Vladislav Toronov, Ph. D.

Using Physics to Image Brain Function

Functional MRI: lack of physiological specificity

Principles of Near Infrared Spectro-Imaging

NIR study of the physiological basis of fMRI signal

NIR imaging of brain function

outline

Quantities used in MRI

Longitudinal relaxation time T1

Transverse relaxation time T2 (T2*)

Proton density

Why MRI provides nice structural images?

Due to the large differences in T1 or T2 between tissues

Can MRI be used for metabolic measurements?

Answer: it is very difficult to do because T1 and T2 can depend on many parameters

Example:

Changes in the blood content during functional activity

Oxygen Transport to Tissue

Oxygen is transported in hemoglobin molecules of red blood cells:

Deoxy-hemoglobin HHb

Oxy-hemoglobin: HbO2

Metabolic measurement: Can MRI be used to

measure [HHb] and [HbO2]?

Blood Oxygen Level Dependent effect: Oxygen in the blood modifies T2*

Functional brain mapping

Quantitative physiological model of the BOLD signal:

R. Buxton, 1998

q=[HHb]/[HHb]0 v=[tHb]/[tHb]0

where

v21 qS

Conclusion: MRI does not allow simple separation of oxygenation effects from blood volume effects

Near-Infrared Spectro-Imaging

(NIRSI)

Optical Spectroscopy

i

iia c

Beer’s law:

NIRSI

Light Propagation in Tissues

NIRSI

Scattering

’s ~ 10 cm-1

Absorption

a ~0.1 cm-1

Boltzmann Transport Equation

Where - radiance [W cm-2 steradian-1]L t

S t

a

s

( , , )

( , , )

r

r

- scattering coefficient [cm-1]

- absorption coefficient [cm-1]

- source term [W cm-3 steradian-1 s-1]

),ˆ,(ˆ)ˆ,ˆ(),ˆ,(

),ˆ,()(ˆ),ˆ,(),ˆ,(

v

1

trSdftrL

trLtrLt

trL

s

sa

Diffusion Approximation

20

1, ,a

Dr r t q r t

c t c

Photon Density

SourceAbsorption

Diffusion coefficient (scattering)

Diffusion Equation:

a s s ' ( cos )1

Type of the source modulation:

Continuous Wave

Time Domain (pulse)

Frequency-Domain

Frequency-domain approach

Light Source: Modulation frequency: >=100 MHz AC, DC and phase

NIRSI

Absolute measurements withfrequency-domain spectroscopy

a: absorption coefficients’: reduced scattering

coefficient

: angular modulation frequency

v : speed of light in tissue S: phase slopeSac: ln(r2ac) slope

multi-distance method

0 10 20 30 40

-9

-8

-7

-6

-5

-4

-3

-2

-1

AC

r (mm)

0

10

20

30

40

50

60

70

80

pha

se (

)

AC*r2

phase

S

SacLog

Frequency-domain solution for Semi-infinite medium

Method of quantitative FD measurements: Multi-distance

Flexible pad

Detector fiber bundle

Source fibers

Direct light block

Estimation of physiological parameters

22][][ 2 HHbHbO HHbHbOa

],[][][ 2 HHbHbOtHB

(%),100][][

][

2

2

HHbHbO

HbOOx

NIRSI

Beer’s law:

Total HB ~CBV

Oxygenation

source fibers

pmt a

RF electronics

multiplexing circuit

laser driver 1

pmt b

laser diodes

laser driver 2

detector bundles

Near-infrared tissue oximeter

NIRSI Instrumentation

NIR Imaging System

Advantages of NIRSI

Non-invasive

Fast (~ 1 ms)

Highly specific (spectroscopy)

Relatively inexpensive (~$100 K)

Can be easily combined with MRI

Study of the physiology of the BOLD effect

BOLD= Blood Oxygen Level Dependent

NIRSI in Functional Magnetic Resonance Imaging

fMRI Mapping of the Motor Cortex

BOLD signal model

q=[HHb]/[HHb]0 v=[tHb]/[tHb]0

where

v21 qS

Study of the BOLD effect

Multi-distance optical probe

Study of the BOLD effect

Detector fiber

Laser diodes690 nm&830 nm

Collocation of fMRI signal and optical sensor

Study of the BOLD effect

Motor Cortex

Optical probe

Activation paradigmActivation paradigm

Sti

mul

atio

n

Rel

axat

ion

Motor activation

Вlock Design - 10s/17s

Study of the BOLD effect

Time

Data analysis:Folding (time-locked) average

Raw data

Folded data

Study of the BOLD effect

Time course of hemodynamicand BOLD signals

Study of the BOLD effect

stimulation

BOLD signal model

q=[HHb]/[HHb]0 v=[tHb]/[tHb]0

where

v21 qS

Study of the BOLD effect

Biophysical Modeling of Functional Cerebral

Hemodynamics

O2 Diffusion Between Blood and Tissue Cells

fin

fout

Modeling

“Balloon” Model

in

outin

fE

tv

tqf

E

tEf

dt

dq

)(

)()(1

0q- normalized Deoxy Hb

v- normalized Total Hb

=V0/F0 – mean transit time

Oxygen Extraction Fraction

Modeling

OEF as function of CBF(Buxton and Frank, 1997)

infin EfE /1

0 )1(1

Modeling

“Balloon” Model

infin

outin

outin

EfE

ffdt

dv

tv

tqf

E

tEf

dt

dq

/10

0

)1(1

1

)(

)()(1

q- normalized Deoxy Hb

v- normalized Total Hb

Oxygen Extraction Fraction

Modeling

Functional Changes in Cerebral Blood Flow from Balloon Model

0 5 10 15 20 25 3098

100

102

104

106

108

110f in,fout(%)

Time (s)

finfout

Stimulation

Modeling

Why oxygenation increases?

The increase in cerebral blood oxygenation during functional activation is mostly due to an increase in the rCBF velocity, and occurs without a significant swelling of the blood vessels.

Modeling

Washout Effect

Outcomes

The time course of the BOLD fMRI signal corresponds to the changes in the deoxy-hemoglobin concentration

BOLD fMRI provides no information about the functional changes in the blood volume

This information can be obtained using NIRSI

Optical Mapping of Brain Activity

in real time

detectors

light sources5

67

123

4 3 cmB A 8

Locations of the sources and detectors of light on the human

head

Brain mapping

Motor Cortex

Backprojection Scheme

detectors

light sources(758 and 830 nm)

Brain mapping

3&4 3 3 3 3 2&3 2 2 2 2 2 2 1&2 1 1 1 1 1&8

3&4 3 3 3 2&3 2 2 2 2 2 2 2 2 1&2 1 1 1 1&8

4 4 3 3 2&3 2 2 2 2&2 2&2 2 2 2 1&2 1 1 8 8

4 4 43&4

2&3 2 2 2&6 2&6 2&6 2&6 2 2 1&2 1&8 8 8 8

4 4 44&5

5&6 6 6 6&2 2&6 2&6 6&2 6 6 6&7 7&8 8 8 8

4 4 5 5 5&6 6 6 6 6&6 6&6 6 6 6 6&7 7 7 8 8

4&5 5 5 5 5&6 6 6 6 6 6 6 6 6 6&7 7 7 7 7&8

4&5 5 5 5 5 5&6 6 6 6 6 6 6 6&7 7 7 7 7 1&8

C34=.75*S3+.25*S413

6

7

8

2

4AB

5

C34=.5*S3 + .5*S4

[Hb] (M)

-1.0

-0.5 0.0

0.5

Real time video of brain activation

Brain mapping

67

8

1

2

3

4AB

5

3D NIR imaging of brain function using structural

MRIS D

A small change in absorption

S D

an

nna

sd

sd LU

U

sdU

Ln –the mean time photon spends in voxel n relative to the total travel time

Solve an equation:

Underdetermined Problem

Number of measurements<< number of voxels

3D imaging

n

nna

sd

sd LU

U

Sensitivity is high near the surface and low in the brain

Source Detector3D imaging

Cerebro-SpinalFluid

Scalp

Scull

BrainCONSTRAINT

3D imaging

Using structural MRI info

How do we find Ln –the relative voxel time?

n

nna

sd

sd LU

U

Monte Carlo Simulation

Structural MR imageis segmented infour tissue types:

• Scalp• Skull• CSF• Brain

10,000,000 “photons”

Source Detector3D imaging

Image Reconstruction

Solution: Simultaneous Iterative Reconstruction Technique

Y=Ax

3D imaging

n

nna

sd

sd LU

U

Underdetermined Problem

Activation of Human Visual Cortex

Flashing or reversing checkerboard

EXPERIMENT

40 mm

10 mm

40 mm

10 mm

40 mm

10 mm

3D imaging

50 mm

Probe for imaging human visual cortexin the MRI scanner

Placement of the optical probe on the head inside the “birdcage” head coil of the MRI scanner

To/from the NIR spectrometer

Optical fibersOptical probe

Birdcage head coil

B0

Magnetic bore of the MRI scanner

Time course of hemodynamic changes in the activated region

0 10 20 30 40 50 60-1

-0.5

0

0.5

1

1.5

2x 10

-4

Time (sec)

Ave

rage

hem

o ch

ange

s (m

M)

Average changes in [HbR] and [HbO] at 2 Hz

[HbO]

[HbR]Vis. Stim.

Results of the group statistical analysis of variance

BOLD -[Hb] [HbO2] 3D imaging

Using AFNI medicalImage processingsoftware

Outcomes

In combination with structural MRI,NIRSI can be used for non-invasive 3D imaging of physiological processes in the human brain

A two-wavelength NIR imaging provides independent spatially-resolved measurements of changes in oxy- and deoxyhemoglobin concentrations.

General Conclusion and Perspective

Alone or in combination with other imaging techniques, NIRSI can be used as a quantitative metabolic imaging tool in a variety of biomedical applications: Neuronal activity ~10 ms temporal resolution Neonatology ~Baby’s head has low size and

absorption Mammography ~ Non-ionizing, specific

Small animals ~ Neuroimaging, fast assessment in cancer

research