Transcript BOLD fMRI - Duke University

BOLD fMRI
BIAC Graduate fMRI Course
September 28, 2004
Why do we need to know
physics/physiology of fMRI?
• To understand the implications of our results
– Interpreting activation extent, timing, etc.
– Determining the strength of our conclusions
– Exploring new and unexpected findings
• To understand limitations of our method
– Choosing appropriate experimental design
– Combining information across techniques to overcome limitations
• To take advantage of new developments
– Evaluating others’ approaches to problems
– Employing new pulse sequences or protocols
Developments for BOLD MRI
• Echoplanar imaging methods
– Proposed by Mansfield in 1977
• Ready availability of high-field scanners
– Technological developments
– Clinical applicability  insurance
reimbursement  clinical prevalence
• Discovery of BOLD contrast mechanism
Developments for BOLD MRI
• Echoplanar imaging methods
– Proposed by Mansfield in 1977
• Ready availability of high-field scanners
– Technological developments
– Clinical applicability  insurance
reimbursement  clinical prevalence
• Discovery of BOLD contrast mechanism
Contrast Agents
• Defined: Substances that alter magnetic
susceptibility of tissue or blood, leading to
changes in MR signal
– Affects local magnetic homogeneity: decrease in T2*
• Two types
– Exogenous: Externally applied, non-biological
compounds (e.g., Gd-DTPA)
– Endogenous: Internally generated biological
compound (e.g., dHb)
External Contrast Agents
• Most common are Gadolinium-based compounds introduced into
bloodstream
– Very large magnetic moments
– Do not cross blood-brain barrier
• Create field gradients within/around vessels
– Reduces T1 values in blood (can help visualize tumor, etc.)
– Changes local magnetic fields
• Large signal changes: 30-50%
– Delay until agent bolus passes through MR imaging volume
– Width of response depends on delivery of bolus and vascular filtering
– Degree of signal change depends on total blood volume of area
• Issues
– Potential toxicity of agents (short-term toxicity, long-term accumulation)
– Cause headaches, nausea, pain at injection
Belliveau et al., 1990
Slice Location
NMR intensity change (CBV)
CBV Maps (+24%)
Common Contrast Agents
Compound
Longitudinal
Relaxivity
Transverse
Relaxivity
Magnetic
Susceptibility
GdCl2
1
1
1
MnCl2
0.96
3.83
0.51
GdDTPA
0.52
0.5
1
DyDTPA
0.03
0.04
1.78
1.6
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-
0.41
0.63
40.7
4.4
15.5
148
GDTPA albumin
Iron oxide particle (3nm)
Iron oxide particle (253nm)
Potential for
Endogenous Contrast
through Hemodynamics
Decreasing Relaxation Time
Blood Deoxygenation affects T2
Recovery
T2
T1
Increasing Blood Oxygenation
Thulborn et al., 1982
Ogawa et al., 1990a
• Subjects: 1) Mice and Rats, 2) Test tubes
• Equipment: High-field MR (7+ T)
• Results 1:
– Contrast on gradient-echo images influenced by
proportion of oxygen in breathing gas
– Increasing oxygen content  reduced contrast
– No vascular contrast seen on spin-echo images
• Results 2:
– Examined signal from tubes of oxygenated and
deoxygenated blood as measured using gradientecho and spin-echo images
Spin Echo
Gradient Echo
?
?
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?
Ogawa 1990
Spin Echo
Gradient Echo
Ogawa 1990
Ogawa et al., 1990b
100% O2
Under anesthesia, rats breathing
pure oxygen have some BOLD
contrast (black lines).
Breathing a mix including CO2 results
in increased blood flow, in turn
increasing blood oxygenation.
There is no increased metabolic load
(no task).
90% O2, 10% CO2
Therefore, BOLD contrast is reduced.
BOLD does not simply reflect blood flow…
0.75% Halothane
(BOLD contrast)
3% Halothane
(reduced BOLD)
100% N2
(enormous BOLD)
Ogawa 1990
BOLD Endogenous Contrast
• Blood Oxyenation Level Dependent Contrast
– Deoxyhemoglobin is paramagnetic, oxyhemoglobin is
less so.
– Magnetic susceptibility of blood increases linearly with
increasing oxygenation
• Oxygen is extracted during passage through
capillary bed
– Arteries are fully oxygenated
– Venous (and capillary) blood has increased proportion
of deoxyhemoglobin
– Difference between oxy and deoxy states is greater
for veins  BOLD sensitive to venous changes
Effects of TE and TR on T2* Contrast
MR
Signal
MR
Signal
T2 Decay
T1 Recovery
50 ms
1s
Kwong et al., 1992
 VISUAL 
 MOTOR 
Ogawa et al., 1992
• High-field (4T) in humans
• Patterned visual
stimulation at 10 Hz
• Gradient-echo (GRE)
pulse sequence used
– Surface coil recorded
• Significant image
intensity changes in
visual cortex
• Image signal intensity
changed with TE change
– What form of contrast?
Blamire et al., 1992
This was the first event-related fMRI
study. It used both blocks and pulses of
visual stimulation.
Gray
Matter
Hemodynamic
response to long
stimulus durations.
Hemodynamic response to short
stimulus durations.
White
matter
Outside Head
Relation of BOLD Activity to
Neuronal Activity
1. Information processing reflects
collected neuronal activity
• fMRI response varies with pooled neuronal
activity in a brain region
– Behavior/cognitive ability determined by
pooled activity
• Alternatively, if single neurons governed
behavior, fMRI activation may be
epiphenomenal
BOLD response reflects pooled
local field potential activity
(Logothetis et al, 2001)
fMRI Hemodynamic
Response
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100ms
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500ms
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500ms
100ms
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Calcarine
Sulci
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-1
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100ms
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500ms
1500ms
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Fusiform
Gyri
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-6
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-1
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Calcarine
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-200
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500ms
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Fusiform
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2. Co-localization
• BOLD response reflects activity of neurons
that are spatially co-localized
• Based on what you know, is this true?
3. Measuring Deoxyhemoglobin
• fMRI measurements are of amount of
deoxyhemoglobin per voxel
• We assume that amount of deoxygenated
hemoglobin is predictive of neuronal
activity
4. Uncoupling of CBF & CMRO2
• Cerebral Blood Flow (CBF) and Cerebral Metabolic Rate
of Oxygen (CMRO2) are coupled under baseline
conditions
– PET measures CBF well, CMRO2 poorly
– fMRI measures CMRO2 well, CBF poorly
• CBF about .5 ml/g/min under baseline conditions
– Increases to max of about .7-.8 ml/g/min under activation
conditions (+ 30%)
• CMRO2 only increases slightly with activation
– May only increase by 10-15% or less
– Note: A large CBF change may be needed to support a small
change in CMRO2
The Hemodynamic Response
Impulse-Response Systems
• Impulse: single event that evokes changes
in a system
– Assumed to be of infinitely short duration
• Response: Resulting change in system
Impulses
Convolution
Response
=
Output
Basic Form of Hemodynamic Response
Peak
Rise
Initial Dip
Baseline
-10
-5
Undershoot
0
5
Peak
10
15
20
25
Sustained
Response
Rise
Initial Dip
Undershoot
Baseline
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Baseline Period
• Why include a baseline period in epoch?
– Corrects for scanner drift across time
Initial Dip (Hypo-oxic Phase)
•
Transient increase in oxygen consumption, before change in blood flow
– Menon et al., 1995; Hu, et al., 1997
•
Shown by optical imaging studies
– Malonek & Grinvald, 1996
•
Smaller amplitude than main BOLD signal
– 10% of peak amplitude (e.g., 0.1% signal change)
•
Potentially more spatially specific
– Oxygen utilization may be more closely associated with neuronal activity than
perfusion response
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Early Evidence for the Initial Dip
A
C
B
Menon et al, 1995
Why is the initial dip controversial?
• Not seen in most studies
– Spatially localized to Minnesota
– May require high field
• Increasing field strength increases proportion of signal drawn from
small vessels
• Of small amplitude/SNR; may require more signal
• Yacoub and Hu (1999) reported at 1.5T
– May be obscured with large voxels or ROI analyses
• May be selective for particular cortical regions
– Yacoub et al., 2001, report visual and motor activity
• Mechanism unknown
– Probably represents increase in activity in advance of flow
– But could result from flow decrease or volume increase
Yacoub et al., 2001
Negative BOLD response caused
by impaired oxygen supply
• Subject: 74y male with
transient ischemic attack
(6m prior)
– Revealed to have arterial
occlusion in left
hemisphere
• Tested in bimanual motor
task
• Found negative bold in
LH, earlier than positive
in right
Rother, et al., 2002
Rise (Hyperoxic Phase)
• Results from vasodilation of arterioles, resulting
in a large increase in cerebral blood flow
• Inflection point can be used to index onset of
processing
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Peak – Overshoot
• Over-compensatory response
– More pronounced in BOLD signal measures
than flow measures
• Overshoot found in blocked designs with
extended intervals
– Signal saturates after ~10s of stimulation
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Sustained Response
• Blocked design analyses rest upon
presence of sustained response
– Comparison of sustained activity vs. baseline
– Statistically simple, powerful
• Problems
– Difficulty in identifying magnitude of activation
– Little ability to describe form of hemodynamic
response
– May require detrending of raw time course
Undershoot
• Cerebral blood flow more locked to stimuli
than cerebral blood volume
– Increased blood volume with baseline flow
leads to decrease in MR signal
• More frequently observed for longerduration stimuli (>10s)
– May not be present for short duration stimuli
– May remain for 10s of seconds
Issues in HDR Analysis
• Delay in the HDR
– Hemodynamic activity lags neuronal activity
• Amplitude of the HDR
• Variability in the HDR
• HDR as a relative measure
The Hemodynamic Response
Lags Neural Activity
Experimental
Design
Convolving
HDR
Time-shifted
Epochs
Introduction
of Gaps
Percent Signal Change
505
1%
500
5
5
0
5
10
15
10
15
205
• Peak / mean(baseline)
• Often used as a basic
measure of “amount of
processing”
• Amplitude variable
across subjects, age
groups, etc.
20
25
20
25
1%
200
0
5
Amplitude of the HDR
• Peak signal change dependent on:
– Brain region
– Task parameters 
– Voxel size
– Field Strength
Kwong et al, 1992
Variability in the Hemodynamic
Response
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Across Subjects
Across Sessions in a Single Subject
Across Brain Regions
Across Stimuli
Relative vs. Absolute Measures
• fMRI provides relative change over time
– Signal measured in “arbitrary MR units”
– Percent signal change over baseline
• PET provides absolute signal
– Measures biological quantity in real units
•
•
•
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CBF: cerebral blood flow
CMRGlc: Cerebral Metabolic Rate of Glucose
CMRO2: Cerebral Metabolic Rate of Oxygen
CBV: Cerebral Blood Volume
Spatial and Temporal Properties of
BOLD fMRI
Why do you need to know?
• Spatial resolution
– Trades off with coverage
– Influences viability of preprocessing steps
– Influences inferences about distinct ROIs
• Temporal resolution
– Tradeoffs between number of slices and TR
– Needed resolution depends upon design
Spatial Resolution
What spatial resolution do we want?
• Hemispheric
– Lateralization studies
– Selective attention studies
• Systems / lobic
– Relation to lesion data
• Centimeter
– Identification of active regions
• Millimeter
– Topographic mapping (e.g., motor, vision)
• Sub-millimeter
– Ocular Dominance Columns
– Cortical Layers
What determines Spatial
Resolution?
• Voxel Size
– In-plane Resolution
– Slice thickness
• Spatial noise
– Head motion
– Artifacts
• Spatial blurring
–
–
–
–
Smoothing (within subject)
Coregistration (within subject)
Normalization (within subject)
Averaging (across subjects)
Why can’t we just collect data
from more/smaller voxels?
K – Space Revisited
A
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B
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FOV: 10cm, Pixel Size: 2 cm
FOV: 10 cm, Pixel Size: 1 cm
To increase spatial resolution we need to sample at higher spatial frequencies.
Costs of Increased Spatial
Resolution
• Acquisition Time
– In-plane
• Higher resolution takes more time to fill
K-space (resolution ~ size of K-space)
– #Slices/second
– Sample rates for 64*64 images
•
•
•
•
Early Duke fMRI: 2-4 sl/s
GE EPI: 12 sl/s
Duke Spiral: 14 sl/s
Duke Inverse Spiral: 21+ sl/s
• Reduced signal per voxel
– What is our dependent measure?
How large are functional voxels?
 5.0mm 
=
3
~.08cm
 3.75mm 
Within a typical brain (~1300cm3), there may be about 20,000
functional voxels.
How large are anatomical voxels?
 5.0mm 
=
3
~.004cm
 .9375mm 
Within a typical brain (~1300cm3), there may be about 300,000+
anatomical voxels.
T2* Blurring
• Signal decays over time needed for collection of
an image
• For standard resolution images, this is not a
critical issue
• However, for high-resolution (in-plane) images,
the time to acquire an image may be a
significant fraction of T2*
• Under these conditions, multi-shot imaging may
be necessary.
Partial Volume Effects
• A single voxel may contain
multiple tissue components
– Many “gray matter” voxels will
contain other tissue types
– Large vessels are often
present
• The signal recorded from a
voxel is a combination of all
components
High Spatial Resolution fMRI:
Ocular Dominance Columns
Early examples of ocular
dominance
Red = Left eye
Blue = Right eye
Pixel size
0.5mm2
Menon et al., 1997
Reliability of Ocular Dominance
Measurements
• Cheng et al., 2001
• Same subject
participated in two
sessions
– Raw data at left
• Boundaries of
dominance columns
match well across
sessions
Effects of Stimulus Duration on
Spatial Extent of Activity
Example: Ocular Dominance
Goodyear & Menon, 2001
4sec 
10sec 
Goodyear & Menon, 2001
Example: Visual System
100
ms
500
ms
1500
ms