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 content vs. blood flow Conclusion: MRI does now allow simple separation of oxygenation effects from blood volume effects

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

Near-Infrared Spectro-Imaging (NIRSI)

Optical Spectroscopy 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 ] - scattering coefficient [cm -1 ] - absorption coefficient [cm -1 ] - source term [W cm -3 steradian -1 s -1 ]

Diffusion Approximation Photon Density Source Absorption Diffusion coefficient (scattering) Diffusion Equation:

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 with frequency-domain spectroscopy  a : absorption coefficient  s ’ : reduced scattering coefficient  : angular modulation frequency v : speed of light in tissue S  : phase slope S ac : ln(r 2 ac) slope multi-distance method SS S ac Log 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 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 Study of the BOLD effect

Multi-distance optical probe Study of the BOLD effect Detector fiber Laser diodes 690 nm & 830 nm

Collocation of fMRI signal and optical sensor Study of the BOLD effect Motor Cortex Optical probe

Activation paradigm 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 hemodynamic and BOLD signals Study of the BOLD effect stimulation

BOLD signal model  q=  [HHb]/[HHb] 0  v=  [tHb]/[tHb] 0 where Study of the BOLD effect

Biophysical Modeling of Functional Cerebral Hemodynamics

O 2 Diffusion Between Blood and Tissue Cells f in f out Modeling

“Balloon” Model q- normalized Deoxy Hb v- normalized Total Hb  =V 0 /F 0 – mean transit time Oxygen Extraction Fraction Modeling

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

“Balloon” Model q- normalized Deoxy Hb v- normalized Total Hb Oxygen Extraction Fraction Modeling

Functional Changes in Cerebral Blood Flow from Balloon Model 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 sources cm B 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&433332& &211111&8 3&43332& &21111& &32222&2 2221& & 4 2&3222&6 221&21& & 5 5&6666&22&6 6& 2 666&77& &66666&6 6666& &55555& &77777&8 4&555555& &777771&8 C 3 4 =.75* S * S A B 5 C 34 =.5* S 3 +.5* S 4

 [Hb] (  M) Real time video of brain activation Brain mapping A B 5

3D NIR imaging of brain function using structural MRI S D

A small change in absorption S D  a L n –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

Sensitivity is high near the surface and low in the brain SourceDetector 3D imaging

Cerebro- Spinal Fluid Scalp Scull Brain CONSTRAINT 3D imaging Using structural MRI info

How do we find L n –the relative voxel time?

Monte Carlo Simulation Structural MR image is segmented in four tissue types: Scalp Skull CSF Brain 10,000,000 “photons” SourceDetector 3D imaging

Image Reconstruction Solution: Simultaneous Iterative Reconstruction Technique Y=Ax 3D imaging Underdetermined Problem

Activation of Human Visual Cortex Flashing or reversing checkerboard

EXPERIMENT 3D imaging 50 mm

Probe for imaging human visual cortex in 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 B0B0 Magnetic bore of the MRI scanner

Time course of hemodynamic changes in the activated region

Results of the group statistical analysis of variance BOLD -  [Hb]  [HbO 2 ] 3D imaging Using AFNI medical Image processing software

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