Time domain diffuse optical imaging and spectroscopy for biomedical diagnostics. Rinaldo Cubeddu

Transcription

1 Time domain diffuse optical imaging and spectroscopy for biomedical diagnostics SIF, Pisa, September 22-26, 2014

2 Introduction: Time-Resolved Diffuse Optical Spectroscopy Time Resolved Diffusion Equation for Homogeneous Media R(ρ,t) = Φ(ρ,μ s,t)exp(-μ a vt) μ s laser pulse TRS Laser datapulse model Model TR data ρ Reflectance and Transmittance geometry µ s, µ a intensity Intensity (a.u.) time Time (ps) μa 1

3 Spectroscopy Clinical Set-up rotating prism adjustable slit graded-index fiber = 100μm f1 = 150mm f1 2f2 2f2 f2 = 25mm sample supercontinuum source Data acquisition TCSPC PMT/SPAD step-index fiber = 1 mm Fully automated set-up Time resolution: 300 ps FWHM Data analysis 2

4 Spectral analysis absorption coefficient (cm -1 ) 0,30 0,25 0,20 0,15 0,10 0,05 0,00 HbO2 [43 um] Hb [22 um] Water [34%] Lipid [53%] wavelength (nm) ln[ reduced scattering (cm -1 ) ] a (cm -1 ) 4.69 a (cm -1 ) 4.69 IL (solid fraction) = 10 IL (solid fraction) = 10-3 b 1.08 b 1.08 r e (µm) 0.24 r e (µm) ln[ wavelength ( m) ] g 0.75 g

5 Breast absorption and scattering spectra absorption (cm -1 ) #1 #2 #3 #4 #5 #6 T PT-40 DC-29 EL-34 LT-23 FM-50 KE-31 water 62% 32% 53% 23% 16% 12% lipids 16% 37% 20% 68% 77% 68% thb/µm SO 2 55% 77% 43% 77% 68% 79% reduced scattering (cm -1 ) T PT-40 DC-29 EL-34 LT-23 FM-50 KE-31 a b wavelength (nm) wavelength (nm) 4

6 EXAMPLE 1: Non-invasive Quantification of Collagen in the Breast BACKGROUND collagen is related to development of breast cancer J. Couzin, Science 309 (2005). non-invasive quantification of collagen could lead to dedicated diagnostic procedures and higher survival Absorption (cm-1) Absorption (cm-1) #10 - Adipose #3 - Mixed #2 - Fibrous Wavelength (nm) Absorption spectrum of collagen powder (0.196 g/cm 3 ) BASIC CHARACTERIZATION measurement absorption spectrum of collagen in the nm range Wavelength (nm) IN VIVO MEASUREMENT first absorption spectra of the breast in the nm range Explore Spectral Region beyond 1100 nm by Time-Domain Diffuse Spectroscopy

7 Breast tissue composition and scattering parameters Tissue composition Scattering parameters Subject ID thb (µm) SO 2 (%) Lipid (mg/cm 3 ) Water (mg/cm 3 ) Collagen (mg/cm 3 ) a (cm -1 ) b Tabàr classification IV: Fibrous I: Mixed I: Mixed II: Adipose II: Adipose III: Adipose with ducts Density Water 1.00 g/cm 3 Lipid 0.91 g/cm 3 Collagen 1.30 g/cm 3 [Batchelar et al., Med. Phys. 33, (2006)] 6

8 System Development: Experimental Set-up Time-gated InGaAs/InP Single Photon Avalanche Diode, Dipartimento di Elettronica e Informazione, Politecnico di Milano nm 40MHz 7

9 Spectroscopy Beyond 1100 nm: Validation on Lipid Sample (pig fat) First characterization of lipids up to 1700 nm Nachabè et al. cw spectrum Time-resolved spectrum Data fitted with Monte Carlo simulations R. Nachabè et al., J. Biomed. Opt. 15, Bargigia et al., Appl. Spectrosc. 66,

10 Spectroscopy Beyond 1100 nm Collagen Type I Dried bone 9

11 Spectroscopy Beyond 1100 nm Arm Breast 10

12 Imaging Optical Mammography NIRS Funtional Imaging 11

13 Absorption of tissue constituents absorption (cm -1 ) HbO2 Hb Lipid Water Collagen wavelength (nm) 12

14 Time domain multi-wavelength optical mammograph laser heads 637 nm d r i v e r 683 nm 785 nm 905 nm 930 nm 975 nm 1060 nm sync variable attenuators TCSPC board (SPC-134, Becker & Hickl): 2 independent channels 16 MHz max count rate coupler collimator Laser driver: Sepia (PicoQuant) Repetition rate: 20 MHz Pulse duration: ps Max incident power: mw Continuous movement: stepping motors & Counter/Timer PC board Maximum scan area: 180 mm x 240 mm Step interval: 1 mm Measurement time: 25 ms per point personal computer TCSPC board TCSPC board AMP sync AMP optics variable attenuators VIS PMT NIR PMT fiber bundle cut-off filter XY translation stage Photomultipliers (Hamamatsu, KK): RED: R5900U-01-L16, 150 ps TTS, λ < 850 nm NIR: H7422P-60, 450 ps TTS, λ < 1100 nm 13

15 Time domain multi-wavelength optical mammograph Laser fibers Fiber bundle 14

16 POLIMI-#043 (CC): Tumor (L) + Cysts (R) Age: 41 y Thickness = 4.7/4.6 cm Late gated intensity R L R L R L cysts tumor Scattering 15

17 POLIMI2-#013 (L_CC): Phylloid Tumor Lesion size = 45 mm Tissue composition Late gated intensity 16

18 POLIMI2-#099 (L_CC): Invasive Ductal Carcinoma Lesion size = 25 mm Late gated intensity Tissue composition 17

19 Breast Density: Background and aims Background Breast density is a strong independent risk factor for developing breast cancer At present, assessed from x-ray mammograms Not widely used in screening programs and clinical practice Aim Non-invasive optical assessment of breast density Personalized diagnostic path Interventions for density reduction Identification of high-risk subjects Direct assessment of cancer risk 18

20 Effect of tissue heterogeneity 52 subjects (with recent x-ray mammograms) Estimate of average properties RCC and LCC images 5 areas (5 x 5 mm 2 ) Correlation with BI-RADS categories 1: Outer 2: Chest RCC 1 5 mm 1 LCC 3: Inner 4: Nipple : Middle 3 3 [Taroni et al, BOE 2012] 19

21 Area 5 (Middle): Correlation with breast density OI2 = ( [ Water ] + [ ] [ Lipid] Collagen ) b p < OI p < p < BI-RADS 3 4 Good correlation between OI2 from a small area and breast density 20

22 Functional imaging Functional imaging gives information about how an organ works and not only about its morphological structure. In particular FI of the Brain is used to determine where and in which manner an activation takes place in the cerebral cortex. STIMULUS EEG MEG ELECTRICAL ACTIVITY PET fmri NIRS METABOLIC RESPONSE - Glucose consumption - Oxygen consumption HEMODINAMIC RESPONSE - Blood Flow - Blood Volume - Blood Oxygenation - Blood deoxygenation PET SPECT

23 DOI Time domain Functional near-infrared spectroscopy Haemodynamic Response ASSORBIMENTO (cm -1 M -1 ) ε (cm -1 M -1 ) HHb wavelength (nm) λ 1 λ 2 LUNGHEZZA D'ONDA (nm) HbO Hb O 2 Hb intensity (ph) time (s) O 2 HB & HHB (µm) TG-MLB HHB (Intra) O 2 HB (Intra) O 2 HB (Extra) HHB (Extra) Rest Task Recovery Time (s) Time-resolved: Depth sensitivity 22

24 PoliMi multi-channel time-resolved fnirs system S1 PicoQuant variable ND PDL nm Laser driver sync TCSPC-1 TCSPC-2 TCSPC-3 TCSPC nm clock variable ND µchip Microchip Technology dspic30f ch router-1 4 ch router-2 4 ch router-3 4 ch router-4 delay 2x2 fused splitter OZOptics VISNIR ch amp-1 8 ch amp-2 4 anodes PMT-1 4 anodes PMT-2 4 anodes PMT-3 4 anodes PMT-4 50% 50% Hamamatsu R M4 Piezojena F-SM19 1x9 fiber switch 1x9 fiber switch clock F1 2x4 fused splitter R1 R2 R3 R4 S8 S9 S16 Becker & Hickl, SPC-134, HRT-41, HAFC-26 F16

25 fnirs results Topographic maps: healthy subject 1 Right vs. Void Low density, brunette, <3cm

26 Brain activation monitoring during a motor task Haemodynamic changes: GLM maps contrast (µm) time (s) Protocol: 20 s baseline, 20 s task (finger tapping with right hand at 2Hz), 40 s recovery, 9 repetitions, acquisition time 1s O 2 Hb (p-val < 0.05) HHb (p-val < 0.05) HHb O2Hb

27 EXAMPLE 2: Functional Diffuse Optical Imaging of the Brain Simultaneous fmri and DOI Time-resolved Oxymeter with capability of simoultaneous activation of 16 source channels and 64 detector channels HHb and O2Hb (a.u.) % BOLD signal time (s) BOLD_RH BOLD_V HHB_RH O2HB_RH HHB_V O2HB_V fnirs BOLD time (s) Maps of brain activation during a motor task with the right hand : increase in blood oxygenation on the left hemisphere

28 Multimodality approach Towards data fusion O 2 Hb and HHb maps (NIRS-SPM) BOLD map (SPM8) fmri max over 10/20 System α ERD maps TMS CoG TMS CoG over 10/20 System

29 Thank you 28