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					BOLD Contrast: Functional Imaging with MRI
Mark A. Elliott, PhD Department of Radiology University of Pennsylvania

Overview
1. 2. 3. 4. Mechanisms of functional imaging with MRI Methodology of fMRI Issues for animal studies Spatial and temporal sensitivy of fMRI

Methods for Imaging Neural Activity
metabolic response electrical activity
- excitatory - inhibitory - soma action potential - ATP tightly regulated - glucose consumption - oxygen consumption
FDG PET

H215O PET

hemodynamic response
- blood flow - blood volume - blood oxygenation

fNIR

electrophysiology EEG MEG

fMRI
Perfusion MRI

Vascular Sensitivity of fMRI and fNIR
Venous
II

Arterial
I

fNIR
Intravascular

Perfusion MRI

II IV III I

fMRI
Extravascular
III
Vessel Size

IV

Vascular Response

fMRI vs fNIR

fMRI

fNIR

Spatial Resolution

8-27 mm3

“Blobs” 1-10 cm3
Fast (50 Hz) important?

Temporal Resolution

Slow (1-2 sec)

Measurement parameter

Mix of blood volume, blood flow, and O2 metabolism

[Hb] and [HbO]

Mechanisms of fMRI Signal: BOLD Contrast
Neural Activity CMR02 CBF BOLD ( CBF - CMR02)

“Flooding the garden to feed the thirsty flower” - ???

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

Magnetic Susceptibility Affects Background Magnetic Field
B  H   r 0 r 1  M

: permeability r : relative permeability M: magnetic susceptibility For biological tissues, | M | << 1 Diagmagnetic: M < 0 Paramagnetic: M > 0

B1  B2
M1 B1 B2 M2

The interface between regions with different M behaves like a magnetized dipole, perturbing the local B field.  M creates larger B

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

Hemoglobin Saturation Affects Magnetic Field Homogeniety
from Ogawa, 1990

Rat brain, 7T

Field Map vs. Hemoglobin Saturation

from Bandettini and Wong, 1995

Normoxia Hypoxia

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

fMRI Methodology: Acqusition
structural T1 weighted ~ 5 min

Temporal series of EPIs

1x1x1 mm voxels

....
~ 300 images
~ 10 min
time

EPI
functional T2* weighted ~ 2 sec/volume
3x3x3 mm voxels

fMRI Methodology: Stimulus
Blocked Design, Event-Related Design, and ISI
On Off On Off Event Related

ISI

Fixed ISI
Blocked Design

Event related designs can have either fixed or variable inter-stimulus interval
ISI
Variable ISI

Variable ISI allows for more stimuli per time. • Increased statistical power in analysis.

fMRI Methodology: Analysis
“Non-Activation”
Signal

Stimulus

Processing

....
“Activation”
Processing
Signal Stimulus

Brain Activation Maps
Statistical Parametric Mapping
T2*-weighted Snapshot Image Average Difference Image Statistical Significance Image Thresholded Statistical Image Overlay on Anatomic Image

ON OFF

task

signal

courtesy J. Detre

Hemodynamic Response Function
The “HRF” the theoretical impulse response of BOLD contrast to brief neuronal activity

FWHM

Peak Amplitude Contrast

Onset Time

Stimulus

Time to Peak

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

Applications of fMRI
• Cognitive Neuroscience – Localization of sensorimotor and cognitive function – Brain-behavior correlations

• Clinical Neuroscience – Presurgical mapping – Differential diagnosis of cognitive disorders Photic Stimulation – Recovery of function/neuroplasticity

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)

T2* Signal Loss in the Pre-Frontal Cortex
Air is highly paramagnetic (like Hb) Air-tissue interface has “static” M Background signal “drop-out” 1 B0
Bn = Normal component
F = frontal sinus E = ethmoidal sinus S = sphenoidal sinus

F

B0
E S

2

Bn = Tangential component

Normal component is unchanged by  B1n = B2n Tangential component is altered by  B1n = 1 / 2 B2n

Signal Dropout in T2* Weighted Images

TE=4ms TE=12ms TE=20ms TE=28ms

TE=36ms TE=44ms TE=52ms TE=60ms

Increasing TE

Spatial Extent of BOLD
Neural Activity CMR02 CBF BOLD ( CBF - CMR02)

Hb Saturation (%, approx.) resting active arterioles 90 90 capillaries 80 90 veins 60 90

draining veins microvessels

Positive T2* contrast derived from CBF > CMR02 Venous compartment experiences largest Hb (and T2*) Draining veins are less spatially specific to site of neural activi

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

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)

% Signal

3T

TE (msec)

from Stroman et al, Proc. ISMRM, Glasgow (200

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

Rat brain, 9.4T

model simulation

from S.P. Lee et al, (2003)