BOLD Contrast:BOLD Contrast:Functional Imaging with MRIFunctional Imaging with MRI
Mark A. Elliott, PhD
Department of Radiology
University of Pennsylvania
Overview
1. Mechanisms of functional imaging with MRI
2. Methodology of fMRI
3. Issues for animal studies
4. Spatial and temporal sensitivy of fMRI
Methods for Imaging Neural ActivityMethods for Imaging Neural Activity
electrical activity- excitatory- inhibitory- soma action potential
metabolic response
- glucose consumption- oxygen consumption
hemodynamic response- blood flow- blood volume- blood oxygenation
FDG PET
H215O PET
fMRIfMRIEEG
MEG
fNIRelectrophysiology
- ATP tightly regulated
Perfusion MRI
Vascular Sensitivity ofVascular Sensitivity offMRI and fNIR fMRI and fNIR
IIIIIIII
IIIIIVIV
Perfusion MRIPerfusion MRI
fNIRfNIRIIIIII
IIIIII IVIV
Vessel Size
Intravascular
Extravascular
Venous Arterial
fMRIfMRI
fMRI vs fNIRfMRI vs fNIR
fMRI fNIR
Spatial Resolution 8-27 mm3 “Blobs” 1-10 cm3
Temporal Resolution Slow (1-2 sec)Fast (50 Hz)Fast (50 Hz)important?important?
Measurement parameterMix of blood volume, blood
flow, and O2 metabolism [Hb] and [HbO]
Vascular Response
Mechanisms of fMRI Signal:Mechanisms of fMRI Signal:BOLD ContrastBOLD Contrast
• 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
spatial dimension
Neural Activity
CMR02
CBF
BOLD ( CBF - CMR02)
“Flooding the garden to feedthe thirsty flower” - ???
Magnetic Susceptibility Affects Magnetic Susceptibility Affects Background Magnetic FieldBackground Magnetic Field
B H r0
r 1M
: permeabilityr : relative permeabilityM: magnetic susceptibility
For biological tissues, | M | << 1Diagmagnetic: M < 0Paramagnetic: M > 0
M1
M2
B1
B2
B1 B2
The interface between regions with different M behaves like a magnetized dipole, perturbing the local B field.
M creates larger B
BOLDBOLD Contrast: Changes in Contrast: Changes in Magnetic Susceptibility of BloodMagnetic 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 Decrease in [Hb] reduces the MM between blood and brain tissue between blood and brain tissue
Magnetic field becomes more uniform Magnetic field becomes more uniform MRI signal affected MRI signal affected
Hemoglobin Saturation AffectsHemoglobin Saturation AffectsMagnetic Field HomogenietyMagnetic Field Homogeniety
NormoxiaNormoxiaHypoxiaHypoxia
from Bandettini and Wong, 1995
from Ogawa, 1990 Rat brain, 7T
Field Map vs. Hemoglobin Saturation
Summary: BOLD Contrast in fMRISummary: BOLD Contrast in fMRI
• BOLD = Blood Oxygenation Level-DependentBOLD = Blood Oxygenation Level-Dependent
• Oversupply of CBF raises [HbO] in regions of increased CMROOversupply of CBF raises [HbO] in regions of increased CMRO22
• Susceptibility mismatch between blood and tissue is Susceptibility mismatch between blood and tissue is reducedreduced
• Magnetic field becomes Magnetic field becomes moremore homogeneous homogeneous
• Temporal T2* contrast generated in T2* sensitive MRITemporal T2* contrast generated in T2* sensitive MRI
Broca’s areaBroca’s area
Wernicke’s areaWernicke’s area
Verbal Fluency TaskVerbal Fluency Task
fMRI Methodology: AcqusitionfMRI Methodology: Acqusition
EPI
structuralT1 weighted
~ 5 min
functionalT2* weighted
~ 2 sec/volume
. . . .
~ 300 images
~ 10 min
Temporal series of EPIs
1x1x1 mm voxels
3x3x3 mm voxels
time
fMRI Methodology: StimulusfMRI Methodology: Stimulus
On
Off
OnOff
Blocked Design
Event Related
ISI
Variable ISI allows for more stimuli per time.• Increased statistical power in analysis.
Event related designs can have either fixed or variable inter-stimulus interval (ISI)
Fixed ISIISI
Variable ISI
Blocked Design, Event-Related Design, and ISI
. . . .
Stimulus
SignalProcessing
Stimulus
Signal
“Activation”
Processing
fMRI Methodology: AnalysisfMRI Methodology: Analysis
“Non-Activation”
T2*-weightedSnapshot
Image
AverageDifference
Image
StatisticalSignificance
Image
ThresholdedStatistical
Image
Overlay onAnatomic
Image
Brain Activation MapsBrain Activation MapsStatistical Parametric MappingStatistical Parametric Mapping
OFFOFF
ONON
courtesy J. Detre
task
signal
Hemodynamic Response FunctionHemodynamic Response Function
FWHMAmplitude
Onset Time
Peak Contrast
Time to Peak
The “HRFHRF” - the theoretical impulse response of BOLD contrast to brief neuronal activity
StimulusStimulus
fMRI Model: HRF Linear SystemfMRI Model: HRF Linear System
stimulus (stimulus (xx))
HRF (HRF (hh))
signal (signal (yy))
Linear Model Assumption y = y = hh xx
Expected signal (y) is convolution of the
stimulus signal (x) with the HRF (h)
Signal is predicted for any arbitrary sequence of stimuli
Applications of fMRIApplications 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/neuroplasticityPhotic Stimulation
Implications for Animal fMRIImplications for Animal fMRI
• Pharmacological effects on neuronal metabolism and hemodynamic Pharmacological effects on neuronal metabolism and hemodynamic responseresponse
• Small voxel sizes reduce SNRSmall voxel sizes reduce SNR
• Smaller volumes enable higher field magnets (7 and 9.4T)Smaller volumes enable higher field magnets (7 and 9.4T)
• Passive stimulus delivery (training possible in some models)Passive stimulus delivery (training possible in some models)
T2* Signal Loss in the Pre-Frontal CortexT2* Signal Loss in the Pre-Frontal Cortex
F
SE
F = frontal sinusE = ethmoidal sinusS = sphenoidal sinus
Air is highly paramagnetic (like Hb)Air-tissue interface has “static” M
Background signal “drop-out”B0
1
2
Bn = Normal componentBn = Tangential component
B0
Normal component is unchanged by B1n = B2n
Tangential component is altered by B1n = 1 / 2 B2n
Signal Dropout in T2* Weighted Images
TE=4msTE=12ms
TE=20ms
TE=28ms
TE=36ms
TE=44ms
TE=52ms
TE=60msIncreasing TE
Spatial Extent of BOLDSpatial Extent of BOLD
Hb Saturation (%, approx.) resting activearterioles 90 90capillaries 80 90veins 60 90
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
Neural Activity
CMR02
CBF
BOLD ( CBF - CMR02)
draining veins microvessels
Extravascular BOLD Signal
from Principles of Functional MRI, Seong-Gi Kim
microvesselmicrovessel macrovesselmacrovessel
B0 “inhomogeneity” from vessel extends into extravascular (EV) space
water diffusion
EV Magnetic Field Gradient
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
Echo Time and Field Strength Echo Time and Field Strength Effects on BOLD ContrastEffects 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
from Stroman et al, Proc. ISMRM, Glasgow (2001)
%
Sign
al%
Si
gnal
TE (msec)
TE (msec)
1.5T
3T
Field Strength EffectField Strength Effecton BOLD Spatial Sensitivityon BOLD Spatial Sensitivity
from S.P. Lee et al, (2003)
Rat brain, 9.4T
• T2* of blood shortens quadratically with B0
• Field dependence of T2,blood T2,tissue
- Decreased venous contribution
Diffusion weighted BOLDIntravascular BOLD component
model simulation