1. Vladislav Toronov, Ph. D. Using Physics to Image Brain Function

2. 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

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

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

9. 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

10. Near-Infrared Spectro-Imaging (NIRSI)

11. Optical Spectroscopy Beer’s law: NIRSI

12. Light Propagation in Tissues NIRSI Scattering  ’ s ~ 10 cm -1 Absorption  a ~0.1 cm -1

13. 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 ]

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

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

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

17. 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

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

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

20. 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

21. NIR Imaging System

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

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

24. fMRI Mapping of the Motor Cortex

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

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

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

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

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

30. Time course of hemodynamic and BOLD signals Study of the BOLD effect stimulation

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

32. Biophysical Modeling of Functional Cerebral Hemodynamics

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

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

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

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

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

38. 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

39. 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

40. Optical Mapping of Brain Activity in real time

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

42. Backprojection Scheme detectors light sources (758 and 830 nm) Brain mapping 3&433332&32222221&211111&8 3&43332&3222222221&21111&8 44332&32222&2 2221&21188 444 3& 4 2&3222&6 221&21&8888 444 4& 5 5&6666&22&6 6& 2 666&77&8888 44555&66666&6 6666&77788 4&55555&6666666666&77777&8 4&555555&66666666&777771&8 C 3 4 =.75* S 3 +.25* S 4 13 6 7 8 2 4 A B 5 C 34 =.5* S 3 +.5* S 4

43.  [Hb] (  M) -0.50.00.5 Real time video of brain activation Brain mapping 6 7 8 1 2 3 4 A B 5

44. 3D NIR imaging of brain function using structural MRI S D

45. A small change in absorption S D  a L n –the mean time photon spends in voxel n relative to the total travel time

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

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

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

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

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

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

52. Activation of Human Visual Cortex Flashing or reversing checkerboard

53. EXPERIMENT 3D imaging 50 mm

54. Probe for imaging human visual cortex in the MRI scanner

55. 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

57. Time course of hemodynamic changes in the activated region

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

59. 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.

60. 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