled diffusible tracers for CBF (1960) • 2-DG for metabolism (1977) • PET used similar methods • Radiolabeled diffusible tracer (1969) • CBV using labeled blood pool agent (1974) • FDG for metabolism (1980s)

4. History of fMRI • First “brain mapping” by fMRI used bolus infusions of gadolinium for assessing CBV (Belliveau, 1991) Not quite what we want in terms of temporal resolution, BUT this study forecast the use of steady-state agents

5. History of fMRI • BOLD signal • Deoxygenated hemoglobin is paramagnetic (1936) • Oxygen changes T2 relation (1982) • Optical “intrinsic signals” depend upon blood oxygenation (1986) • Respiration produces “BOLD signal” in large veins in rats • fMRI using BOLD signal (1992) • CBF • Demonstration of arterial spin labeling (1992) • fMRI using ASL (1992)

6. fMRI characteristics • Good spatial resolution (1 mm) • … but only good enough to study systems biology, not biomolecular or mechanisms • Good temporal resolution (1 sec) • … but only good enough to study the blood supply, not electrical activity • Strongly affected by contrast agents • … but only those within the blood stream, as MRI agents do not cross the BBB • Good for activation studies • … but less good for assessing basal physiology

7. Methods based upon comparisons: • human versus animal • young versus old • personality versus post-mortem Pride & Arrogance Firmness of purpose Love of offspring Poetic talent Cleverness Wisdom Instinct of reproduction Tendency to Murder Function of the brain: 1800 Shared by human & animal Only human Gall, 1810

8. Example: temporal response • Typical BOLD time response • For analysis, we predict response based upon the stimulus timing and the hemodynamic response function (impulse response model)

9. Example: brain mapping • Visually-cued reward produces activation in visual areas (sensory) and frontal areas (cognitive) Tri-planar view of 3D Inflated cortical view (2D)

10. Allrelated fMRI: general considerations • Time & space • … a trade-off that is regulated by SNR • Contrast mechanisms • We have to encode physiology into MR signal • CNR & SNR • determine how we approach fMRI in terms of contrast mechanisms, averaging, …

11. time: 3 considerations for fMRI • Want sampling time ~ T1 • T1 for gray matter >~ 1 second • Want TR/T1< ~ 2 seconds • Want sampling time ~ hemodyamic response • arterial response ~ 1-2 seconds • add time for wash-out (BOLD) or wash-in (ASL) of contrast  ~ 2-3 seconds • We need many time point for averaging of small signal changes

12. SNR per unit time • Loss of SNR per unit time is significant only for TR >> T1 • Example: Averaging every 10 images using 100 ms sampling produces an SNR only about 4% larger than collecting the data at 1 second resolution For TR < T1, SNR ~ sqrt(TR/T1)

13. space: 2 considerations for fMRI • Spatial resolution must produce enough SNR every 2-3 seconds • SNR ~ r3 * sqrt(time) •  for a given SNR, time ~ (1/r)6!!! • Want to freeze motion by “snapshot” imaging (1 image per excitation) • Less necessary in certain models (e.g., anesthesia)

14.  G is a velocity in k-space Time & Space: acquisition Review of k-space: conjugate relationships: FOV & resolution determine gradients & sampling rate; Images can be obtained following one excitation or many.

15. Time & Space: acquisition • EPI = echo-planar imaging Spiral EPI Rectilinear EPI Most common

16. Advanced acquisition strategies • Parallel imaging

17. fMRI Contrast Mechanisms • Goal: encode physiology into MR signal • Experimental knobs: T1, T2, T2* • One potential method: use a contrast agent: • Think about a vial of water: we can progressively shorten T1 & T2 by adding more agent. • The brain is mostly water! And CBV increases during brain activation, so a blood-borne agent will alter MRI signal! • Potential strategies using agents or “labels”: • CBV (cerebral blood volume) • CBF (cerebral blood flow) • BOLD signal (blood oxygen level dependent)

18. Contrast mechanism: CBV Bolus method: fix physiology & measure temporal response as contrast agent flows through the tissue: CTissue(t) = Cblood(t) V Steady state method: fix blood concentration so that every sample reflects tissue physiology through CBV(t) CTissue(t) = Cblood(t) V

19. Contrast mechanism: CBV Let’s be a little bit more quantitative: • Think about relaxation rates, not times: R2 = 1/T2 • Relaxation has components independent & dependent upon agent: • MRI signal for long TR: • We can calculate V/V (t):

20. visual stimulation control respiratory challenge (rabbit) Ken Kwong, Ph.D. time space 1st BOLD experiments @ MGH Kwong et al. 1992

21. Contrast mechanism: BOLD Very similar to CBV, because deoxygenated hemoglobin is a paramagnetic contrast agent • Relaxation has components independent & dependent upon agent: • A difference versus injected agent: we can’t easily separate the BOLD component from the static component, but we can measure changes in signal related to changes in [dHb]

22. Modeling BOLD signal Goal: relate [Hbr] to CBF (F), CBV (V), and CMRO2 (M) Y = venous oxygen saturation Accounting for mass; no physiology yet So Hbr (or dHB) Depends upon CBF, Total Hb (CBV), & CMRO2

23. Modeling BOLD signal (cont.) • So, functional changes in deoxyhemoglobin are: • Linearize: drop terms of order small2, and HbT  V • Convert to BOLD • Convert to percent signal change: • SO FINALLY

24. BOLD overview “Simple” BOLD equation • Factors that increase BOLD signal: CBF • Factors that decrease BOLD signal: CBV & CMRO2 • How is BOLD different from CBV as an fMRI technique: 1) endogenous 2) blood magnetization changes in addition to CBV 3) baseline is difficult to assess

25. BOLD coupling • So far we have taken an account’s point of view by adding up the oxygen; but CBF, CBV, and CMRO2 presumably don’t change in arbitrary ways • CBF versus CBV • Regional relationship: v  f v, f = normalized values • Functional relationship: v = f,  = 2.6 from data ( = 2 for pipe) • CBF versus CMRO2 • Regional relationship: v  f • Functional relationship: m < f (MRI) OR m<<f (PET investigators)

26. Model: diffusion limitation on oxygen • Oxygen is delivered from capillaries to brain by diffusion. • All capillaries are perfused in normal brain. • Oxygen reserve in brain is small. Delivery to capillaries follows CBF Implication: CBF & CMRO2 are coupled Net oxygen increase to brain is small Extraction fraction falls due to reduced MTT Buxton & Frank, JCBFM 1997

27. fMRI sensitivity 3 very general considerations • T1 contrast agents effect brain signal weakly due to the BBB • T2* agents/methods effect brain signal strongly through gradients extending from the vessels into the tissue • T2 methods (spin echoes) refocus a large portion of available signal, and so are weak compared to T2*

28. fMRI sensitivity • “sensitivity” means CNR per unit time • The sensitivity dependence upon SNR is only indirect (always think CNR): • BOLD signal: maximize CNR at the expense of SNR by using TE = T2* • IRON signal: maximize CNR at the expense of SNR by injecting agent (losing SNR) to get bigger signal changes

29. BOLD CNR versus TE CNR is a compromise between: 1) SNR ~ exp(-TE/T2) 2) % change ~ TE Err on the side of low TE to reduce susceptibility artifacts

30. IRON CNR • More complicated/flexible than BOLD, because • BOLD has only one “knob”: TE • IRON has two “knobs”: TE & dose • IRON dose has analogies with BOLD magnetic field strength, in that both modulate blood magnetization • Cut along TE axis: • Looks like BOLD curve • Cut along dose axis: • Same basic curve

31. IRON as a model for BOLD • Increasing blood magnetization using IRON signal (dose) or BOLD signal (mgnetic field) both increase CNR and tissue selectivity relative to vessels scale factor Baseline physiology activation 3T, versus basal CBV Dose as a model for field

32. BOLD CBV Cocaine, 0.5 mg/kg IV (n = 5) Exogenous agent @ low field (2 T) Mandeville et al., MRM 2001

34. Arterial spin labeling • By magnetically labeling water proximal to the imaging slice, changes in signal can be related to changes in CBF • similar to microspheres or diffusible tracers • Label is magnetic, not radioactive

35. Arterial spin labeling ASL signal difference (label - nonlabel) is proportional to CBF (F), labeling efficiency (), and exponential decay of label analogies to PET

36. Wald, MGH Labeling a single corotid artery, 3 Tesla, 8 minutes control control - tag CBF BOLD CBF: baseline & activation 7 Tesla CBF Flow activation @ 7 T

37. fMRI designs • Block designs • Long stimuli with periodic sampling of the baseline • Best CNR per unit time • Event-related designs • Short stimulus units, multiple interleaved event types, randomized stimulus presentation periodic periodic, too fast periodic, faster randomized, same ISI

38. Current roles for fMRI mechanisms • BOLD signal • fMRI work horse for human imaging • ASL • Targeted studies of baseline physiology or CMRO2 reactivity • IRON fMRI • Method of choice for animal fMRI; not yet available for human studies (future clinical role??)