declaration of conflict of interest or relationship speaker name: thomas liu i have no conflicts of...
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Declaration of Conflict of Interest or Relationship
Speaker Name: Thomas LiuSpeaker Name: Thomas Liu
I have no conflicts of interest to disclose with regard to the subject matter I have no conflicts of interest to disclose with regard to the subject matter ofofthis presentation.this presentation.
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Thomas LiuUniversity of California, San
DiegoMay 4, 2008
Functional MRISignal Interpretation and Calibration
Topics
• BOLD signal model• Sources of Variability and Confounds• Normalization Methods• Calibration Methods
BOLD Contrast
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Source: Ogawa et al., 1992
BOLD Signal Change
€
ΔBOLDBOLD0
=SA − SBSB
= exp −TE ⋅ R2,A∗ − R2,B
∗( )( ) −1
= exp −TE ⋅ΔR2∗
( ) −1
€
SB = M0 exp −TE ⋅R2,B*
( )
Baseline Signal
TE
Activation Signal
€
SA = M0 exp −TE ⋅R2,A*
( )
€
ΔBOLDBOLD0
≈ −TE ⋅ΔR2∗
Hemoglobin and Field Inhomogeneities
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Oxygen binds to the iron atoms to form oxyhemoglobin HbO2
Release of O2 to tissue results in deoxyhemoglobin dHBO2
http://www.people.virginia.edu/~rjh9u/hemoglob.html
B0
Field Maps
More dHB Less dHB
Signal Decay
time0 TE
Some dHB, Some dephasing
More dHB, More dephasing, Decrease in MR signal
BOLD Signal Equation
€
R2,dHB∗ = A ⋅CBV ⋅ dHb[ ]v
β
Ogawa et al, 1993; Boxerman et al 1995, Hoge et al. 1999
€
R2∗ = R2,dHb
∗ + R2,OTHER∗
Ogawa et al, 1993
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Large vesselsLinear =1
Diffusion around small vesselsQuadratic =2
Simulations suggest 1.5 is a reasonable value
Cerebral Blood Volume
Blood Flow and Oxygen Metabolism
Cerebral Blood Flow (CBF) measures delivery of blood to brain tissue (units of ml/(g-min))
Cerebral Metabolic Rate of (CMRO2) is the rate of oxygen consumption (units of mol/(g-min))
CBF [O2]arterial
CMRO2
Oxygen extraction fraction (E)
CMRO2= E CBF [O2]arterial
Deoxyhemoglobin
= CMRO2 / 4CBF
CMRO2 [dHB]venous
CBF [dHB]venous
O2
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[dHB]venous E [O2]arterial / 4
fMRI: Spatial Temporal Dynamicsarteriole venulecapillary bed
CMRO2
CBF
oxyHbdeoxyHb
Initial dip
Positive BOLD
Post-stimulus Response
Neural activity
CMRO2
CBV
CBF
dHb
CMRO2
CBV
CBF
dHb
CMRO2
CBV
CBF
dHb
BOLD Signal Equation (Davis Model)
€
ΔBOLDBOLD0
≈ −TE ⋅ΔR2,dHB∗
€
ΔBOLDBOLD0
≈ M 1−CBF
CBF0
⎛
⎝ ⎜
⎞
⎠ ⎟
α −βCMRO2
CMRO2,0
⎛
⎝ ⎜
⎞
⎠ ⎟
β ⎛
⎝ ⎜ ⎜
⎞
⎠ ⎟ ⎟
€
M = TE ⋅A ⋅CBV0 ⋅[dHb0]βMaximal BOLD signal
€
CBV
CBV0
⎛
⎝ ⎜
⎞
⎠ ⎟=CBF
CBF0
⎛
⎝ ⎜
⎞
⎠ ⎟
α
Grubb’s Relation; 0.38
Davis Model
Hoge et al. 1999
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ΔBOLDBOLD0
≈ M 1−CBF
CBF0
⎛
⎝ ⎜
⎞
⎠ ⎟
α −βCMRO2
CMRO2,0
⎛
⎝ ⎜
⎞
⎠ ⎟
β ⎛
⎝ ⎜ ⎜
⎞
⎠ ⎟ ⎟
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BOLD Signal Path
NeuralActivity
Metabolism(CMRO2)
Cerebral Blood Flow
Cerebral Blood Volume
deoxyHbBOLDSignal
Interpreting BOLD
• Most fMRI studies assume that the BOLD signal is is proportional to brain activity.
• This is a reasonable assumption for basic studies of healthy young unmedicated subjects.
• However, the assumption is less valid for studies where disease, medication, and age may be a factor. Boynton et al, 1996
Variability in BOLD amplitude
Data courtesy of J. Liau
BOLD Signal Chain
Ianetti and Wise, MRI, 2007
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Effect of Age
D’Esposito et al 2003
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Effects of Vascular Disease
D’Esposito et al 2003
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Iadecola et al 2003
Cohen et al 2002
Carbon DioxideHigher CBFLower CBF
Caffeine
Liu et al 2004
Lower CBF
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Interpreting BOLD
Ianetti and Wise, MRI, 2007
NeuralActivity
Metabolism(CMRO2)
Cerebral Blood Flow
Cerebral Blood Volume
deoxyHbBOLDSignal
Trust MRI Measures of whole brain venous
oxygenation
Response to Breathhold or CO2;
Resting-state Fluctuations
ASL measures of regional baseline CBF
BOLD and Venous Oxygenation
€
ΔBOLDBOLD0
≈ M 1−CBF
CBF0
⎛
⎝ ⎜
⎞
⎠ ⎟
α −βCMRO2
CMRO2,0
⎛
⎝ ⎜
⎞
⎠ ⎟
β ⎛
⎝ ⎜ ⎜
⎞
⎠ ⎟ ⎟
€
M = TE ⋅A ⋅CBV0 ⋅[dHb0]β Inter-subject Differences in M can lead to inter-subject differences in BOLD
€
[dHb0]∝ E =1−Yv
TRUST MRI (Lu et al 2007): Measures of whole brain venous oxygenation saturation.
Yv [dHB]venous
BOLD
Venous Oxygenation (TRUST MRI)
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Lu, ISMRM 2007
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TRUST MRI
Lu et al, Abstract 855, ISMRM 2008
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BOLD and Baseline CBF
€
ΔBOLDBOLD0
≈ M 1−CBF
CBF0
⎛
⎝ ⎜
⎞
⎠ ⎟
α −βCMRO2
CMRO2,0
⎛
⎝ ⎜
⎞
⎠ ⎟
β ⎛
⎝ ⎜ ⎜
⎞
⎠ ⎟ ⎟
€
M = TE ⋅A ⋅CBV0 ⋅[dHb0]β
€
≈TE ⋅A ⋅CBF0α ⋅[dHb0]β
?dHb BOLD
ΔCBF BOLD
CBF0 M BOLD
BOLD variability and Baseline CBF
• M appears to be independent of CBF -- effects of increased CBF and decreased [dHb] appear to cancel out• Variability in the BOLD response across subjects appears to be driven by inter-subject differences in the
CBF response.
Liau et al, Abstract 854, ISMRM 2008
Breathold/Hypercapnic Normalization
€
ΔBOLDBOLD0
≈ M 1−CBF
CBF0
⎛
⎝ ⎜
⎞
⎠ ⎟
α −βCMRO2
CMRO2,0
⎛
⎝ ⎜
⎞
⎠ ⎟
β ⎛
⎝ ⎜ ⎜
⎞
⎠ ⎟ ⎟
€
ΔBOLDBOLD0
⎛
⎝ ⎜
⎞
⎠ ⎟BH
≈ M 1−CBFBHCBF0
⎛
⎝ ⎜
⎞
⎠ ⎟
α −βCMRO2,BH
CMRO2,0
⎛
⎝ ⎜
⎞
⎠ ⎟
β ⎛
⎝ ⎜ ⎜
⎞
⎠ ⎟ ⎟
1
€
ΔBOLDBOLD0
⎛
⎝ ⎜
⎞
⎠ ⎟BH
≈ M 1−CBFBHCBF0
⎛
⎝ ⎜
⎞
⎠ ⎟
α −β ⎛
⎝ ⎜ ⎜
⎞
⎠ ⎟ ⎟
€
ΔBOLDBOLD0
ΔBOLD
BOLD0
⎛
⎝ ⎜
⎞
⎠ ⎟BH
≈
M 1−CBF
CBF0
⎛
⎝ ⎜
⎞
⎠ ⎟
α −βCMRO2
CMRO2,0
⎛
⎝ ⎜
⎞
⎠ ⎟
β ⎛
⎝ ⎜ ⎜
⎞
⎠ ⎟ ⎟
M 1−CBFBHCBF0
⎛
⎝ ⎜
⎞
⎠ ⎟
α −β ⎛
⎝ ⎜ ⎜
⎞
⎠ ⎟ ⎟
€
ΔBOLDBOLD0
ΔBOLD
BOLD0
⎛
⎝ ⎜
⎞
⎠ ⎟BH
≈
1−CBF
CBF0
⎛
⎝ ⎜
⎞
⎠ ⎟
α −βCMRO2
CMRO2,0
⎛
⎝ ⎜
⎞
⎠ ⎟
β ⎛
⎝ ⎜ ⎜
⎞
⎠ ⎟ ⎟
1−CBFBHCBF0
⎛
⎝ ⎜
⎞
⎠ ⎟
α −β ⎛
⎝ ⎜ ⎜
⎞
⎠ ⎟ ⎟
Breathhold Calibration
Thomason et al, 2007
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Bre
athh
old
Sig
nal
Breathhold Calibration
Thomason et al, 2007
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Hypercapnic Calibration
Cohen et al, 2004
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Scaling with Resting-State Fluctuations
Wise et al 2004;
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Scaling with Resting-State Fluctuations
Birn et al 2006;
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Scaling with Resting-State Fluctuations
Kannapurti and Biswal 2008; also Abstract 750
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Summary of Normalization Approaches
• Additional measures can account for BOLD variability due to variations in baseline blood flow, volume, oxygenation, field strength, etc.
• Measures of venous oxygenation, cerebral blood flow, and resting fluctuations have the advantage of not requiring the subject to perform additional tasks.
• These approaches offer some insight into the factors that can affect the BOLD response between subjects, groups, and conditions.
NeuralActivity
Metabolism(CMRO2)
Cerebral Blood Flow
Cerebral Blood Volume
deoxyHbBOLDSignal
ASLSignal
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Calibrated fMRI (Davis et al 1998)
€
ΔBOLDBOLD0
≈ M 1−CBF
CBF0
⎛
⎝ ⎜
⎞
⎠ ⎟
α −βCMRO2
CMRO2,0
⎛
⎝ ⎜
⎞
⎠ ⎟
β ⎛
⎝ ⎜ ⎜
⎞
⎠ ⎟ ⎟
€
ΔBOLDBOLD0
⎛
⎝ ⎜
⎞
⎠ ⎟CO2
≈ M 1−CBFCO2
CBF0
⎛
⎝ ⎜
⎞
⎠ ⎟
α −βCMRO2,CO2
CMRO2,0
⎛
⎝ ⎜
⎞
⎠ ⎟
β ⎛
⎝ ⎜ ⎜
⎞
⎠ ⎟ ⎟
1
€
ΔBOLDBOLD0
⎛
⎝ ⎜
⎞
⎠ ⎟CO2
≈ M 1−CBFCO2
CBF0
⎛
⎝ ⎜
⎞
⎠ ⎟
α −β ⎛
⎝ ⎜ ⎜
⎞
⎠ ⎟ ⎟
€
M =
ΔBOLD
BOLD0
⎛
⎝ ⎜
⎞
⎠ ⎟CO2
1−CBFCO2
CBF0
⎛
⎝ ⎜
⎞
⎠ ⎟
α −β ⎛
⎝ ⎜ ⎜
⎞
⎠ ⎟ ⎟
€
CMRO2
CMRO2,0
⎛
⎝ ⎜
⎞
⎠ ⎟
β
=
1−ΔBOLD
M ⋅BOLD0
⎛
⎝ ⎜
⎞
⎠ ⎟
CBF
CBF0
⎛
⎝ ⎜
⎞
⎠ ⎟
α −β
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Experimental Protocol
2x Block design visual stimulus
20s 60s
%∆CBF%∆BOLD
2x 5% CO2 Scans
2minair
3minCO2
2minair
M
%∆CMRO2
Calibrated fMRIAnces et al, NIMG 2007
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Calibrated fMRI of HIV
Ances et al, in preparation
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Effect of age on CBF and BOLD
Restom et al, NIMG 2007
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Young Old
%ΔC
MR
O2
Young OldNorm
aliz
ed
CM
RO
2
Calibrated fMRI
• Can provide insights that BOLD measures alone cannot provide.
• Can be difficult to apply to cognitive tasks and special populations, due to low sensitivity of ASL.
• The need for breathhold or hypercapnia can also be an issue. Hyperoxia-based method may be an alternative.
Conclusions
• The BOLD signal is a complex function of the baseline state and changes in blood flow, volume, and metabolism.
• Differences in the BOLD signal do NOT always reflect differences in neural activity.
• Instead they may reflect differences in the baseline vascular or metabolic state.
• Normalization methods can help to reduce inter-subject variability.
• Calibrated fMRI can provide additional insights into differences in brain activity, especially in the presence of disease, medication, and age.
Acknowledgements
Beau AncesYashar BehzadiRick BuxtonDavid DubowitzJoy LiauOleg LeontievJoanna PerthenKhaled RestomEric Wong
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