ADVANCES IN BIOMEDICAL OPTICS

The last decade has seen major advances towards clinically relevant optical tomographic imaging methods. For example, it is well established that he most accurate image reconstruction schemes are based on the equation of radiative transfer (ERT). However, the accuracy comes at the cost of long computation times, which have hampered its practical utility. Besides a general overview on how to implement ERT-based reconstruction algorithms, we focus on various method that accelerated the image reconstruction process. PDE-constrained algorithms, SPN methods and parametric reconstruction techniques, as well as domain decomposition and parallel programming approaches will be discussed. All of these approaches combined have reduced the image reconstruction times from hours or even days to minutes or seconds. Furthermore, instrumentation that incorporates digital-signal-processing (DSP) chip technology has significantly increased the signal-to-noise ratios, and ever smaller signals can be detected in shorter times. This opens the doors to novel applications in dynamic optical tomography. Practical examples encountered in clinical and preclinical imaging such as monitoring of tumor growth and regression, effects of anti-angiogenic drugs, breast cancer screening, and detection of arthritis will be presented.

In recent years, Diffuse Optical Tomography (DOT) has been increasingly utilized for functional brain studies. Due to its low spatial resolution and limited penetration depth, however, DOT has not been popularly introduced to clinicians and neural scientists. Researchers in the DOT field have discussed and attempted to identify optimal or practical clinical uses for translating this non-invasive neuroimaging tool to bedside. In our study, we have focused on two clinical applications of DOT: one is to study connectivity among the brain areas during and after repetitive transcranial magnetic stimulation (rTMS), which is used to treat depression patients and will become FDA-approved treatment soon; another is to investigate cortical reorganization in children with cerebral palsy (CP). These two studies allow us to take full advantages of DOT: In the rTMS study, we measured the hemodynamic signals from both motor and pre- frontal cortexes without any concern on depth or on interference between magnetic and optical signals. In the study for children with CP, the measurement areas were also from the motor cortex, giving us the best signals that DOT can obtain. In this talk, introduction to the methodology, protocols for the human measurement, physiological noise removal, and specific algorithms for connectivity calculations and cortical laterization will be presented and discussed. Overall, it will show that DOT can be well adapted and utilized in these two clinical applications.

Photodynamic therapy (PDT) elicits significant molecular and host responses, which are understood to be important to long-term tumor control. The tools of molecular biology together with optical fluorescence imaging techniques have made it possible to image some of these responses in tumors in living mice. Using tumors grown from mouse mammary sarcoma cells transfected with a plasmid that places the expression of green fluorescent protein under the control of the promoter for the heat shock protein 70, we have successfully imaged the time course of a PDT-induced heat shock response in living mice. Recently, we have implemented an antibody labeling technique that enables high resolution, high contrast imaging of specific host cell populations in vivo. Images are acquired to depths of approximately 100 μm using a custom, single-photon-excitation laser scanning confocal fluorescence microscope. Host cells are rendered fluorescent via intradermal injection of small volumes of fluorophore- conjugated antibodies directed against cell-specific surface proteins. Using this method and antibodies against the endothelial-cell-surface protein CD31, we have obtained images of normal and tumor vasculature in vivo. Antibody conjugates directed against GR-1 and major histocompatibility complex class II (MHC-II) enable imaging of granulocytes and MHC-II (+) cells in vivo. The latter include macrophages and dendritic cells. Imaging of intradermal EMT6 tumors pre- and post-PDT reveals significant increases in GR-1 (+) cells, most of which are neutrophils, in response to therapy.