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Functional MRI. Daniel Bulte. Centre for Functional Magnetic Resonance Imaging of the Brain University of Oxford. Overview. BOLD Contrast Metabolic and cerebral blood flow response Mechanism of MR signal change Neurovascular coupling Noise Factors affecting BOLD More detail

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Functional MRI

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Functional mri

Functional MRI

Daniel Bulte

Centre for Functional Magnetic Resonance Imaging of the Brain

University of Oxford


Overview

Overview

  • BOLD Contrast

    • Metabolic and cerebral blood flow response

    • Mechanism of MR signal change

  • Neurovascular coupling

  • Noise

  • Factors affecting BOLD

    • More detail

    • Changing physiological baseline

  • Metabolic modelling


Activation

“Activation”


Functional mri

Deoxy-Haemoglobin

paramagnetic

different to tissue

=0.08ppm


Functional mri

Oxy-Haemoglobin

diamagnetic

same as tissue


Field homogeneity oxygenation state

Field homogeneity & oxygenation state

  • Red blood cell

    • 6 m diameter, 1-2 m thick

  • Susceptibility

    • An object with differing magnetic properties distorts the field


Water

Water

  • Freely diffusing water is the source of image signal

  • Two water spaces

    • Intravascular (blood)

      • Capillaries and venules

    • Extravascular - a larger pool

      • In 50ms (FMRI TE) water diffuses 4 capillary diameters


Magnetic field in a vessel

Magnetic field in a vessel

B0

q

a

r

Inside Cylinder

f

∆cos2

= 2(1-Y)  '

D

w

'


Magnetic field around a vessel

Magnetic field around a vessel

B0

Outside Cylinder

q

r,

sin2a/r2cos

a

r

Inside Cylinder

f

∆cos2

= 2(1-Y)  '

D

w

'


Vessel orientation

Vessel orientation

  • Field inside and outside depends on angle  with respect to B0

Bandettini and Wong. Int. J. Imaging Systems and Technology. 6:133 (1995)


Blood oxygenation

Blood oxygenation

  • Field inside and outside depends on Y, oxygenation

Bandettini and Wong. Int. J. Imaging Systems and Technology. 6:133 (1995)


Signal dependence

Signal dependence

  • Macroscopic behaviour of NMR, gradient echo signal

  • More extravascular at high field

  • BOLD signal depends on the amount of dHb in the voxel

R2* = 4.3 (1-Y) B0 CBV

(venules, larger vessels)

R2* = 0.04 {(1-Y)}2B02 CBV

(smaller capillaries)


Bold signal

BOLD signal

  • Blood Oxygen Level Dependent signal

  • T2* change from the haemodynamic perturbation associated with neural activation


From neural activity to bold signal

Neural activity

Signalling

Vascular response

BOLD signal

Vascular tone (reactivity)

Autoregulation

Blood flow,

oxygenation

and volume

Synaptic signalling

arteriole

B0 field

glia

Metabolic signalling

venule

From neural activity to BOLD signal


Factors affecting bold signal

Factors affecting BOLD signal?

  • Physiology

    • Cerebral blood flow (baseline and change)

    • Metabolic oxygen consumption

    • Cerebral blood volume

  • Equipment

    • Static field strength

    • Field homogeneity (e.g. shim dependent T2*)

  • Pulse sequence

    • Gradient vs spin echo

    • Echo time, repeat time, flip angle

    • Resolution


Functional mri

T2* weighted signal

T2* weighted signal

T2* weighted signal

T2* weighted signal

T2* weighted signal

T2* weighted signal

T2* weighted signal

T2* weighted signal

T2* weighted signal

T2* weighted signal

T2* weighted signal

Oxygen

Consumption

Neural

Activity

Neural

Activity

Oxygen

Consumption

Neural

Activity

Oxygen

Consumption

Neural

Activity

Oxygen

Consumption

Neural

Activity

Neural

Activity

Neural

Activity

Oxygen

Consumption

Neural

Activity

Neural

Activity

Oxygen

Consumption

Oxygen

Consumption

Neural

Activity

Neural

Activity

Oxygen

Consumption

Oxygen

Consumption

Oxygen

Consumption

Oxygen

Consumption

Image

Image

Image

Image

Image

Image

Image

Image

Image

Image

Image

Blood

Flow

Blood

Flow

Blood

Volume

Blood

Flow

Blood

Volume

Blood

Flow

Blood

Flow

Blood

Volume

Blood

Flow

Blood

Flow

Blood

Volume

Blood

Volume

Blood

Volume

Blood

Volume

Oxy-

haemoglobin

Oxy-

haemoglobin

Oxy-

haemoglobin

Oxy-

haemoglobin

Oxy-

haemoglobin

Oxy-

haemoglobin

Oxy-

haemoglobin

Oxy-

haemoglobin

Oxy-

haemoglobin

Oxy-

haemoglobin

Oxy-

haemoglobin

Deoxy-

haemoglobin

Deoxy-

haemoglobin

Deoxy-

haemoglobin

Deoxy-

haemoglobin

Deoxy-

haemoglobin

Deoxy-

haemoglobin

Deoxy-

haemoglobin

Deoxy-

haemoglobin

Deoxy-

haemoglobin

Deoxy-

haemoglobin

Deoxy-

haemoglobin


Haemodynamic changes underlying bold

Haemodynamic changes underlying BOLD

CBF

positive

BOLD response

3

initial

dip

BOLD response, %

post stimulus

undershoot

2

overshoot

CBV

1

0

time

CMRO2

stimulus

stimulus


Bold contrast

BOLD contrast

  • Transverse relaxation

    • Described by a time constant

    • Time for NMR signal to decay

      • Loss of spins phase coherence (out of step)

    • Spin echo, T2

      • Time varying field seen by diffusing spins

    • Gradient echo, T2*

      • Time varying field seen by diffusing spins

      • … plus spatial field variation across voxel

  • Why is magnetic field non uniform?


Modelling of the bold effect

Modelling of the BOLD effect

  • Effects of oxygenation on T2*

    • Ogawa et al., J. Biophys., 64:803-812 (1993)

    • Kennan et al., MRM, 31:9-21 (1994)

    • Boxerman et al., MRM, 34:4-10 (1995)

  • Flow and oxygenation coupling

    • Buxton and Frank, JCBFM, 17:64-72 (1997)

  • CBV effects

    • Buxton et al., MRM, 39:855-864 (1998)

    • Mandeville et al., JCBFM, 19:679-689 (1999)


Signal evolution

Signal evolution

  • Monte Carlo simulation

    • Signal dephasing in the vascular tree amongst vessels of differing size, oxygenation and orientation

    • Boxerman J. et al. MRM 1995

  • Deoxy-Hb contribution to relaxation

  • Gradient echo

R2* (1-Y) CBV

Y=O2 saturation

b~1.5

S = Smax . e-TE/R2*


Echo time and bold sensitivity

Echo time and BOLD sensitivity

  • BOLD contrast-to-noise optimised when TE~T2*

  • T2* shorter at higher field

Relative

CNR

TE optimization similar to T2 structural optimizations, just between different states rather than different tissues

TE (ms)


Vessel density

Vessel density

500 m

100 m

Harrison RV et al. Cerebral cortex. 2002


Arteriole

Arteriole

100 m


Even smaller

Even smaller

50 m


Arterial side

Arterial side

Capillaries

8 m 40% CBV

  • Capillaries are randomly orientated

  • Oxygen exchange in capillaries

  • Arterioles perform local CBF control

Arterioles

25 m 15% of CBV

Artery

Blood oxygen saturation, 98-100%


Venous side

Venous side

Capillaries

  • Venules

    • are (approx) randomly orientated

    • have the same blood volume as capillaries

    • have twice the deoxyHb concentration of capillaries

    • are more (para)magnetic than capillaries and arteries

Venules

25-50 m 40% of CBV

Vein

Blood oxygen saturation (resting), 60%


Activation1

Activation

O2 Sat100%80%60%

Rest

  • Active: 50% increase in CBF, 20% increase in CMRO2

  • O2 Sat100%86%72%


Decrease in deoxy hb concentration

Decrease in deoxy-Hb concentration


Bold fmri

electrical

activity

hemodynamic

response

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

BOLD FMRI

Basal (resting) state

MRI signal

capillary

bed

capillary

bed

- normal flow

- basal level [Hbr]

- basal CBV

- normal MRI signal

arterioles

arterioles

venules

venules

CBV

FLOW

= HbO2

= HbO2

Field gradients

= Hbr

= Hbr


Bold fmri1

electrical

activity

hemodynamic

response

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

BOLD FMRI

Activated state

MRI signal

capillary

bed

capillary

bed

arterioles

arterioles

- increased flow

- decreased [Hbr] - increased CBV

- increased MRI signal

venules

venules

CBV

CBV

FLOW

FLOW

= HbO2

= HbO2

= Hbr

= Hbr


Dissecting bold

Dissecting BOLD

  • SBOLD=f(CBV,CBF,CMRO2)

Purer measures of neuronal activity?

Buxton et al. Neuroimage 2004


Fmri modelling the haemodynamic response

FMRI Modelling: TheHaemodynamic Response

  • The stimulus is convolved with an assumed or modeled impulse response function, the haemodynamic response function (HRF), to give the assumed BOLD response


Functional mri

HRF

Stimulus (Single Event)

Haemodynamic Response Function (HRF)

Time

0 10 20 30 seconds

The haemodynamic response to a stimulus is blurred and delayed


Predicted response

Predicted Response

  • The process can be modeled by convolving the activity curve with the HRF

HRF

Predicted neural activity

=

Predicted response


Functional mri

GLM

  • Standard GLM Analysis:

    • Correlate model at each voxel separately

    • Measure residual noise variance

    • T-statistic = model fit / noise amplitude

    • Threshold T-stats and display map

  • Signals of no interest (e.g. artifacts) can affect both activation strength and residual noise variance

  • Use pre-processing to reduce/eliminate some of these effects


A typical scan at 3t

A typical scan at 3T…

  • Gradient echo EPI

  • TR 2000 – 4000 ms

  • TE 30 ms

  • Flip angle 60 – 90 degrees

  • 64 x 64

  • 4 – 8 mm thick slices

  • 20 – 40 slices


Why epi

Why EPI?

  • A typical T2-weighted imaging series requires that TR be two to three times longer than the intrinsic tissue magnetization parameter, T1.

  • The T1 of biological samples is typically on the order of a second; TR must therefore be 3 seconds or more.

  • A typical MR image is formed from 128 repeated samples, so that the imaging time for our canonical T2 weighted scan is about 384 seconds, or more than 6.5 minutes.

  • By comparison, the EPI approach collects all of the image data, for an image of the same resolution, in 40 to 150 milliseconds

  • A nearly 10,000-fold speed gain!


However

However…

  • Bandwidth and Artifacts

  • Chemical Shift

  • Shape Distortion

  • Ghosting

  • Resolution


Purer physiological measures

Purer physiological measures

  • Perfusion and perfusion change

  • CMRO2 change

  • Cerebral blood volume

  • Oxygen extraction fraction


Correlates of brain activity

neuronal activity

FDG PET

- excitatory

autoradiography

- inhibitory

- soma action potential

H215O PET

NIRS

Neurovascular coupling

optical imaging

EEG

FMRI

MEG

Correlates of brain activity

electrophysiology

metabolic response

-  glucose consumption

-  oxygen consumption

hemodynamic response

-  blood flow

-  blood volume

-  blood oxygenation


Oxidative metabolism attenuates bold signal

Oxidative metabolism attenuates BOLD signal

BOLD

CBF

  • Hoge R et al


Cmro2 measurement

CMRO2 measurement

Measured

BOLD

R2*(BOLD) = k CBVa [dHb]b

  • k = field dependent constant

  • CBV = cerebral blood volume fraction

  • [dHb] = concentration of dHb in blood

  •  = theoretical CBV dependence (=1)

  •  = theoretical [dHb] dependence

    •  1.5 (1.5T) [Boxerman et al, 1995]

    •   1 (>3T) [Ogawa et al, 1993]


Cmro 2 measurement

CMRO2 measurement

Substitutions:

CMRO2 = CBF. OEF . Ca

(Fick’s principle)

[dHb] = CMRO2 / CBF

CBV

CBF

)

(

(Grubb et al., 1974)

=

CBV0

CBF0

 = 0.38 (steady state value)

ASL measured


Cmro 2 measurement1

CMRO2

DR2*(BOLD)

CBF

]

-b

)

(

)

(

b

=

1 -

CBF0

R2*0(BOLD)

CMRO2(0)

CMRO2 measurement

A flow increase without increase in CMRO2

Calibrate R2*0 using a hypercapnia challenge


Calibrated bold for measuring cmro 2

Calibrated BOLD for measuring CMRO2

CMRO2-CBF coupling:

slope ~2

Calibrated BOLD

  • Hoge R et al


What else

What else?

  • ASL

  • VASO

  • MRS

  • DWI

  • ???


Functional mri

CBV

BOLD

Neural Response

CBF

Neurovascular Coupling

CMRO2

Stimulus


Arterial spin labeling

movement of blood water:

measure

of CBF

Arterial Spin Labeling

Relies on endogenous contrast agent

Magnetically label water at the neck (below imaging plane)

Labeled blood moves downstream and mixes with stationary tissue water

CBF (ml g-1 min-1)

pCO2 (mmHg)

Williams et al. PNAS 1992


Asl tagging strategies

Wait for tag blood water spins to arrive

tag delay: 500 - 2000 msec

image

ASL: Tagging Strategies

Universal concept: “tag” and “control”

tag

time


Asl tagging strategies1

ASL: Tagging Strategies

Universal concept: “tag” and “control”

no tag

image

Wait the same amount of time but no tagging


Asl tagging strategies2

ASL: Tagging Strategies

Universal concept: “tag” and “control”

Control image is important

same tag location

off-resonance

no tag

image

global tag

Wait the same amount of time but no tagging


A bit about baselines

A bit about baselines

hemodynamic

response


Physiological baseline

Physiological baseline

  • Baseline CBF,

  • But CBF CMRO2 unchanged (probably) (Brown et al JCBFM 2003)

  • BOLD response  (probably)

Cohen et al JCBFM 2002


Implications

Implications

  • Factors altering baseline state

    • Disease

    • Sedation

    • Anxiety

    • Vasoactive medications

      • Global and local

  • CBF (ASL) may be more robust?


Noise sources

Noise sources

  • What is noise in a BOLD experiment?

    • Unmodelled variation in the time-series

    • Intrinsic MRI noise

      • Independent of field strength, TE

      • Thermal noise from subject and RF coil

  • Physiological noise

    • Increases with field strength, depends on TE

    • Cardiac pulsations

    • Respiratory motion and B0 shift

    • Vasomotion, 0.1Hz

    • Blood gas fluctuations

    • “Resting state” networks

  • Also

    • Scanner drift (heating up)


At 3tesla

At 3Tesla

Physiological noise >scanner + thermal noisePhysiological noise GM > Physiological noise WM


Spatial distribution of noise

Spatial distribution of noise

  • Motion at intensity boundaries

    • volunteer

    • Respiratory B0 shift

  • Physiological noise in blood vessels and grey matter


Noise structure

Noise structure

BOLD noise

  • 1/f dependence

    • BOLD is bad for detecting long time-scale activation

frequency


Noise or signal

Noise or signal?

  • Noise is unmodelled signal

    • Spatially structured

    • Temporally structured

  • “Physiological” signal

    • Vascular properties

  • “Neuronal” signal

    • Resting state networks

    • Resting fluctuations

    • Stimulus induced deactivation

Separation:

all haemodynamic


Physiological noise

Physiological noise

  • Motion

    • McFLIRT correction

  • Cardiac

    • Pulsations (aliased)

  • Respiratory

    • Motion

    • B0 shift

RETROICOR correction


Physiological signal

Physiological signal

  • Low frequency haemodynamic oscillations

    • Information about vascular properties

    • CO2 reactivity

    • Autoregulation

  • Is it a problem?

  • Can we use it?


Bold response to co 2

100

5.0

50

CBV ml/100g

CBF ml/100g/min

4.0

3.0

Normal

20

40

60

80

mmHg

PaCO2

BOLD response to CO2

  • CO2 is a potent vasodilator

  • Hypercapnia:

  • CBF, CBV   [deoxyHb]   T2*   SBOLD 

  • Previous investigations use sustained hyper/hypocapnia challenges to investigate regional sensitivity (1.5T)

  • e.g. Posse et al. 1997, 2001, Rostrup et al. 2000


Spontaneous co 2 fluctuations

Spontaneous CO2 fluctuations

Resting PETCO2

PETCO2 power spectrum

  • End-tidal CO2 (PETCO2) is a good measure of arterial CO2

  • Fluctuations 0 - 0.05 Hz (Van den Aardweg & Karemaker, 2002)

  • Overlaps with stimulus frequencies

  • Can correlate with stimulation

Wise et al Neuroimage 2004


Bold co 2 resting correlation

BOLD-CO2 (resting) correlation

r=0.5, Z=5.5


What about 7t

What about 7T?


Fmri at 7t

FMRI at 7T


Bigger is better

Bigger is better

  • High field = high SNR and high BOLD CNR

  • At higher magnetic fields, the short T2 of blood means that its signal is attenuated relative to that from tissue at the TE’s used for fMRI.

  • Hence it is expected that higher spatial specificity can be obtained in BOLD data acquired at high field as the intra-vascular signal contribution from draining veins is reduced


Pros and cons

Pros and Cons

  • The increase in physiological noise can reduce the gains in BOLD CNR at ultra-high field

  • Higher BOLD signal means more signal drop-out

  • However, an increased BOLD CNR allows fMRI to be performed at higher spatial resolution, which has the potential advantage of reduced signal drop-out due to magnetic field inhomogeneities and longer baseline T2⁎

  • At high resolution the effect of intrinsic noise can dominate that of physiological noise


Functional mri

http://www.fmrib.ox.ac.uk/Members/bulte/

Extra Reading:

Buxton et al. Modeling the hemodynamic response to brain activation.

NeuroImage 23 (2004) S220–S233

Raichle & Mintun. BrainWork and Brain Imaging. Annu. Rev. Neurosci. 2006. 29:449–76


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