Significance: Low-frequency oscillations (LFOs) (<0.1Hz) with respect to cerebral blood flow (CBF) have shown promise as an indicator of altered neurologic activity in the abnormal brain. Portable optical instruments have evolved to offer a noninvasive alternative for continuous CBF monitoring at the bedside compared with many large neuroimaging modalities. However, their utilization for acquiring LFOs of CBF has only been studied to a limited extent. Aim: We aim to optimize an innovative speckle contrast diffuse correlation tomography (scDCT) system for the detection of LFOs within CBF variations. Approach: The scDCT was optimized to achieve a higher sampling rate and a faster image reconstruction using a moving window 3D reconstruction algorithm with parallel computation. Power spectral density (PSD) analysis was performed to investigate altered LFOs during transient global cerebral ischemia in neonatal piglets. Results: Transient global cerebral ischemia resulted in reductions in both CBF and PSD compared with their baseline values. Conclusions: Spontaneous LFOs, combined with CBF, provide a more comprehensive assay with the potential to clarify pathological mechanisms involved in brain injury. These results support scDCT's inclusion and application in the growing area of LFO analysis and demonstrate its inherent advantage for neurological studies in preclinical and clinical settings, such as neonatal intensive care units. (c) The Authors. Published by SPIE under a Creative Commons Attribution 4.0 International License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.

Objective: Wearable technologies for functional brain monitoring in freely behaving subjects can advance our understanding of cognitive processing and adaptive behavior. Existing technologies are lacking in this capability or need procedures that are invasive and/or otherwise impede brain assessments during social behavioral conditions, exercise, and sleep. Methods: In response a complete system was developed to combine relative cerebral blood flow (rCBF) measurement, O 2 and CO 2 supplies, and behavior recording for use on conscious, freely behaving mice. An innovative diffuse speckle contrast flowmetry (DSCF) device and associated hardware were miniaturized and optimized for rCBF measurements in small subject applications. The use of this wearable, fiber-free, near-infrared DSCF head-stage/probe allowed no craniotomy, minimally invasive probe implantation, and minimal restraint of the awake animal. Results and Conclusions: Significant correlations were found between measurements with the new DSCF design and an optical standard. The system successfully detected rCBF responses to CO 2 -induced hypercapnia in both anesthetized and freely behaving mice. Significance: Collecting rCBF and activity information together during natural behaviors provides realistic physiological results and opens the path to exploring their correlations with pathophysiological conditions.

Imaging of tissue blood flow (BF) distributions provides vital information for the diagnosis and therapeutic monitoring of various vascular diseases. The innovative near-infrared speckle contrast diffuse correlation tomography (scDCT) technique produces full 3D BF distributions. Many advanced features are provided over competing technologies including high sampling density, fast data acquisition, noninvasiveness, noncontact, affordability, portability, and translatability across varied subject sizes. The basic principle, instrumentation, and data analysis algorithms are presented in detail. The extensive applications are summarized such as imaging of cerebral BF (CBF) in mice, rat, and piglet animals with skull penetration into deep brain. Clinical human testing results are described by recovery of BF distributions on preterm infants (CBF) through incubator wall, and on sensitive burn tissues and mastectomy skin flaps without direct device-tissue interactions. Supporting activities outlined include integrated capability for acquiring surface curvature information, rapid 2D blood flow mapping, and optimizations via tissue-like phantoms and computer simulations. These applications and activities both highlight and guide the reader as to the expected abilities and limitations of scDCT for adapting into their own preclinical/clinical research, use in constrained environments (i.e., neonatal intensive care unit bedside), and use on vulnerable subjects and measurement sites.

We developed a novel EMCCD-based speckle contrast diffuse correlation tomography (scDCT) system for 3-dimensional imaging of deep tissue blood flow distribution. The system has been validated in tissue-simulating phantoms and applied in human tissues.

This study used a hybrid near-infrared diffuse optical instrument to monitor tumor hemodynamic responses to chemoradiation therapy for early prediction of treatment outcomes in patients with head and neck cancer. Forty-seven patients were measured once per week to evaluate the hemodynamic status of clinically involved cervical lymph nodes as surrogates for the primary tumor response. Patients were classified into two groups: complete response (CR) (n=29) and incomplete response (IR) (n=18). Tumor hemodynamic responses were found to be associated with clinical outcomes (CR/IR), wherein the associations differed depending on human papillomavirus (HPV-16) status. In HPV-16 positive patients, significantly lower levels in tumor oxygenated hemoglobin concentration ([HbO2]) at weeks 1 to 3, total hemoglobin concentration at week 3, and blood oxygen saturation (StO2) at week 3 were found in the IR group. In HPV-16 negative patients, significantly higher levels in tumor blood flow index and reduced scattering coefficient (μs′) at week 3 were observed in the IR group. These hemodynamic parameters exhibited significantly high accuracy for early prediction of clinical outcomes, within the first three weeks of therapy, with the areas under the receiver operating characteristic curves (AUCs) ranging from 0.83 to 0.96.

Radiation therapy is a principal modality for head and neck cancers and its efficacy depends on tumor hemodynamics. Our laboratory developed a hybrid diffuse optical instrument allowing for simultaneous measurements of tumor blood flow and oxygenation. In this study, the clinically involved cervical lymph node was monitored by the hybrid instrument once a week over the treatment period of seven weeks. Based on treatment outcomes within one year, patients were classified into a complete response group (CR) and an incomplete response group (IR) with remote metastasis and/or local recurrence. A linear mixed models was used to compare tumor hemodynamic responses to the treatment between the two groups. Interestingly, we found that human papilloma virus (HPV-16) status largely affected tumor hemodynamic responses. For HPV-16 negative tumors, significant differences in blood flow index (BFI, p = 0.007) and reduced scattering coefficient (μs', p = 0.0005) were observed between the two groups; IR tumors exhibited higher μs' values and a continuous increase in BFI over the treatment period. For HPV-16 positive tumors, oxygenated hemoglobin concentration ([HbO2]) and blood oxygen saturation (StO2) were significant different (p = 0.003 and 0.01, respectively); IR group showed lower [HbO2] and StO2. Our results imply HPV-16 negative tumors with higher density of vasculature (μs') and higher blood flow show poor responses to radiotherapy and HPV-16 positive tumors with lower tissue oxygenation level (lower StO2 and [HbO2]) exhibit poor treatment outcomes. Our diffuse optical measurements show the great potential for early prediction of radiotherapy in head and neck cancers.

Noncontact diffuse correlation tomography (ncDCT) is an emerging technology for 3D imaging of deep tissue blood flow distribution without distorting hemodynamic properties. To adapt the ncDCT for imaging in vivo breast tumors, we designed a motorized ncDCT probe to scan over the breast surface. A computer-aided design (CAD)-based approach was proposed to create solid volume mesh from arbitrary breast surface obtained by a commercial 3D camera. The sources and detectors of ncDCT were aligned on the breast surface through ray tracing to mimic the ncDCT scanning with CAD software. The generated breast volume mesh along with the boundary data of ncDCT at the aligned source and detector pairs were used for finite-element-method-based flow image reconstruction. We evaluated the accuracy of source alignments on mannequin and human breasts; largest alignment errors were less than 10% in both tangential and radial directions of scanning. The impact of alignment errors (assigned 10%) on the tumor reconstruction was estimated using computer simulations. The deviations of simulated tumor location and blood flow contrast resulted from the alignment errors were 0.77 mm (less than the node distance of 1 mm) and 1%, respectively, which result in minor impact on flow image reconstruction. Finally, a case study on a human breast tumor was conducted and a tumor-to-normal flow contrast was reconstructed, demonstrating the feasibility of ncDCT in clinical application.

PURPOSE Developed herein is a three-dimensional (3D) flow contrast imaging system leveraging advancements in the extension of laser speckle contrast imaging theories to deep tissues along with our recently developed finite-element diffuse correlation tomography (DCT) reconstruction scheme. This technique, termed speckle contrast diffuse correlation tomography (scDCT), enables incorporation of complex optical property heterogeneities and sample boundaries. When combined with a reflectance-based design, this system facilitates a rapid segue into flow contrast imaging of larger, in vivo applications such as humans. METHODS A highly sensitive CCD camera was integrated into a reflectance-based optical system. Four long-coherence laser source positions were coupled to an optical switch for sequencing of tomographic data acquisition providing multiple projections through the sample. This system was investigated through incorporation of liquid and solid tissue-like phantoms exhibiting optical properties and flow characteristics typical of human tissues. Computer simulations were also performed for comparisons. A uniquely encountered smear correction algorithm was employed to correct point-source illumination contributions during image capture with the frame-transfer CCD and reflectance setup. RESULTS Measurements with scDCT on a homogeneous liquid phantom showed that speckle contrast-based deep flow indices were within 12% of those from standard DCT. Inclusion of a solid phantom submerged below the liquid phantom surface allowed for heterogeneity detection and validation. The heterogeneity was identified successfully by reconstructed 3D flow contrast tomography with scDCT. The heterogeneity center and dimensions and averaged relative flow (within 3%) and localization were in agreement with actuality and computer simulations, respectively. CONCLUSIONS A custom cost-effective CCD-based reflectance 3D flow imaging system demonstrated rapid acquisition of dense boundary data and, with further studies, a high potential for translatability to real tissues with arbitrary boundaries. A requisite correction was also found for measurements in the fashion of scDCT to recover accurate speckle contrast of deep tissues.

Computer simulations with different tissue geometries were conducted to investigate the potential of a novel noncontact diffuse correlation tomography (NC-DCT) system for 3-D imaging of blood flow contrast in breast tumors.

A novel noncontact diffuse correlation tomography (NC-DCT) technique was developed to acquire 3-D blood flow index contrast images from a mouse with dorsal mammary tumors, resulting in evident tumor-healthy contrasts.

This study extended our recently developed noncontact diffuse correlation spectroscopy flowmetry system into noncontact diffuse correlation tomography (ncDCT) for three-dimensional (3-D) flow imaging of deep tissue. A linear array of 15 photodetectors and two laser sources connected to a mobile lens-focusing system enabled automatic and noncontact scanning of flow in a region of interest. These boundary measurements were combined with a finite element framework for DCT image reconstruction implemented into an existing software package. This technique was tested in computer simulations and using a tissue-like phantom with anomaly flow contrast design. The cylindrical tube-shaped anomaly was clearly reconstructed in both simulation and phantom. Recovered and assigned flow contrast changes in anomaly were found to be highly correlated: regression slope = 1.00, R2 = 1.00, and p < 10-5 in simulation and regression slope ≥ 0.97, R2 ≥ 0.96, and p < 10-3 in phantom. These results exhibit promise of our ncDCT technique for 3-D imaging of deep tissue blood flow heterogeneities.

We used a computer-aided-design (CAD) approach to create the solid mesh of breast and align the sources and detectors on the mesh surface for finite element method (FEM) based noncontact diffuse correlation tomography (NC-DCT).

The influences of optical property assumptions on DCS flow index measurements were evaluated by phantom experiments, computer simulation and in-vivo measurements. The results suggest tissue scattering influence is greater than that of absorption.

In this study we evaluate the influences of optical property assumptions on near-infrared diffuse correlation spectroscopy (DCS) flow index measurements. The optical properties, absorption coefficient (µ(a)) and reduced scattering coefficient (µ(s)'), are independently varied using liquid phantoms and measured concurrently with the flow index using a hybrid optical system combining a dual-wavelength DCS flow device with a commercial frequency-domain tissue-oximeter. DCS flow indices are calculated at two wavelengths (785 and 830 nm) using measured µ(a) and µ(s)' or assumed constant µ(a) and µ(s)'. Inaccurate µ(s)' assumptions resulted in much greater flow index errors than inaccurate µ(a). Underestimated/overestimated µ(s)' from -35%/+175% lead to flow index errors of +110%/-80%, whereas underestimated/overestimated µ(a) from -40%/+150% lead to -20%/+40%, regardless of the wavelengths used. Examination of a clinical study involving human head and neck tumors indicates up to +280% flow index errors resulted from inter-patient optical property variations. These findings suggest that studies involving significant µ(a) and µ(s)' changes should concurrently measure flow index and optical properties for accurate extraction of blood flow information.

Muscle blood flow and oxygenation were continuously monitored by diffuse optical spectroscopies during electrical stimulation (ES). Muscle blood flow increased significantly during 5-minute ES and remained high for more than 15 minutes after ES.

A portable diffuse optical tissue flow-oximeter has been developed for evaluation of revascularization effects on ischemic muscle blood flow and oxygenation. The revascularization repairs of macro-circulation result in acute blood flow improvements in muscle microvasculature.

A portable diffuse correlation spectroscopy (DCS) flowmeter has been extended to measure both tissue blood flow and oxygenation (namely, DCS flow oximeter). For validation purposes, calf muscle blood oxygenation during cuff inflation and deflation was measured concurrently using the DCS flow oximeter and a commercial tissue oximeter. The oxygenation traces from the two measurements exhibited similar dynamic responses, and data were highly correlated (r(mean)>0.9, P<10(-5), n=10). The portable, inexpensive, and easy-to-use DCS flow oximeter holds promise for bedside monitoring of tissue blood flow and oxygenation in clinics.