Near-infrared Diffuse Optical Measurement of Tissue Blood Flow, Oxygenation and Metabolism

1. Near-infrared Diffuse Optical Measurement of Tissue Blood Flow, Oxygenation and Metabolism Guoqiang Yu Bio-photonics Lab Center for Biomedical Engineering University of Kentucky Diffuse Correlation Spectroscopy (DCS) • Research Supported by: • NIH R01 CA149274 (Yu) • NIH R21 HL083225 (Yu) • AHA BGIA 2350015 (Yu) • AHA BGIA 0665446 (Yu) • DOD W81XWH-04-1-0006 (Yu) • NIH R21 PA-08-162 (Peterson & Crofford) • University of Kentucky Research Foundation (Yu) • Tissue Blood flow • Tissue Blood oxygenation

2. Outline • Study Motivation • Near-infrared Diffuse Optical Spectroscopies • In-vivo Applications: From Small Animals to Adults • Brain • Cancer • Muscle

3. Oxygen Exchange In Tissues Circulatory System Microvasculatures Oxygen Exchange Arterioles Venules

4. Tissue Hypoxia Oxygen Supply Oxygen Consumption • Arterial oxygen too low (e.g. apnea)? • Blood flow too slow (e.g. ischemic stroke)? • Local tissue metabolism too high (e.g. cancer)? Hypoxia

5. Diseases Associated with Tissue Hypoxia • Brain • Stroke • Sleep Apnea • Traumatic Injury • … • Muscle • Peripheral Arterial Disease (PAD) • Diabetes • Pressure Ulcer • … • Tumor

6. Study Motivations Diagnosis of Diseases Evaluation of Therapies Tissue Blood Flow Blood Oxygenation Oxygen Metabolism Techniques Needed in Clinic Non-invasive Fast (~ms) Portable (bed side) Low cost Longitudinal Monitoring Deep Tissue Volume (brain, tumor, muscle)

7. Existing Techniques for Tissue Hemodynamics and Metabolism • Doppler ultrasound • Magnetic resonance angiography (MRA) blood flow within large vessels • Laser Doppler flowmetry (LDF) • Laser speckle imaging • Doppler optical coherence tomography (DOCT) microvascular flow at superficial tissues • Positron emission tomography (PET) • Arterial-spin labeled MRI, fMRI • Computed tomography (CT) • Photon emission computed tomography (SPECT) • Xenon-enhanced computed tomography (XeCT) large instrumentation high cost, patient transport radiation damage invasive • Electrode--tissue oxygen levels (PO2) • Near-infrared spectroscopy (NIRS) can monitor microvascular hemodynamics in deep tissues noninvasively, frequently, inexpensively

8. Outline • Study Motivation • Near-infrared Diffuse Optical Spectroscopies • In-vivo Applications: From Small Animals to Adults • Brain • Cancer • Muscle

9. Light Spectrum (100 nm to 1 mm) NIR Light (700-2500 nm)

10. Why Near-infrared Light? www.internationalcancertherapy.com NIR Light Diffuses Through Thick/Deep Tissues

11. Light Diffuses In Biological Tissue r Absorbers:Hemoglobins, Water, Lipids (µa) Scatterers: Organelles, Mitochondria (µs’), Moving Blood Cells (BF) Tissue Optical Properties: µa : Tissue absorption coefficient µs’: Tissue scattering coefficient BF: Blood Flow

12. Semi-infinite Medium Light Diffuses In Biological Tissue Photon Diffuse Equation: Φ (r,t)[photons/cm2/s]~ (µs’, µa,r, S) µa-- absorption coefficient D ≈ v/3 µs’--photon diffusion coefficient µs’– reduced scattering coefficient ν – light velocity S – isotropic source term r

13. Separate Amplitude Reduction Phase Shift µa, µs’ NIRS: Frequency Domain System r Photon Fluence Rate: Φ (r,t) [photons/cm2/s]~ (µa, µs’, r, S) Yu et al, Applied Optics (2003)

14. Near-infrared Spectroscopy (NIRS)Can Probe Tissue Oxygenation ε (cm-1/µM) Wavelength (nm) 830 nm Fantini et al, Phys. Med. Biol. (1999),Shang et al, Optics Letters (2009)

15. SourceDetectors NIR Diffuse Correlation Spectroscopy (DCS) CanProbe Tissue Blood Flow Blood Flow (BF) ~ Motion of Red Blood Cells~ Decay of Correlation Function Pine et al, PRL (1988); Maret et al, Z. Phys(1987); Boas et al, PRL(1995), Yu et al, JBO (2005), Shang et al, Opt Lett (2009)

16. Correlation Diffuse Equation G1 : Electric field temporal autocorrelation function = - G1 (r, t) ~ (µa, µs’, r, αr2(t)) Mean Square Displacement of Moving Scatterers: r2(t) = 6DBt G – electric field temporal autocorrelation function DB -- effective diffusion coefficient α – percentage of moving scatterers over all scatterers αDB ~ Blood Flow (BF) Boas, Campbell, and Yodh, PRL, (1995)

17. 785 nm Tissue Correlation Curve Correlator rBF APDs Portable DCS Flowmeter: Tissue Blood Flow (rBF) DCS Flowmeter

18. A Hybrid Diffuse Optical System Yu Shang, Youquan Zhao, Ran Cheng, Lixin Dong, Daniel Irwin, Guoqiang Yu, Optics Letters (2009)

19. 785 nm Tissue Correlation Curves rBF Correlator APDs Δ[HbO2] Δ[Hb] Light Intensities Portable DCS Flow-oximeter: Tissue Blood Flow & Oxygenation DCS Flow-oximeter TTL control 854 nm • Functional Parameters: • rBF, Δ[HbO2], Δ[Hb], rMRO2 • Instrumentation: • Portable, fast, inexpensive, easy to construct and operate Shang et al, Optics Letters (2009)

20. Portable DCS Flow-oximeter Vs. Hybrid Instrument Hybrid System DCS Flow-oximeter • Function: • rBF, Δ[HbO2], Δ[Hb] • Instrumentation: • portable, inexpensive, easy to construct and operate • Probe: • small (shared fibers) • cover the same tissue volume for both flow and oxygenation measurements • Function: • rBF, • Absolute [HbO2], [Hb], THC • Absolute StO2 Shang et al, Optics Letters (2009)

21. Validation Studies of DCS Flow Measurement • Doppler Ultrasound • Menon et al, Cancer Res (2003) • Yu et al, Clin Cancer Res (2005) • Buckley et al, Opt Exp (2009) • Roche-Labarbe et al, Human Brain Mapping (2009) • ASL Perfusion-MRI • Yu et al, Opt Exp (2007) • Durduran, OpticsLett (2004) • Xenon-CT • -- Kim et al, Neurocritical Care (2010) • Laser Doppler • Durduran, PhD Thesis (2004) • Fluorescent microsphere measurement • -- Zhou et al, J Bio Opt (2009) • DCS vs. Literatures • Cheung et al, Phys Med Bio (2001) • Durduran et al, Opt Letters (2004) • -- Yu et al, J Bio Opt (2005)

22. MRI Room Non-magnetic probe Optical Fibers (>12 meters) Control Room 90º MRI Coil Optical Instrument (DCS) Validation: DCS vs. Perfusion MRI (n = 7) Time (sec) Guoqiang Yu et al, Optics Express (2007)

23. Advantage and Limitation of NIRS/DCS • Noninvasive • Fast (up to 100 Hz) • Inexpensive (vs. MRI, CT) • Portable (vs. MRI, CT) • Longitudinal (vs. MRI, CT) • Microvasculature (vs. Doppler Ultrasound) • Deep/Thick Tissue (vs. laser Doppler) • Small and Large Animals (e.g., mouse, rat, piglet, pig) • Children and Adults • Limited penetration depth (~ several cm) • Low spatial resolution (mm to cm)

24. Outline • Study Motivation • Near-infrared Diffuse Optical Spectroscopies • In-vivo Applications: From Small Animals to Adults • Brain • Cancer • Muscle

25. Brain • Cerebral hemodynamic responses to functional activities • Finger taping • Verbal fluency • Visual stimulation • Diagnosis of cerebral diseases • Stroke • Sleep apnea • Monitoring of therapies • Stroke in ICU • Carotid endarterectomy Carotid Endarterectomy

26. Cerebral Functional Activations in Human Cortex Durduran et al, Optics Letters (2009)

27. Stroke Management in ICU Acute Ischemic Stroke • Early diagnosis • Early treatment: maximize blood flow • Bed-side continuous monitoring of progress/treatment

28. Stroke Management in ICU • Patients: Unilateral ischemic stroke in middle cerebral artery (MCA) territory • Probe Placement: Both hemispheres (infarct vs. non-infarct) • Protocol: Optical measurement of rCBF during head-of-bed (HOB) positioning (30, 15, 0, -5 and 0°) Infarct • Hemisphere effect? • HOB angle to get maximal rCBF? • Longitudinal Monitoring of treatment effect? Durduran et al, Optics Express (2009)

29. Cerebral Autoregulation

30. CBF vs. HOB: Healthy Controls (n = 5) Durduran et al, Optics Express (2009)

31. CBF vs. HOB: Patient 1

32. CBF vs. HOB: Patient 2

33. Group Patient Results (N = 17) • HOB position influenced rCBF significantly (P<0.05) in both hemispheres (healthy and stroke) • HOB was a stronger factor in the infarcted hemisphere (larger variation, p<0.02) • -- Impaired autoregulation? • Paradoxical Response (25% of stroke group): the maximal CBF occurred at an elevated angle • -- Cardiac Disease? Others? • -- Individualized management Durduran et al, Optics Express (2009)

34. L R Stroke Flow Recovery (3 days after) • Left middle cerebral artery • rCBF variability L > R

35. Cerebral Hemodynamics During Carotid Endarterectomy (CEA) Surgical side • Two fiber-optic probes were taped on both sides of frontal head • EEG electrodes were placed all over the scalp • ICA clamping resulted in a significant CBF decrease and cerebral deoxygenation at the surgical side

36. Cerebral Hemodynamics During Carotid Endarterectomy (CEA) Surgical side Control side

37. Comparison of CBF and EEG Responses: Individual • The large CBF slope (S = -1.25) (a) The time duration of CBF decrease and maximal CBF change (b) • The EEG power changes were small and slow (c), and reached its minimum in a long period of time (d)

38. Comparison of CBF and EEG Responses: 12 Subjects • Faster CBF change (slope) • Larger CBF change • Shorter CBF time-to-minimum • DCS measurements are more sensitive in detecting cerebral ischemia compared to EEG monitoring

39. S1 S2 Mouse Cerebral Ischemia Model: Layer Effects D1 D2 L R ICA- internal carotid artery 3 1 CCA- Common carotid artery ECA- External carotid artery 2 4 4 Left 3 1 2 Right • DCS is sensitive to the local CBF changes • Blood flow from the scalp are much smaller than that fro brain

40. Tumor • Diagnosis of tumors • Human Breast tumor • Human Head/Neck tumor • Human Prostate tumor • Mouse radiation-induced fibrosarcoma (RIF) tumor • Monitoring of therapies • Chemotherapy • Chemo/Radiation therapy • Photodynamic therapy • Antivascular therapy in mice Optical probe tumor scan Tumor

41. Diagnosis of Breast Tumors: Flow Contrast • High blood flow contrast in tumor T. Durduran, R. Choe, G. Yu, C. Zhou, J. C. Tchou, B. J. Czerniecki, and A. G. Yodh Optics Letters (2005)

42. Photodynamic Therapy (PDT) Monitoring • Photodynamic Therapy (PDT) Dosimetry • Photosensitizer • Light • Tissue oxygen • Blood flow • Blood oxygenation

43. SO2 SO2 SO2 SO2 Photofrin-Mediated RIF mice Tumor • Radiation-Induced Fibrosarcoma (RIF) Mice Tumors: • Treated group = light + Photofrin (5 mg/Kg) • Treatment Efficacy: • Days for tumor growth to a volume of 400 mm3 • (starting volume ~100 mm3) Tumor Light off Light on 3h 6.5h 10 min 15 min 30 min rBF rBF rBF rBF

44. Probe Map Sources (13) Detectors (4) Measurement of Blood Flow During PDT Filter > 650 nm 630 nm 785nm Tumor Measurement light : 785 nm Treatment light: 630 nm Yu et al, Clin Cancer Res(2005)

45. Slope Slope Large slope  Poor treatment efficacy Predict Treatment Efficacy (During PDT) Time-to-400 mm3 Time (minute) Yu et al, Clin Cancer Res (2005)

46. Hemodynamic Responses During Radiation Delivery Optical Probe Ultrasound Imaging of H/N Tumor Treatment

47. Hemodynamic Variations During Radiation Therapy on Head/Neck Tumors P = 0.0002 P = 0.007 (7 responders) Sunar et al, J. Biomedical Optics (2006)

48. Large Hemodynamic Variations in Response to Radiation Therapy on Head/Neck Tumors Responders (n = 7) Partial responder(n = 1)

49. Skeletal Muscle • Healthy muscle physiology • Cuff Occlusion • Exercise • Diagnosis of vascular diseases • Peripheral arterial disease (PAD) • Fibromyalgia • Diabetes • Hypercholesterolemia (mice) • Monitoring of therapies • Arterial revascularization • Electrical stimulation (ES) • Massage therapy (MT) • Erdman (heat/cold) therapy

50. SourceDetectors Muscle Hemodynamics During Arterial Cuff Occlusion: Layer Responses Occlusion 3.0 cm Pressure cuff Probe • Light penetration depth depends on the source-detector separation. • Muscle demonstrates stronger hemodynamic responses. G. Yu, T. Durduran, G. Lech, C. Zhou, B. Chance, E. R. Mohler III, A. G. Yodh, J. Biomedical Optics (2005)