This short note covers some of my favorite scientific accomplishments of Britton Chance

In this personal and reflective article, I honor the memory of Britton Chance and explain how his mentorship during my tenure at the Johnson Research Foundation greatly impacted my scientific career. I emphasize the critical role of mentors on the development of scientists and present some wonderful and remarkable attributes that characterized Britton Chance's scientific and personal style.

Britton Chance has pioneered magnetic resonance spectroscopy (MRS) and near-infrared (NIR) spectroscopy (NIRS) as noninvasive methods for measuring muscle metabolism in vivo from the late 1970s. This review honoring Britton Chance will highlight the progress that has been made in developing and utilizing MRS and NIRS technologies for evaluating skeletal muscle O2 dynamics and energetics. Adaptation of MRS and NIRS technology has focused on the validity and reliability of the measurements and extending the methods in physiological and clinical research. Britton Chance has conducted MRS and NIRS research on elite athletes and a number of chronic health conditions, including patients with chronic heart failure, peripheral vascular disease, and neuromuscular myopathies. As MRS and NIRS technologies are practical and useful for measuring human muscle metabolism, we will strive to continue Chance's legacy by advancing muscle MRS and NIRS studies.

In the late 1980s and early 1990s, Dr. Britton Chance and his colleagues, using picosecond-long laser pulses, spearheaded the development of time-resolved spectroscopy techniques in an effort to obtain quantitative information about the optical characteristics of the tissue. These efforts by Chance and colleagues expedited the translation of near-infrared spectroscopy (NIRS)-based techniques into a neuroimaging modality for various cognitive studies. Beginning in the early 2000s, Dr. Britton Chance guided and steered the collaboration with the Optical Brain Imaging team at Drexel University toward the development and application of a field deployable continuous wave functional near-infrared spectroscopy (fNIR) system as a means to monitor cognitive functions, particularly during attention and working memory tasks as well as for complex tasks such as war games and air traffic control scenarios performed by healthy volunteers under operational conditions. Further, these collaborative efforts led to various clinical applications, including traumatic brain injury, depth of anesthesia monitoring, pediatric pain assessment, and brain-computer interface in neurology. In this paper, we introduce how these collaborative studies have made fNIR an excellent candidate for specified clinical and research applications, including repeated cortical neuroimaging, bedside or home monitoring, the elicitation of a positive effect, and protocols requiring ecological validity. This paper represents a token of our gratitude to Dr. Britton Chance for his influence and leadership. Through this manuscript we show our appreciation by contributing to his commemoration and through our work we will strive to advance the field of optical brain imaging and promote his legacy.

A frequent consequence of traumatic brain injury (TBI) is cognitive impairment, which results in significant disruption of an individual's everyday living. To date, most clinical rehabilitation interventions still rely on behavioral observation, with little or no quantitative information about physiological changes produced at the brain level. Functional brain imaging has been extensively used in the study of cognitive impairments following TBI. However, its applications to rehabilitation have been limited. This is due in part to the expensive or invasive nature of these modalities. The objective of this study is to apply functional near-infrared spectroscopy (fNIR) to the assessment of attention impairments following TBI. fNIR provides a localized measure of prefrontal hemodynamic activation, which is susceptible to TBI, and it does so in a noninvasive, affordable and wearable way, thus partially overcoming the limitations of other modalities. Participants included 5 TBI subjects and 11 healthy controls. Brain activation measurements were collected during a target categorization task. Significant differences were found in the hemodynamic response between healthy and TBI subjects. In particular, the elicited responses exhibited reduced amplitude in the TBI group. Overall, the results provide first evidence of the ability of fNIR to reveal differences between TBI and healthy subjects in an attention task. fNIR is therefore a promising neuroimaging technique in the field of neurorehabilitation. The use of fNIR in neurorehabilitation applications would benefit from its noninvasiveness and cost-effectiveness and the neurophysiological information obtained through the evaluation of the hemodynamic activation could provide invaluable information to guide the choice of intervention.

Since the dual-wavelength spectrophotometer was developed, it has been widely used for studying biological samples and applied to extensive investigations of the electron transport in respiration and redox cofactors, redox state, metabolic control, and the generation of reactive oxygen species in mitochondria. Here, we discuss some extension of dual-wavelength approaches in our research to study the physiological and functional changes in intact hearts and in vivo brain. Specifically, we aimed at (1) making nonratiometric fluorescent indicator become ratiometric fluorescence function for investigation of Ca2+ dynamics in live tissue; (2) eliminating the effects of physiological changes on measurement of intracellular calcium; (3) permitting simultaneous imaging of multiple physiological parameters. The animal models of the perfused heart and transiently ischemic insult of brain are used to validate these approaches for physiological applications.

Ultrasound-guided biopsy procedure for prostate cancer diagnosis, which is the current gold standard, involves quasi-random sampling of prostate tissue without any functional guidance. In this study, we discuss the possibility to augment the detection of prostate cancer using a dual-modality optical approach, which can be coupled with the current needle biopsy setup. Two techniques are light reflectance spectroscopy (LRS) that uses a broadband light source and a CCD array spectrometer, and auto-fluorescence lifetime measurement (AFLM) that uses a custom- designed, time-correlated single photon counting (TCSPC) system. Both LRS and AFLM were employed sequentially in this study to measure cancer tissue along with control tissue on a rat prostate tumor model. At an excitation wavelength of 447 nm, we investigated auto-fluorescence decay curves at the emission wavelengths of 532, 562, 632 and 684 nm for in vivo and ex vivo AFLM. These results show that auto-fluorescence lifetimes at all measured emission wavelengths differ between control and cancerous tissues with 100% specificity and sensitivity. Moreover, absolute values of hemoglobin derivatives and scattering coefficient were quantified using in vivo LRS. This part of study also demonstrates that light scattering and absorption are significantly different between the control and cancerous tissue. Overall, the study demonstrates that both LRS and AFLM may provide several intrinsic biomarkers for in vivo detection of prostate cancer.

Redox state mediates embryonic stem cell (ESC) differentiation and thus offers an important complementary approach to understanding the pluripotency of stem cells. NADH redox ratio (NADH/(Fp+ NADH)), where NADH is the reduced form of nicotinamide adenine dinucleotide and Fp is the oxidized flavoproteins, has been established as a sensitive indicator of mitochondrial redox state. In this paper, we report our redox imaging data on the mitochondrial redox state of mouse ESC (mESC) colonies and the implications thereof. The low-temperature NADH/Fp redox scanner was employed to image mESC colonies grown on a feeder layer of gamma-irradiated mouse embryonic fibroblasts (MEFs) on glass cover slips. The result showed significant heterogeneity in the mitochondrial redox state within individual mESC colonies (size: ~200-440 μm), exhibiting a core with a more reduced state than the periphery. This more reduced state positively correlates with the expression pattern of Oct4, a well-established marker of pluripotency. Our observation is the first to show the heterogeneity in the mitochondrial redox state within a mESC colony, suggesting that mitochondrial redox state should be further investigated as a potential new biomarker for the stemness of embryonic stem cells.

Two-photon excited fluorescence (TPEF) spectroscopy and imaging were used to investigate the effects of gamma-irradiation on neural stem and precursor cells (NSPCs). While the observed signal from reduced nicotinamide adenine dinucleotide (NADH) was localized to the mitochondria, the signal typically associated with oxidized flavoproteins (Fp) was distributed diffusely throughout the cell. The measured TPEF emission and excitation spectra were similar to the established spectra of NAD(P)H and Fp. Fp fluorescence intensity was markedly increased by addition of the electron transport chain (ETC) modulator menadione to the medium, along with a concomitant decrease in the NAD(P)H signal. Three-dimensional (3D) neurospheres were imaged to obtain the cellular metabolic index (CMI), calculated as the ratio of Fp to NAD(P)H fluorescence intensity. Radiation effects were found to differ between low-dose (≤ 50 cGy) and high-dose (≥ 50 cGy) exposures. Low-dose irradiation caused a marked drop in CMI values accompanied by increased cellular proliferation. At higher doses, both NAD(P)H and Fp signals increased, leading to an overall elevation in CMI values. These findings underscore the complex relationship between radiation dose, metabolic state, and proliferation status in NSPCs and highlight the ability of TPEF spectroscopy and imaging to characterize metabolism in 3D spheroids.

Near-infrared fluorescence (NIRF) imaging involves the separation of weak fluorescence signals from backscattered excitation light. The measurement sensitivity of current NIRF imaging systems is limited by the excitation light leakage through rejection filters. In this contribution, the authors demonstrate that the excitation light leakage can be suppressed upon using appropriate filter combination and permutations. The excitation light leakage and measurement sensitivity were assessed and compared in this study by computing the transmission ratios of excitation to emission light collected and the signal-to-noise ratios in well-controlled phantom studies with different filter combinations and permutations. Using appropriate filter combinations and permutations, we observe as much as two orders of magnitude reduction in the transmission ratio and higher signal-to-noise ratio.

Laminar optical tomography (LOT) is a mesoscopic tomographic imaging technique ranging between confocal microscopy and diffuse optical tomography (DOT). Fluorescence LOT (FLOT) provides depth-resolved molecular information with 100-200μm resolution over 2-3mm depth. In this study, we use Monte Carlo simulation and singular-value analysis (SVA) to optimize the source-detector configurations for potential enhancement of FLOT imaging performance. The effects of different design parameters, including source incidence and detector collection angles, detector number, and sampling density, are presented. The results indicate that angled incidence/ detection configuration might improve the imaging resolution and depth sensitivity, especially for low-scattering medium. Increasing the number of detectors and the number of scanning steps will also result in enhanced imaging performance. We also demonstrate that the optimal imaging performance depends upon the background scattering coefficient. Our result might provide an optimization strategy for FLOT or LOT experimental setup.

Sensitivity and data processing speed are important in spectral domain Optical Coherence Tomography (SD-OCT) system. To get a higher sensitivity, zero-padding interpolation together with linear interpolation is commonly used to re-sample the interference data in SD-OCT, which limits the data processing speed. Recently, a time-domain interpolation for SD-OCT was proposed. By eliminating the huge Fast Fourier Transform Algorithm (FFT) operations, the operation number of the time-domain interpolation is much less than that of the zero-padding interpolation. In this paper, a numerical simulation is performed to evaluate the computational complexity and the interpolation accuracy. More than six times acceleration is obtained. At the same time, the normalized mean square error (NMSE) results show that the time-domain interpolation method with cut-off length L = 21 and L = 31 can improve about 1.7 dB and 2.1 dB when the distance mismatch is 2.4mm than that of zero-padding interpolation method with padding times M = 4, respectively. Furthermore, this method can be applied the parallel arithmetic processing because only the data in the cut-off window is processed. By using Graphics Processing Unit (GPU) with compute unified device architecture (CUDA) program model, a frame (400 A-lines × 2048 pixels × 12 bits) data can be processed in 6 ms and the processing capability can be achieved 164,000 line/s for 1024-OCT and 71,000 line/s for 2048-OCT when the cut-off length is 21. Thus, a high-sensitivity and ultra-high data processing SD-OCT is realized.