Wearable Frequency-Domain Near-Infrared Spectroscopy

Individuals often lack field-based tools to monitor exercise effectiveness. New sensing methods may allow for an improved measurement of the individualized response to exercise by monitoring oxygen kinetics directly in muscle tissue. This study aimed to validate a non-invasive wearable sensor capable of measuring muscle oxygen saturation (SmO2) using continuous wave near-infrared spectroscopy (CW-NIRS) against a laboratory-validated frequency-domain NIRS (FDNIRS) device. Ten physically fit adults performed an incremental cycling test until voluntary exhaustion. Devices were placed on contralateral rectus femoris muscles, respectively. SmO2 was simultaneously measured continuously for the duration of the protocol. Time series alignment and dataset resampling were performed to enable direct comparison. Z-score normalization accounted for inter-individual differences in a group-level analysis. Individual subject validation showed strong correlations between the two devices (r = 0.792, range: 0.69-0.88, p < 0.001) with an RMSD < 5% for most subjects, a mean bias of 0.005 and low proportional bias (-0.199) between all paired measurements. Group-level analysis demonstrated a correlation of r = 0.788. Bland-Altman analysis revealed 95% of all measurements fell between -8.1% to 7.6% SmO2. The CW-NIRS device delivered reliable performance compared to the FDNIRS device, offering potential applications for real-time physiological monitoring during exercise and performance assessment.

We present theoretical and experimental demonstrations of a novel, to the best of our knowledge, diffuse optical imaging method that is based on the concept of dual slopes (DS) in frequency-domain near-infrared spectroscopy. We consider a special array of sources and detectors that collects intensity (I) and phase (ϕ) data with multiple DS sets. We have recently shown that DSϕ reflectance data features a deeper sensitivity with respect to DSI reflectance data. Here, for the first time, we describe a DS imaging approach based on the Moore-Penrose inverse of the sensitivity matrix for multiple DS data sets. Using a circular 8-source/9-detector array that generates 16 DS data sets at source-detector distances in the range 20-40 mm, we show that DSI images are more sensitive to superficial (<5mm) perturbations, whereas DSϕ images are more sensitive to deeper (>10mm) perturbations in highly scattering media.

Neurovascular coupling is the generic term for changes in cerebral metabolic rate of oxygen (CMRO 2), cerebral blood flow, and cerebral blood volume related to brain activity. The goal of this paper is to better understand the effects of neurovascular coupling in the visual and motor cortices using frequency-domain near-infrared spectroscopy. Maps of concentration changes in oxyhemoglobin [O 2Hb], deoxyhemoglobin [HHb], and total hemoglobin of the visual and motor cortices were generated during stimulation using a reversing checkerboard screen and palm-squeezing, respectively. Seven healthy volunteers of 18–37 years of age were included. In the visual cortex the patterns of [O 2Hb] and [HHb] were strongly linearly correlated ( r 2 > 0.8 in 13 of a total of 24 locations). In 20 locations the change in [O 2Hb] was larger than 0.25 μM. The mean slope of the linear regression between [O 2Hb] and [HHb] was −3.93 ± 0.31 (SE). The patterns of the [O 2Hb] and [HHb] traces over the motor cortex looked different. The [O 2Hb] reached its maximum change a few seconds before the [HHb] reached its minimum. This was confirmed by the linear regression analysis ( r 2 > 0.8 in none of 40 locations). In 20 locations the change in [O 2Hb] was larger than 0.25 μM. The mean slope of the regression line was −1.76 ± 0.20, which is significantly higher than that in the motor cortex ( P < 0.0000001). Patterns of [O 2Hb] and [HHb] differ among cortex areas. This implies that the regulation of perfusion in the visual cortex is different from that in the motor cortex. There is evidence that the CMRO 2 increases substantially in the visual cortex, while this is not the case for the motor cortex.

We are developing an MR-compatiblepositron emission tomography (PET) detector system comprising silicon photomultipliers (SiPMs), and application specific integrated circuits (ASICs) mounted in the same printed circuit board (PCB). Since the heat generated from the ASICs can affect the performance of temperature-dependent SiPMs, a scalable PCB cooling method for stable and uniform SiPM performance was designed, developed and investigated.To cool the SiPM surface within the PCB, a thermal layer is added below the SiPM layer, which is then connected to the bottom layer through thermal vias for efficient heat conduction. Then, either a “cooling plate” or “square tubes” is attached to the bottom layers of multiple detector modules. A proof-of-concept thermal experiment was performed to test the feasibility of the PCB cooling method for SiPM-ASIC PET detector modules, then a 3D transient heat transfer simulations was performed to analyze the temperature profile on the SiPM surface of the more realistic PCB. The thermal experiments were performed using a prototype PCB with a 6 W heater strip mimicking the ASICs and 15° water flowing through the cooling structure; the plate which has more contact to the PCB resulted in 18.0° average temperature and 0.8° maximum temperature difference across the 5 cm width SiPM layer, while square tubes showed slightly worse results of 18.7° and 1.3°, respectively. In realistic thermal simulations, the square tubes with thermal vias showed deviation from the experimental results with 21° average temperature and 6.5° maximum temperature difference. In addition, the thermal gradient was significantly worse without the thermal vias. Considering the compact and simple geometry of the square tubes compared to the plate configuration, the former with thermal vias are an attractive choice to cool the SiPM-ASIC PET detector modules; ASICs can further optimize the minor non-uniform SiPM performance using digital calibrations.

This report documents the results and findings of a one-year scoping study investigating multichannel readout application specific integrated circuits (ASICs) for interfacing to, and processing data from, silicon photomultiplier (SiPM) arrays. We document ASIC desired and required specifications for four applications supporting national security mission areas: neutron radiography, associated particle imaging, and two versions of kinematic neutron imaging cameras. While each application has a few unique requirements that stress capability, there is generally good agreement among most. Two recently developed ASIC devices were evaluated in a system-like configuration by interfacing these to scintillator crystals exposed to gamma and neutron sources. The 64-channel ORNL device delivered functional capability while meeting most mission requirements for neutron radiography. The Nalu Scientific device, a 32-channel full waveform digitizer, did not demonstrate reliable neutron / gamma separation but it is unclear if this was an ASIC issue or problems with test setup or firmware. A literature survey of other commercial and academic ASICs was undertaken to with the conclusion that existing devices do not meet all requirements.

A custom front-end ASIC for the readout and timing of 64 SiPM photosensors

Background: Optical-based imaging modalities play an important role in assessing breast tissue composition by measuring optical property contrast from endogenous chromophores. The advantages of optical techniques are the use of non-ionizing radiation, ease of use, and relatively low cost. The primary objective of this study is to examine changes in optically derived parameters (i.e., deoxy-hemoglobin concentration, ctHHb) from different breast cancer subtypes under neoadjuvant chemotherapy (NAC), and correlate with tumor pathologic complete response (pCR). Methods: This retrospective study evaluated 89 tumors in total divided into three distinct subtypes: HR+/HER2- (n=34), HER2+ (n=27), and TNBC (n=28). All patients were imaged at baseline, before starting NAC (TP0), and two weeks after receiving one cycle of taxane-based chemotherapy (TP1). HER2+ breast cancer patients also received HER2-target therapy. pCR was defined as complete absence of invasive carcinoma in the breast and lymph node(s) (ypT0/is ypN0 Mx) at the time of surgery. Whole breast volume was imaged by a diffuse optical tomography breast imaging system (DOTBIS) using low-intensity near-infrared light. ctHHb tumor volume concentration was normalized by the non-affected health tissue ctHHb mean value (ctHHbN). For each molecular subgroup, we conducted an independent-samples t-test to determine if there was a difference in ctHHbN levels at TP1 compared to TP0 between patients with a pCR and non-pCR. Significance was assumed at a confidence interval of 95% (α = 0.05). Results: In total, 69 patients were imaged with DOTIBS at both time points, TP0 and TP1. HR+/HER2-, TNBC and HER2+ accounted for 32% (n=23), 37% (n=22) and 30% (n=22), respectively. The ratio between ctHHbN levels measured at TP1 and TP0 was statistically significantly lower in the pCR group than non-pCR for the HER2+ and HR+/HER2- molecular subgroups, Table 1. Conclusion: Aligned to the current practices in breast cancer management based on the characterization of breast cancer subtypes, our work evaluated changes in DOTBIS optically derived features and pCR status for different subtypes. We observed that ctHHbN levels change after two weeks of NAC and these changes are modifiable according to pCR status and are dependent on immunophenotype. Table 1.Ratio between ctHHbN levels measured at TP1 and TP0 between pCR and non-pCR according to different molecular subtypes.Molecular SubtypepCR (mean ± SD )non-pCR (mean ± SD )p-valueHR+/HER2- (n=23)0.77 ± 0.22 (n=6)1.14 ± 0.24 (n=17).01HER2+ (n=24)0.74 ± 0.30 (n=15)1.54 ± 0.98 (n=9).04TNBC (n=22)0.96 ± 0.38 (n=4)1.29 ± 0.37 (n=18).18Bold values indicate statistical significance at p&amp;lt;.05 level. Citation Format: Mirella L Altoe, Kevin M Kalinsky, Hua Guo, Hanina Hibshoosh, Mariella Tejada, Katherine D Crew, Melissa K Accordino, Meghna S Trivedi, Alessandro Marone, Hyun K Kim, Andreas H Hielscher, Dawn L Hershman. Prediction of breast cancer response to neoadjuvant chemotherapy in different biological breast cancer subtypes using diffuse optical tomography [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-02-04.

Diffuse optical imaging (DOI) is a label-free, safe, inexpensive, and quantitative imaging modality that provides metabolic and molecular contrast in tissue using visible or near-infrared light. DOI modalities can image up to several centimeters deep in tissue, providing access to a wide range of human tissues and organ sites. DOI technologies have benefitted from several decades of academic research, which has provided a variety of platforms that prioritize imaging depth, resolution, field-of-view, spectral content, and other application-specific criteria. Until recently, however, acquisition and processing speeds have represented a stubborn barrier to further clinical exploration and implementation. Over the last several years, advances in high-speed data acquisition enabled by high-speed digital electronics, newly available sources and detectors, and innovative new scanning methods have led to major improvements in DOI rates. These advances are now being coupled with new data processing algorithms that utilize deep learning and other computationally efficient methods to provide rapid or real-time feedback in the clinic. Together, these improvements have the potential to help advance DOI technologies to the point where major impacts can be made in clinical care. Here, we review recent advances in acquisition and processing speed for several important DOI modalities.

Diffuse optical tomography(DOT) is a nonlinear optimization problem to find optical coefficients using near-infrared light. Linearized methods was used by many researchers to avoid the nonlinearity of DOT. In this paper, the nonlinearity of DOT is studied using Born expansion and some parameters measuring the nonlinearity of DOT is suggested.

Abstract #805 Background: Diffuse optical tomography (DOT) uses near-infrared light to non-invasively image total hemoglobin concentration and blood oxygen saturation in the human breast. Given its low cost, ease of use, and possibility of repeated measured over time, DOT is a promising adjunctive imaging modality for screening, diagnosis and monitoring of neoadjuvant therapy. In this study we explored the performance of DOT to differentiate benign and malignant breast lesions.&amp;#x2028; Method and Materials: Forty-seven women with clinical or mammographic abnormalities were prospectively recruited for DOT. Most patients underwent gadolinium-enhanced MRI examination. Three-dimensional oxy-, deoxy-hemoglobin, total hemoglobin concentration, blood oxygen saturation and scattering coefficient images of each breast were reconstructed. Tumor-to-normal (T/N) ratios of these parameters were computed by defining tumor regions with guidance from MRI and radiology reports. In addition, optical index was constructed based on these parameters to maximize the T/N contrast. Only the biopsy-proven lesions were selected (51 breast lesions) and classified into three groups: benign lesions (N=10), malignant lesions where DOT preceded core biopsy (N=20) and malignant lesions where DOT was performed after core-biopsy (N=21). We fit a mixed effects model that estimated the mean optical T/N ratios and optical index for each group, and using the resulting standard errors developed 95% confidence intervals and tested the hypothesis that each optical contrast parameter was unity.&amp;#x2028; Results: Malignant cancers showed statistically significant higher total hemoglobin concentration, scattering, oxy-hemoglobin concentration and optical index (P=0.01-0.04) compared to normal tissue. Furthermore, malignant lesions exhibited a two-fold average increase in an optical index derived from the endogenous optical parameters (95% CI: 1.4 - 2.4). To test whether bleeding due to core biopsy influence DOT results, we compared if there was statistically significant differences between two groups measured before or after core-biopsy. There were no statistically significant differences in these groups, suggesting that post biopsy hemorrhage did not alter the DOT results. Benign tumors did not show statistical significance in all of the T/N ratios. AUC of total hemoglobin concentration, scattering, oxy-hemoglobin and optical index suggested good discriminatory power with values between 0.90 and 0.99.&amp;#x2028; Discussion: The data demonstrates the feasibility of differentiating benign and malignant lesions by quantitative three-dimensional DOT when the tumor location information is provided by other imaging modality. The main drawback of this study is the small number of benign lesions, which warrants further study. DOT technology is still at its developing stage and needs more investigation to find its niche in breast imaging. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 805.

A three layer Compton telescope for dose monitoring in hadron therapy is under development at IFIC - Valencia. It will consist of three detector layers and each layer will be made of a continuous LaBr <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">3</sub> crystal coupled to four Silicon Photomultiplier (SiPM) arrays. A prototype made of two detector layers has already been assembled and tested. The detector layers consist of a 32×36×5 mm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">3</sup> and 32×36×10 mm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">3</sup> LaBr <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">3</sub> crystal, each coupled to four SiPM arrays. The front-end electronics of each detector is based on the VATA64HDR16 application specific integrated circuit (ASIC). The gamma rays coming from a <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">22</sup> Na source have been detected with the two detector layers working in time coincidence, allowing energy and position estimation.

We have designed FlexToT, a flexible application specific integrated circuit (ASIC) using time-over-threshold (ToT) techniques for the readout of silicon photomultiplier (SiPM) arrays in positron emission tomography (PET) detectors. The FlexToT ASIC accommodates 16 independent channels in a small die size (2.93 mm by 2.54 mm) with low power consumption (10 mW per channel), providing output signals whose duration is proportional to the current amplitude at its inputs. The threshold, gain and other parameters can be independently set for each channel in a flexible configuration that can be tailored to different applications and devices. Herein we present the results on the evaluation of the FlexToT ASIC operating as front-end electronics for SiPM arrays S11828-3344M from Hamamatsu (Japan) coupled to LYSO:Ce scintillators in a simple PET tomograph demonstrator. Each detector block is composed of a LYSO:Ce matrix coupled to 4 SiPM arrays in a 2×2 mosaic, totaling 64 pixels (8×8) which are read out by 4 FlexToT ASICs. Using this demonstrator we have obtained PET images of <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">22</sup> Na point sources with spatial resolutions better than 2 mm full width at half maximum (FWHM), validating our design of the FlexToT ASIC on the readout of SiPM matrices and scintillators in PET applications.

We present the design of a miniaturized probe integrating silicon photomultiplier and light-pulsing electronics in a single 2 × 2mm2 complementary metal-oxide-semiconductor (CMOS) chip which includes functional blocks such as a fast pulse-laser driver and synchronized single-photon detection circuit. The photon pulses can be either counted on-chip or processed by an external high-speed electronic module such as time-corelated single photon counting (TCSPC) unit. The integrated circuit was assembled on a printed circuit board (PCB) and also on a 2.5D silicon interposer platform of size 1 cm and interfaced with a silicon photomultiplier (SiPM), vertical cavity surface emitting laser (VCSEL) and other ancillary components such as capacitors and resistors. Our approach of integrating an optical interface to optimize light collection on the small active area and light emission from the vertical-cavity surface-emitting laser (VSCEL) will facilitate clinical adoption in many applications and change the landscape of Near Infrared Spectroscopy (NIRS) hardware commercially due to significant optode-size reduction and the elimination of optical fibers.

Brain-Computer Interfaces (BCI) and Neurofeedback (NFB) approaches, which both rely on real-time monitoring of brain activity, are increasingly being applied in rehabilitation, assistive technology, neurological diseases and behavioral disorders. Functional near-infrared spectroscopy (fNIRS) and diffuse optical tomography (DOT) are promising techniques for these applications due to their non-invasiveness, portability, low cost, and relatively high spatial resolution. However, real-time processing of fNIRS/DOT data remains a significant challenge as it requires establishing a baseline of the measurement, simultaneously performing real-time motion artifact (MA) correction across all channels, and (in the case of DOT) addressing the time-consuming process of image reconstruction. This study proposes a real-time processing system for fNIRS/DOT that integrates baseline calibration, denoising autoencoder (DAE) based MA correction model with a sliding window strategy, and a pre-calculated inverse Jacobian matrix to streamline the reconstructed 3D brain hemodynamics. The DAE model was trained on an extensive whole-head high-density DOT (HD-DOT) dataset and tested on separate motor imagery dataset augmented with artificial MA. The system demonstrated the capability to simultaneously process approximately 750 channels in real-time. Our results show that the DAE-based MA correction method outperformed traditional MA correction in terms of mean squared error and correlation to the known MA-free data while maintaining low latency, which is critical for effective BCI and NFB applications. The system’s high-channel, real-time processing capability provides channel-wise oxygenation information and functional 3D imaging, making it well-suited for fNIRS/DOT applications in BCI and NFB, particularly in movement-intensive scenarios such as motor rehabilitation and assistive technology for mobility support.

Clinically, the level of Ki67 expression is used as a biomarker for cancer proliferation. In this clinical study, we focus on malignant tumor properties and investigate the correlations between macroscopically measured Diffuse Optical Tomography (DOT) physiological parameters with the Ki67 proliferation marker. The DOT tumor-to-normal tissue parameters were previously shown to have excellent tumor sensitivity and specificity by Choe and co-workers (JBO, 14(2):024020). In order to quantify cell proliferation, the percent of Ki67-expressing nuclei (i.e., from all the nuclei in an ROI) was used to specify Ki67 expression in cancer and normal tissues. Then, the tumor-to-normal ratio of Ki67-expressing nuclei was calculated to derive “relative” Ki67 values (i.e., rKi67). For this analysis, only normal glandular tissues with Ki67 expression were used. For these determinations of rKi67, the range of the Ki67-nuclei present in cancer tissues was 0.36-23.45% (N = 8), and in normal tissues it was 0.19-7.41% (N = 8). Ki67-expression in cancer-only tissues was also compared to DOT parameters. The range of the Ki67 present in cancer used for the analysis of the cancer-only tissues was 0.36-27.77% (N = 15). Among the DOT parameters, rStO2 (relative tissue oxygenation) and rHbO2 (relative oxy-hemoglobin concentration) were highly correlated with rKi67 as shown in table 1 (Pearson correlation: 0.92, p-value: 0.001 for rStO2 and correlation: 0.93, p-value: 0.002 for rHbO2). Also, for cancer-only Ki67, rHb (relative deoxy-hemoglobin concentration) showed a weak inverse correlation with cancer Ki67%: correlation: -0.58, p-value: 0.026. We additionally tested if the Diffuse Optical Tomography parameters are significantly different in more proliferative cancer compared to the less proliferative cancer (as determined by the 15% cutoff point). For this purpose, only rHb differentiated Ki67-positive from Ki67-negative cancer, with lower values of rHb occurring for the Ki67-positive cancer (p-value: 0.018, Wilcoxon-ranked-sum test). In this correlation study, we observed that rKi67 was highly correlated with rStO2 and rHbO2. Further, the cancer-only Ki67 showed lower correlations with the relative DOT parameters. However, we found that rHb was inversely correlated with cancer-only Ki67 percent values. Additionally, rHb was lower in the Ki67-positive cancer compared to the Ki67-negative cancer (using the 15% cutoff point). Taken together, these results suggest that in more proliferative cancers, although more oxy-hemoglobin might be supplied to the cancer, the level of oxygenated-hemoglobin remains high and less oxygen is utilized for cancer metabolism (i.e., consistent with lower rHb). This finding appears to be consistent with the Warburg effect, which accounts for the fact that proliferative cells will go through glycolysis to increase biomass without using oxygen, despite sufficient presence of oxygen in the tissue environment. Overall, the results of this study corroborate expectations that macroscopic measurement of breast cancer physiology using DOT can reveal information microscopic pathological properties of breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-03-10.