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

2. What is fMRI Many ways to measure “function” “fMRI” usually refers to
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 really starts long before fMRI)
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 CBF
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. Function of the brain: 1800 Methods based upon comparisons:
human versus animal
young versus old
personality versus post-mortem
Shared by human & animal
Only human
Poetic talent
Firmness of purpose
Wisdom
Cleverness
Pride &
Arrogance
Instinct of reproduction
Love of
offspring
Tendency to
Murder
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. 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, …
All related

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

15. Time & Space: acquisition
EPI = echo-planar imaging
Rectilinear EPI
Spiral 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. 1st BOLD experiments @ MGH
respiratory challenge
(rabbit)
visual stimulation
Ken Kwong, Ph.D.
control
time
space
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. “Simple” BOLD equation
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. 3 very general considerations
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 Cut along TE axis: Cut along dose axis:
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. Exogenous agent @ low field (2 T)
BOLD
Cocaine, 0.5 mg/kg IV (n = 5)
CBV
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. CBF: baseline & activation
Labeling a single corotid artery, 3 Tesla, 8 minutes
control
- tag
Wald, MGH
7 Tesla CBF
Flow 7 T
CBF
BOLD

37. fMRI designs Block designs Event-related 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??)