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1. Using Physics to Image Brain Function ____________ _________ _______ ___________ Vladislav Toronov, Ph. D.

2. outline 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

3. Quantities used in MRI • Longitudinal relaxation time T1 • Transverse relaxation time T2 (T2*) • Proton density

4. Why MRI provides nice structural images? Due to the large differences in T1 or T2 between tissues

5. 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

6. 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]?

7. Blood Oxygen Level Dependent effect: Oxygen in the blood modifies T2* Functional brain mapping

8. Quantitative physiological model of the BOLD signal:R. Buxton, 1998 where Dq=D[HHb]/[HHb]0 Dv=D[tHb]/[tHb]0 Conclusion: MRI does not allow simple separation of oxygenation effects from blood volume effects

9. Near-Infrared Spectro-Imaging (NIRSI)

10. Optical Spectroscopy Beer’s law: NIRSI

11. Absorption ma ~0.1 cm-1 Scattering m’s ~ 10 cm-1 Light Propagation in Tissues NIRSI

12. Boltzmann Transport Equation Where - radiance [W cm-2 steradian-1] -absorption coefficient [cm-1] -scattering coefficient [cm-1] - source term [W cm-3 steradian-1 s-1]

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

14. Type of the source modulation: • Continuous Wave • Time Domain (pulse) • Frequency-Domain

15. Frequency-domain approach Light Source: • Modulation frequency: >=100 MHz • AC, DC and phase NIRSI

16. Absolute measurements withfrequency-domain spectroscopy multi-distance method Frequency-domain solution for Semi-infinite medium ma: absorption coefficient ms’: reduced scattering coefficient w: angular modulation frequency v : speed of light in tissue SF: phase slope Sac: ln(r2ac) slope SF Log Sac

17. Method of quantitative FD measurements: Multi-distance Detector fiber bundle Source fibers Flexible pad Direct light block

18. Estimation of physiological parameters Beer’s law: Total HB ~CBV Oxygenation NIRSI

19. Near-infrared tissue oximeter detector bundles pmt b RF electronics pmt a laser driver 2 laser driver 1 source fibers multiplexing circuit laser diodes NIRSI Instrumentation

20. NIR Imaging System

21. Advantages of NIRSI • Non-invasive • Fast (~ 1 ms) • Highly specific (spectroscopy) • Relatively inexpensive (~$100 K) • Can be easily combined with MRI

22. NIRSI in Functional Magnetic Resonance Imaging Study of the physiology of the BOLD effect BOLD= Blood Oxygen Level Dependent

23. fMRI Mapping of the Motor Cortex

24. BOLD signal model where Dq=D[HHb]/[HHb]0 Dv=D[tHb]/[tHb]0 Study of the BOLD effect

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

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

27. Activation paradigm Motor activation Вlock Design - 10s/17s Time Study of the BOLD effect

28. Data analysis:Folding (time-locked) average Raw data Folded data Study of the BOLD effect

29. Time course of hemodynamicand BOLD signals stimulation Study of the BOLD effect

30. BOLD signal model where Dq=D[HHb]/[HHb]0 Dv=D[tHb]/[tHb]0 Study of the BOLD effect

31. Biophysical Modeling of Functional Cerebral Hemodynamics

32. O2 Diffusion Between Blood and Tissue Cells fout fin Modeling

33. “Balloon” Model q- normalized Deoxy Hb v- normalized Total Hb t=V0/F0 – mean transit time Oxygen Extraction Fraction Modeling

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

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

36. Functional Changes in Cerebral Blood Flow from Balloon Model Stimulation Modeling

37. 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. Washout Effect Modeling

38. 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

39. Optical Mapping of Brain Activityin real time

40. Locations of the sources and detectors of light on the human head 3 2 1 3 cm 4 detectors B A 8 light sources 6 5 7 Motor Cortex Brain mapping

41. Backprojection Scheme C34=.5*S3 + .5*S4 C34=.75*S3+.25*S4 3 1 2 4 8 B A detectors 6 light sources (758 and 830 nm) 5 7 Brain mapping

42. 3 1 2 A B 4 8 6 5 7 Real time video of brain activation D [Hb] (mM) -1.0 -0.5 0.0 0.5 Brain mapping

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

44. dma Ln –the mean time photon spends in voxel n relative to the total travel time A small change in absorption S D

45. Underdetermined Problem Solve an equation: Number of measurements<< number of voxels 3D imaging

46. Sensitivity is high near the surface and low in the brain Source Detector 3D imaging

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

48. How do we find Ln –the relative voxel time?

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

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