1. BOLD Contrast: Functional Imaging with MRI
Mark Elliott, PhD
Associate Director of CMROI,
Department of Radiology,
University of Pennsylvania School of Medicine, Philadelphia, PA

2. Overview Mechanisms of functional imaging with MRI Methodology of fMRI
Issues for animal studies
Spatial and temporal sensitivy of fMRI

3. Methods for Imaging Neural Activity
metabolic response
FDG PET
- ATP tightly regulated
- glucose consumption
electrical activity
- excitatory
- inhibitory
- soma action potential
- oxygen consumption
H215O PET
hemodynamic response
- blood flow
fNIR
- blood volume
electrophysiology
- blood oxygenation
fMRI
EEG
MEG
Perfusion MRI

4. Vascular Sensitivity of fMRI and fNIR
Venous
Arterial II I
fNIR
Intravascular
Perfusion MRI II IV
fMRI
III I
Extravascular
III IV
Vessel Size

5. Mix of blood volume, blood flow, and O2 metabolism
Vascular Response
fMRI vs fNIR
fMRI
fNIR
Spatial Resolution
8-27 mm3
“Blobs”
1-10 cm3
Temporal Resolution
Slow (1-2 sec)
Fast (50 Hz)
important?
Measurement parameter
Mix of blood volume, blood flow, and O2 metabolism
[Hb] and [HbO]

6. Mechanisms of fMRI Signal: BOLD Contrast
Neural Activity
CMR02
“Flooding the garden to feed
the thirsty flower” - ???
CBF
BOLD ( CBF - CMR02)
spatial dimension
Hemodynamic response is a surrogate marker for neural activity
BOLD = Blood Oxygenation Level-Dependent
BOLD signal is a complex interaction of CBF + CBV + CMRO2:
CBF >> CMRO2  less deoxyhemoglobin with activation
CBF is monitored indirectly
“Tracer” is primarily venous
“Tracer” is endogenous

7. Magnetic Susceptibility Affects Background Magnetic Field
: permeability
r : relative permeability
M: magnetic susceptibility
For biological tissues, | M | << 1
Diagmagnetic: M < 0
Paramagnetic: M > 0
The interface between regions with different M behaves like a magnetized dipole, perturbing the local B field.
 M creates larger B
B1  B2 B1
M1 B2
M2

8. BOLD Contrast: Changes in Magnetic Susceptibility of Blood
Blood and brain tissue are diamagnetic.
Hb0 is diamagnetic.
Hb is strongly paramagnetic.
HbO is paramagnetic.
Increased Neuronal activity:
blood flow increases ≈ 30%
02 consumption increases ≈ 5%
[Hb0] 
[Hb] 
Decrease in [Hb] reduces the M between blood and brain tissue
Magnetic field becomes more uniform  MRI signal affected

9. Hemoglobin Saturation Affects Magnetic Field Homogeniety
Rat brain, 7T
from Ogawa, 1990
Field Map vs. Hemoglobin Saturation
Hypoxia
Normoxia
from Bandettini and Wong, 1995

10. Summary: BOLD Contrast in fMRI
Verbal Fluency Task
Broca’s area
Wernicke’s area
BOLD = Blood Oxygenation Level-Dependent
Oversupply of CBF raises [HbO] in regions of increased CMRO2
Susceptibility mismatch between blood and tissue is reduced
Magnetic field becomes more homogeneous
Temporal T2* contrast generated in T2* sensitive MRI

11. fMRI Methodology: Acqusition
structural
T1 weighted
~ 5 min
Temporal series of EPIs
1x1x1 mm voxels
EPI
functional
T2* weighted
~ 2 sec/volume
~ 300 images
~ 10 min
time
3x3x3 mm voxels

12. fMRI Methodology: Stimulus
Blocked Design, Event-Related Design, and ISI
ISI
Fixed ISI On
Blocked Design
Off On
Off
Event Related
Event related designs can have either fixed or variable inter-stimulus interval (ISI)
ISI
Variable ISI
Variable ISI allows for more stimuli per time.
Increased statistical power in analysis.

13. fMRI Methodology: Analysis
“Non-Activation”
Signal
Stimulus
Processing
“Activation”
Signal
Processing
Stimulus

14. Brain Activation Maps Statistical Parametric Mapping
T2*-weighted
Snapshot
Image
Average
Difference
Statistical
Significance
Thresholded
Overlay on
Anatomic ON
task
OFF
signal
courtesy J. Detre

15. Hemodynamic Response Function
The “HRF” -
the theoretical impulse response of BOLD contrast to brief neuronal activity
Peak Contrast
Amplitude
FWHM
Onset Time
Stimulus
Time to Peak

16. fMRI Model: HRF Linear System
Linear Model Assumption
y = h  x
Expected signal (y) is convolution of the stimulus signal (x) with the HRF (h)
stimulus (x)
HRF (h)
signal (y)
Signal is predicted for any arbitrary sequence of stimuli

17. Applications of fMRI Cognitive Neuroscience
Localization of sensorimotor and cognitive function
Brain-behavior correlations
Clinical Neuroscience
Presurgical mapping
Differential diagnosis of cognitive disorders
Recovery of function/neuroplasticity
Photic Stimulation

18. Implications for Animal fMRI
Pharmacological effects on neuronal metabolism and hemodynamic response
Small voxel sizes reduce SNR
Smaller volumes enable higher field magnets (7 and 9.4T)
Passive stimulus delivery (training possible in some models)

19. T2* Signal Loss in the Pre-Frontal Cortex
Air is highly paramagnetic (like Hb)
Air-tissue interface has “static” M
Background signal “drop-out” F B0 E 1 S B0 2
Bn = Normal component
Bn = Tangential component
This rotation angle a is called the flip angle and it is proportional to the amplitude of B1 and to the pulse duration.
If the flip angle is 90 degrees, all the magnetization will lie in the transverse plane.
A flip angle of 180 degrees will invert the magnetization.
F = frontal sinus
E = ethmoidal sinus
S = sphenoidal sinus
Normal component is unchanged by 
B1n = B2n
Tangential component is altered by  B1n = 1 / 2 B2n

20. Signal Dropout in T2* Weighted Images
In 2D imaging, images are acquired slice by slice.
The slice is selected using a slice selection gradient, which is a gradient in the direction perpendicular to the slices (normally z direction).
The slice selection gradient is switch on during the application of the RF pulse.
Similarly to the read-out gradient, it will generate a frequency distribution, along z.
For a slice thickness dz, a band of frequencies need to be excited as shown here.
Increasing TE

21. Spatial Extent of BOLD
Neural Activity
CMR02
Hb Saturation (%, approx.)
resting active
arterioles
capillaries
veins
CBF
BOLD ( CBF - CMR02)
microvessels
draining veins
Positive T2* contrast derived from CBF > CMR02
Venous compartment experiences largest Hb (and T2*)
Draining veins are less spatially specific to site of neural activity

22. Extravascular BOLD Signal
B0 “inhomogeneity” from vessel extends into extravascular (EV) space
EV Magnetic Field Gradient
microvessel
macrovessel
Diffusion of water molecules through B0 gradients
Large vessels: static dephasing, T2* effect
Small vessels: dynamic dephasing, T2 and T2* effect
Spin-echo fMRI less sensitive to large vessel (venous)
extravascular space
water diffusion
from Principles of Functional MRI, Seong-Gi Kim

23. Echo Time and Field Strength Effects on BOLD Contrast
BOLD contrast increase with echo time (TE)
SNR decreases with echo time
Optimal CNR when TE  resting T2*
BOLD contrast increases with magnetic field
SNR increases with magnetic field
1.5T
% Signal
TE (msec) 3T
% Signal
TE (msec)
from Stroman et al, Proc. ISMRM, Glasgow (2001)

24. Field Strength Effect on BOLD Spatial Sensitivity
T2* of blood shortens quadratically with B0
Field dependence of T2,blood  T2,tissue
- Decreased venous contribution
Diffusion weighted BOLD
Intravascular BOLD component
model simulation
Rat brain, 9.4T
from S.P. Lee et al, (2003)