An Introduction to Functional MRI

Bruce Pike

McConnell Brain Imaging Centre

Montreal Neurological Institute McGill University

B. Pike, MNI 2

Outline •  MRI review (4 slide crash course) •  fMRI overview

–  basic premise –  experimental design and analysis

•  BOLD fMRI physiology –  biophysical basis –  CBF, CBV, and CMRO2

•  fMRI Experiment Designs –  block, event, phase, resting state

•  BOLD fMRI issues –  spatial specificity –  field strength –  Noise –  EPI artifacts

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NMR

B0

external field B0

M M

x

y

z

B0

f = (42 x B0) MHz

Felix Bloch (1905-1983)

Edward Purcell (1912-1997)

1952 1952

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Excitation and Relaxation excitation

M

x’

y’

z

RFTx

B0

relaxation

x

y

z

B0

T1 T2 (spin echo) T2* (gradient echo)

RFRx

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MRI Scanner

Head Coil B1 [µT] x

y

Main Magnet B0 [T] z

Gradient coils Gx, Gy, Gz [mT/m]

main magnet (T) gradient coils (mT/m)

RF coils (µT)

Gradient amps RF amp Receiver

Computer

Display

•  gradients vary the field strength with position •  gradients encode location (i.e. produce image) •  gradients make all the noise •  EPI - echo planar imaging is a way to image fast

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MRI Review

•  based on the NMR phenomenon •  static magnetic field and radio waves •  image primarily water distribution •  can select contrast weighting based on water

content (PD) and relaxation mechanisms (T1, T2, T2*)

Paul Lauterbur (1929-2007)

T1W T2W T2* W EPI PDW

2003

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Functional MRI (fMRI) •  indirect detection of neuronal activity

•  BOLD: Blood Oxygenation Level Dependent –  magnetic properties of hemoglobin

•  deoxyhemoglobin is like a contrast agent

•  dynamically monitor changes in [dHb] changes and correlate with tasks or stimuli

9

4

t value

Seiji Ogawa (1934 -)

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Basic Premise of BOLD fMRI: Neurovascular Coupling

Buckner et al., 2002

neural activity

linearly transforms: spatial & temporal blur

BOLD fMRI signal

Hemodynamic Response Function (HRF)

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neuronal activity

tissue energy demand

Glucose, O2 consumption

blood flow and volume

local dHb content of blood

local dHb-induced magnetic field disturbance

BOLD fMRI signal

neurovascular coupling

fMRI relevant physiological correlates

Activation Physiology & fMRI

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Hemoglobin, Oxygenation, and MR Relaxation

Oxyhemoglobin χ ~ -0.3

B0

longer T2, T2*

↑ BOLD upon activation

Deoxyhemoglobin χ ~ 1.6

shorter T2,T2*

↓ BOLD at rest

oxyRBC deoxyRBC

Linus Pauling (1901-1994)

!

1954 1962

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BOLD Contrast: deoxy-Hb Effects

•  Hb compartmentalized in RBCs

•  H20 motion –  diffusion

•  IV: D ~ 2 µm2/ms •  EV: D ~ 1 µm2/ms

–  exchange •  IV: fast across erythrocytic membrane: τex < ~5ms •  EV: slow across capillary wall: τex > ~500ms

•  effects on MR signal –  IV: T2 and T2* shortening –  EV: T2 and T2* shortening

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Total Steady-state BOLD Signal

•  a weighted sum of extravascular (EV) and intravascular (IV) signals components

•  relative contributions determined by the voxel architecture

BOLD = xtissue BOLDEV + xblood BOLDIV

Harrison 2002 50 µm

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BOLD and Neuronal Activation

•  metabolic response –  ↑ Glc consumption –  ↑ O2 consumption : ↑ dHb : ↓ BOLD

•  steady-state hemodynamic response –  ↑↑ cerebral blood flow (CBF) : ↓ dHb : ↑ BOLD –  ↑ cerebral blood volume (CBV) : ↑ dHb : ↓ BOLD

x CMRO2 CBV CBF

∴ BOLD ∝

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BOLD: Activation Physiology

O2!

MRI voxel at rest

O2!

MRI voxel upon activation

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fMRI Experiment: Block Design

stimulus off

on

image acquisition

time

-2

2

6

14

10

t - value

correlation

0

time

voxel response

0 20 40 60 80 100 120 140 160 180

-1.5

0

3

4.5

Time [s]

ΔSi

gnal

[%]

1.5 predicted response

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fMRI Experiment: Event-Related Design

-2

2

6

14

10

t - value

time

ROI

stimulus off

on

image acquisition

time

time

0 5 10 15 20 25 99 100 101 102 103 104 105

ΔSi

gnal

[%]

Time [s]

Average Time Course

stim

ulus

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fMRI Experiment: Phase-Encoded Design

eccentricity

0! 50! 100! 150! 200! 250! 300! 350!810!

820!

830!

840!

850!

860!

870!

880!

890!

Time (s)!

Sign

al!

Time FFT

magnitude phase

•  periodically varying stimulus –  e.g. eccentricity and polar angle visual stimulation

•  Fourier transform time series of images –  activated regions show magnitude response at stimulus frequency –  phase of response shows position within stimulus field

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fMRI mapping of Primary Visual Cortex: Polar Angle

Resting State fMRI

B. Pike, MNI 19 Van den Heuvel, 2010

Independent Component Analysis (ICA)

image acquisition

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BOLD fMRI Issues •  Is the BOLD response magnitude linear?

–  does 2 x BOLD signal mean 2 x neuronal activity?

•  Is the BOLD response uniform? –  does the relationship between activity and BOLD signal vary across

the brain or with stimulus?

•  What do negative BOLD responses mean?

•  Is BOLD a valid marker of neuronal activity in pathology?

•  What is the spatial accuracy of the BOLD response?

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Event-Related Design and Linearity

Birn et al, NeuroImage 2001

measured measured

linear linear

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BOLD Signal Model is Nonlinear Deoxyhemoglobin Dilution Model

0 Δ CBF/CBF0!

M

ΔB

OLD

/BO

LD0!

CMRO2+!

CMRO2-!

0

Davis et al., 1998 Hoge et al., 1999.

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Flow-Metabolism Coupling: V1 & M1

Hoge et al., PNAS 96: 9403-8, 1999. Hoge et al., MRM 42:849-63,1999.

N=12"

0

5

10

15

20

25

CM

RO

2 (%

incr

ease

)

0 10 20 30 40 50

CBF (% increase)

Slope = 0.51

Atkinson et al., Neuroimage,11:5 Sup 2, 2000.

0 10 20 30 40 50 60 70 0

5

10

15

20

25

30

35

Slope = 0.38 CM

RO

2 (%

incr

ease

) CBF (% increase)

N=30"Primary Visual Cortex Primary Motor Cortex

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Negative BOLD Responses •  ‘blood stealing’ vs neuronal inhibition

•  various conditions are associated with inhibition and produce negative BOLD –  partial visual field stimulation –  unilateral fine motor tasks

•  mirror movement suppression, manual dexterity

•  paradigm –  right hand pinch grip –  low force (within 4-7% of MVC) –  phasic (1Hz)

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BOLD and CBF Responses

N = 8

2 3

6 5

0 1

4

- +

2 3

6 5

0 1

4

+ -

BOLD

L N = 1

CBF

L

0 20 40 60 80 100 120 -1

-0.5

0

0.5

1

1.5

ΔB

OLD

[%]

Time [s]

120 -40!

0 20 40 60 80 100

ΔC

BF

[%]

Time [s]

-30!-20!-10!

0!10!20!30!40!50!60!

contralateral ipsilateral

Stefanovic et al., NeuroImage 2004

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Activation and Deactivation CMRO2 - CBF Coupling

-40! -20! 0! 20! 40! 60! 80! 100!-40!

-30!

-20!

-10!

0!

10!

20!

30!

40!

50!

60!

ΔC

MR

O2 [

%]!

ΔCBF [%]!•  maximal motor cortex BOLD: M ~ 7.2 ± 1.0 % •  consistent coupling: ΔCMRO2 / ΔCBF ~ 0.44 ± 0.04

Stefanovic et al., NeuroImage 2004

N = 8

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BOLD Spatial Specificity: Draining Veins

•  factors –  vascular architecture –  spatial extent of neural activity

•  rough calculations* based on mean vascular geometry

–  distance of draining vessel showing full ΔY Aact ~ 100mm2 ⇒ dfull ~ 4.2mm Aact ~ 100mm2 ⇒ d0.25 ~ 25mm

*Turner, NeuroImage 2002

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BOLD Spatial Specificity: GE vs SE

Vessel Radius [µm]

ΔR

2* [s

-1]

GE EV (TE = 40ms)

Vessel Radius [µm]

ΔR

2 [s-1

]

SE EV (TE = 100ms)

Buxton, 2002

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Diffusion Effects on BOLD

field offset averaging by diffusion

Capillary Venule

dynamic narrowing

static dephasing

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BOLD fMRI as a Function of B0

•  greater susceptibility (BOLD) effect •  greater extravascular ΔT2* / T2* •  shorter optimal TE •  ~ 2/3 of BOLD is IV @ 1.5 T •  ~ 1/2 of BOLD is IV @ 3 T •  ~ 1/4 of BOLD is IV @ 7 T

•  improved activation localization and sensitivity

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SNR Gains in fMRI at High B0: BOLD Signal Power Spectrum

Buxton, 2002

Frequency (Hz)

Pow

er

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Practical fMRI SNR Gains

tSNR = fMRI times series SNR SNR0 = single image SNR

Phantom Human

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EPI - Echo Planar Imaging

•  fast imaging technique –  typically acquire image in a single shot (~20-50ms) –  trade off SNR and resolution for speed

•  GE-EPI is most common BOLD sequence –  geometric distortion in areas of magnetic field non-

uniformity –  signal loss in areas of magnetic field non-uniformity –  EPI acquisition details affect distortion and signal loss

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fMRI GE-EPI Bandwidth

410 µs (2.4 kHz)

660 µs (1.5 kHz)

1250 µs (0.8 kHz)

decreasing EPI readout times (increasing bandwidth)

GE-EPI 4x4x4mm voxels 64x64 matrix TE = 40 ms

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fMRI GE-EPI Echo Time

decreasing TE (decreasing BOLD sensitivity)

GE-EPI 4x4x4mm voxels 64x64 matrix 410 µs (2.4 kHz BW)

TE = 60 ms

TE = 40 ms

TE = 20 ms

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8 mm

6 mm

4 mm

decreasing slice thickness

fMRI GE-EPI Slice Thickness

GE-EPI 4x4 mm voxels 64x64 matrix 410 µs (2.4 kHz BW)

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Conclusion •  fMRI detects physiological correlates of neuronal

activation

•  BOLD –  BOLD ∝ [dHb]

•  [dHb] = f(CBF, CBV, CMRO2 and vascular anatomy) –  valid marker of neuronal activity under normal physiological

conditions •  V1, M1, activation, deactivation

–  more complex for pathological states (e.g. stroke) –  spatial specificity

•  IV & EV components •  improves with SE & field strength

–  SNR increases with field strength •  physiological noise limits

–  EPI artifacts •  acquisitions require optimization

Rick Hoge

Bojana Stefanovic Jan Warnking Jeff Atkinson

Karin Rylander Karma Advani Claire Cohalan Eva Alonso-Ortiz

Ilana Leppert Mike Ferreira Keith Worsley

Jean Chen Clarisse Mark

Eva Ortiz

CIHR NSERC FRSQ CFI

Acknowledgements

END