Declaration of Conflict of Interest or Relationship Speaker Name: Thomas Liu I have no conflicts of interest to disclose with regard to the subject matter.

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.

QuickTime™ and aTIFF (LZW) decompressor

are needed to see this picture.

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





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

QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.

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



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

QuickTime™ and a decompressor


[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



€

ΔBOLDBOLD0

≈ M 1−CBF

CBF0

⎛

⎝ ⎜

⎞

⎠ ⎟

α −βCMRO2

CMRO2,0

⎛

⎝ ⎜

⎞

⎠ ⎟

β ⎛

⎝ ⎜ ⎜

⎞

⎠ ⎟ ⎟

QuickTime™ and a decompressor


BOLD Signal Path

NeuralActivity

Metabolism(CMRO2)

Cerebral Blood Flow


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





Effect of Age

D’Esposito et al 2003



Effects of Vascular Disease

D’Esposito et al 2003


are needed to see this picture.QuickTime™ and a

TIFF (LZW) decompressorare needed to see this picture.

Iadecola et al 2003

Cohen et al 2002

Carbon DioxideHigher CBFLower CBF

Caffeine

Liu et al 2004

Lower CBF



Interpreting BOLD

Ianetti and Wise, MRI, 2007

NeuralActivity

Metabolism(CMRO2)

Cerebral Blood Flow


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)





Lu, ISMRM 2007



TRUST MRI

Lu et al, Abstract 855, ISMRM 2008



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



Bre

athh

old

Sig

nal

Breathhold Calibration

Thomason et al, 2007





Hypercapnic Calibration

Cohen et al, 2004





Scaling with Resting-State Fluctuations

Wise et al 2004;




Birn et al 2006;




Kannapurti and Biswal 2008; also Abstract 750





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


deoxyHbBOLDSignal

ASLSignal








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








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





Calibrated fMRI of HIV

Ances et al, in preparation



Effect of age on CBF and BOLD

Restom et al, NIMG 2007









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



Declaration of Conflict of Interest or Relationship Speaker Name: Thomas Liu I have no conflicts of interest to disclose with regard to the subject matter.

Documents

iadecola et

caffeineliu et

boxerman et

liau et

boynton et

trust mrilu et

bold variability

carbon dioxidecohen