Previous Work in Multi-Modal Imaging

Multi-modal imaging with diffuse optics can focus onvalidationof the diffuse optical measurement,com- parisonof diffuse optics with a measurement using another technique, orsynthesisof different types of information into a composite index. A validation study, for example, might compare DOT to MRI imaging for detection of breast cancer. A comparison study might superpose functional MRI (fMRI) Blood Oxygena- tion Level Dependent (BOLD) imaging and functional DOS/DOT, as both signals depend on neurovascular

Laser Diodes CW Camera TD PMTs

Detector Fibers

Source Fibers

MRI Shielding

MRI Control Room

MRI Magnet

Patient Bed

Figure 3.12: Cartoon of instrument and subject placement for simultaneous DOT and MRI measurement. This is the basic configuration of the GenIIm system, as described in detail in Chapter4.

coupling211_{. A synthesis study could use the tissue structural information from X-ray mammography or}

ultrasound to constrain an optical tomographic reconstruction showing Hbtand StO2distributions212.

Diffuse optics can be combined relatively easily with several standard clinical techniques, such as

MRI7, 198, ultrasound9, 28, magnetoencephalography213, 214and X-ray mammography10, 215. Fiber optics are

often easily integrated into clinical devices with little disturbance to other instrumentation. For example, fiber optics can carry light more than 10 meters to and from the tissue of interest, permitting the opto- electronic portions of diffuse optical instruments to be placed outside of the shielding of an MRI device, as we have done with both our GenII and GenIII systems (Figure3.12).

This ease of integration is inspiring researchers to conduct multi-modality studies. In this thesis, I focus on applications of optical-MR multi-modality imaging for breast cancer.

Various groups have focused on combining the functional information (i.e. oxygen metabolism, angio- genesis) from optical imaging with high resolution structural information provided by other modalities. Zhu9

demonstrated that ultrasound is a natural co-modality for hand-held DOS. Both technologies are inexpensive, easily integrated into a hand-held probe, and non-ionizing28, 216, 217. This last point permits ultrasound and

DOS to be used for frequently repeated measurements (for example, to monitor patients during the course of treatment73). Ultrasound provides structural information, permitting reconstruction of the tissue volume to improve quantification. DOS can alert operators to changes in blood oxygen saturation, total hemoglobin, etc.. The MGH group has combined X-ray tomosynthesis with a two wavelength FD system215, 218_{and later}

Figure 3.13: Simultaneous Optical and MRI measurements of ductal carcinoma by Ntziachristos5_{, showing}

ICG and Gd-DTPA spatial correlation. (a) Sagittal Gd-enhanced MRI with optical field of view marked in yellow. (b) Coronal DOT image of ICG uptake. Note that this plane is perpendicular to that shown in (a). (c) Coronal Gd-enhanced MRI with the same field of view as (b).

incorporated an eight wavelength FD system166_{by ISS Inc. in their studies of the effects of compression on}

breast physiology; see Section3.1.

Few researchers worldwide have concurrently utilized structural information from non-optical modali- ties and injected optical contrast agents for improved diffuse optics based diagnosis and detection. Ntzi- achristos, Yodh, Schnall, and Chance198 _{pioneered simultaneous contrast-enhanced DOT and MRI (the}

University of Pennsylvania ‘GenI’ system). Figure3.13shows an example of co-localization of the two agents. This work employed a TD diffuse optical instrument to obtain simultaneous optical measurements of breast with ICG contrast and with Gd-DTPA enhanced MRI. The DOT system employed 24 sources, 8 detectors, and one optical wavelength (830 nm) across a 5x10 cm grid. Ntziachristos produced co-registered optical and Gd-subtraction images, permitting comparison of the spatial distribution of agent uptake and measurements of ICG kinetics. This system was later expanded to three optical wavelengths5, 6

The Dartmouth optical breast cancer group conducted a study of 11 healthy subjects, with Brooksby7, 219

performing FD-DOT constrained with spatial tissue type distribution from Gd-enhanced MRI. Carpenter8

extended this study into a cancerous subject with the addition of gadolinium contrast agent (Gd-DTPA), applying a regularization scheme permitting gradual changes inside a tissue type and abrupt changes on the boundaries between types. This instrument has 16 sources and 15 detectors, operated at 100 MHz, and uses a circular geometry. Combined DOT/MR imaging systems are summarized in Table3.2.

Practical limitations on recruitment and restrictions on modification of clinical instruments have led many researchers to compare DOT images with sequentially acquired clinical data. Azar30 _{has developed}

Year Sources Detectors λ Type Notes

Penn, GenI 1998 24 8 3 TRS Parallel-Plate

Penn, GenII 2004 32 8 6 TRS Parallel-Plate

Penn, GenIIm 2006 32 8 (16) 6 (1) TRS/CW Parallel-Plate

Penn, GenIII 2009 32 5 (54) 6 (5) TRS/CW Parallel-Plate (Current) Penn, GenIII 2009 64 16 (256) 6 (6) TRS/CW Parallel-Plate (Planned)

PTB 2005 35 8 4 TRS Parallel-Plate220

Dartmouth 2003 16 15 5 FD Ring221_{, later Parallel-Plate}222

Table 3.2: Summary of Clinical Optical-MRI systems for breast cancer. Dates shown are year of first publication; previous generation systems shown only for Penn. Thayer at UCI has presented a progress report223on the development of a new FD system.

modalities taken non-concurrently; particularly,Gd-DTPAenhanced MRI. These fused data sets offer infor- mation from or comparison of both modalities, when simultaneous data acquisition is impractical. Positron emission tomography (PET) using fluoro-deoxyglucose (FDG) is a clinical imaging modality which shows cellular glucose uptake and therefore offers a measurement of glycolytic cellular metabolism; combining PET and DOT offers the opportunity to compare this to blood oxygenation saturation. At University of Pennsylvania, Konecky and collaborators have applied Azar’s data set fusion techniques to show correlation between optical parameters, especially total hemoglobin and scattering with FDG uptake measured with whole body PET29. Saturation measured by optical methods had little correlation with FDG uptake, but the

study was fairly small (N=9). These researchers also extended their study with an experimental breast-only PET scanner to show co-localization of tumors in three subjects. Work applying this deformation technique to hand-held optical measurements and MRI is ongoing in collaboration with University of California Irvine, who have previously correlated sequential hand-held DOS measurements with MRI11_.