Motor response investigation in individuals with cerebral palsy using near infrared spectroscopy: pilot study.

Cerebral palsy (CP) describes a group of motor impairment syndromes secondary to genetic that may be due to acquired disorders of the developing brain. In this study, near infrared spectroscopy (NIRS) is used to investigate the prefrontal cortical activation and lateralization in response to the planning and execution of motor skills in controls and individuals with CP. The prefrontal cortex, which plays a dominant role in the planning and execution of motor skill stimulus, is noninvasively imaged using a continuous wave-based NIRS system. During the study, 7 controls (4 right-handed and 3 left-handed) and 2 individuals with CP (1 right-handed and 1 left-handed) over 18 years of age performed 30 s of a ball throwing task followed by 30 s rest in a 5-block paradigm. The optical signal acquired from the NIRS system was processed to elucidate the activation and lateralization in the prefrontal region of controls and individuals with CP. The preliminary result indicated a difference in activation between the task and rest conditions in all the participant types. Bilateral dominance was observed in the prefrontal cortex of controls in response to planning and execution of motor skill tasks, while an ipsilateral dominance was observed in individuals with CP. In conjunction, similar contralateral dominance was observed during rest periods, both in controls and individuals with CP.

Effect of chronic kidney disease induced calcification on peripheral vascular perfusion using near-infrared spectroscopic imaging.

Low-cost techniques that can detect the presence of vascular calcification (VC) in chronic kidney disease (CKD) patients could improve clinical outcomes. In this study, we established a near-infrared spectroscopy-based imaging technique to determine changes in peripheral hemodynamics due to CKD-induced VC. Mice were fed a high-adenine diet with either normal or high levels of phosphate to induce CKD with and without VC, respectively. The mice tail was imaged to evaluate hemodynamic changes in response to occlusion. The rate of change in oxyhemoglobin in response to occlusion showed a statistically significant difference in the presence of VC in the mice.

Resolution of a Gen-2 handheld optical imager: diffuse and fluorescence imaging studies.

A generation-2 (Gen-2) handheld optical imager capable of two-dimensional surface and three-dimensional tomographic imaging has recently been developed. Herein, the ability of the handheld imager to detect and resolve two targets under diffuse and fluorescence imaging conditions has been demonstrated via tissue phantom studies. Two-dimensional surface imaging studies demonstrated that two 0.96 cm diameter Indocyannine Green targets were detected and resolved ~0.5 cm apart (between edges) at a target depth of 1 cm during diffuse imaging and up to 2 cm depth during fluorescence imaging. Preliminary 3D tomographic imaging capability to resolve the two targets was also demonstrated, but requires extensive future studies.

Diabetic Foot Ulcer Imaging: An Overview and Future Directions.

Diabetic foot ulcers (DFUs) affect one in every three people with diabetes. Imaging plays a vital role in objectively complementing the gold-standard visual yet subjective clinical assessments of DFUs during the wound treatment process. Herein, an overview of the various imaging techniques used to image DFUs is summarized. Conventional imaging modalities (e.g., computed tomography, magnetic resonance imaging, positron emission tomography, single-photon emitted computed tomography, and ultrasound) are used to diagnose infections, impact on the bones, foot deformities, and blood flow in patients with DFUs. Transcutaneous oximetry is a gold standard to assess perfusion in DFU cases with vascular issues. For a wound to heal, an adequate oxygen supply is needed to facilitate reparative processes. Several optical imaging modalities can assess tissue oxygenation changes in and around the wounds apart from perfusion measurements. These include hyperspectral imaging, multispectral imaging, diffuse reflectance spectroscopy, near-infrared (NIR) spectroscopy, laser Doppler flowmetry or imaging, and spatial frequency domain imaging. While perfusion measurements are dynamically monitored at point locations, tissue oxygenation measurements are static two-dimensional spatial maps. Recently, we developed a spatio-temporal NIR-based tissue oxygenation imaging approach to map for the extent of asynchrony in the oxygenation flow patterns in and around DFUs. Researchers also measure other parameters such as thermal maps, bacterial infections (from fluorescence maps), pH, collagen, and trans-epidermal water loss to assess DFUs. A future direction for DFU imaging would ideally be a low-cost, portable, multi-modal imaging platform that can provide a visual and physiological assessment of wounds for comprehensive wound care intervention and management.

Spatial-Temporal Oxygenation Mapping Using a Near-Infrared Optical Scanner: Towards Peripheral Vascular Imaging.

Near-infrared spectroscopy (NIRS)-based peripheral perfusion, or microcirculation, can be used to assess the severity of peripheral vascular dysfunction. A low-cost, portable non-contact near-infrared optical scanner (NIROS) was developed for spatio-temporal mapping of tissue oxygenation and perfusion in tissues. In vivo validation studies were carried out on control subjects (n = 3) to assess the ability of NIROS to measure real-time oxygenation changes in response to an occlusion paradigm on the dorsum of the hand. NIROS captured real-time tissue oxygenation changes with 95% correlation when compared to a commercial device. A feasibility peripheral imaging study was performed in a mouse model (n = 5) of chronic kidney disease (CKD) induced vascular calcification to assess differences in microcirculatory peripheral tissue oxygenation. The tissue oxygenation (in terms of oxy-, deoxy-, and total hemoglobin changes) due to the occlusion paradigm was distinctly different prior to (week-6) and after the onset of vascular calcification (week-12) in the murine tails. Future work will involve extensive studies to correlate these microcirculatory tissue oxygenation changes in the peripheral tail to the vascular calcification in the heart.

Gen-2 hand-held optical imager towards cancer imaging: reflectance and transillumination phantom studies.

Hand-held near-infrared (NIR) optical imagers are developed by various researchers towards non-invasive clinical breast imaging. Unlike these existing imagers that can perform only reflectance imaging, a generation-2 (Gen-2) hand-held optical imager has been recently developed to perform both reflectance and transillumination imaging. The unique forked design of the hand-held probe head(s) allows for reflectance imaging (as in ultrasound) and transillumination or compressed imaging (as in X-ray mammography). Phantom studies were performed to demonstrate two-dimensional (2D) target detection via reflectance and transillumination imaging at various target depths (1-5 cm deep) and using simultaneous multiple point illumination approach. It was observed that 0.45 cc targets were detected up to 5 cm deep during transillumination, but limited to 2.5 cm deep during reflectance imaging. Additionally, implementing appropriate data post-processing techniques along with a polynomial fitting approach, to plot 2D surface contours of the detected signal, yields distinct target detectability and localization. The ability of the gen-2 imager to perform both reflectance and transillumination imaging allows its direct comparison to ultrasound and X-ray mammography results, respectively, in future clinical breast imaging studies.

Tissue Oxygenation Measurements to Aid Scalpel Debridement Removal in Patients With Diabetes.

BACKGROUND: Callus formation in the diabetic foot increases the risk of ulcer onset. It is standard procedure to remove these dead tissue layers to reduce rising pressures. In a surgical procedure known as scalpel debridement, or chiropody the callus tissue is removed up to the epidermal layer. Factors may influence the outcome of this surgical process such as clinician inexperience. In an effort to standardize the debridement process, tissue oxygenation (TO) measurements are obtained before and after to study the effect of debridement on callus tissue. METHODS: Fifteen debridement cases were analyzed using near infrared (NIR) imaging to study changes in TO. The NIR-based device used in this study estimates effective changes in TO in terms of oxy-, deoxy-, total hemoglobin, and oxygen saturation. Weber contrasts between callus tissue and the surrounding normal tissue were compared following debridement for all TO parameters. In a secondary analysis, callus tissue was segmented into quadrants and a percent of significance (in terms of total TO change) was calculated using a t-test. RESULTS: Results show majority of cases displayed greater than 80% as the significant change in TO following debridement, except in cases with the presence of blood clot (a common precursor for ulceration). In cases where incomplete debridement was suspected, a significant change in TO was still observed. CONCLUSIONS: With extensive systematic studies in the future, NIR imaging technique to measure changes in TO may be implemented as a low-cost hand-held imaging device useful for objectively assessing the effectiveness of the scalpel debridement process.

Assessment of Tissue Oxygenation and Radiation Dermatitis Pre-, During, and Post-Radiation Therapy in Breast Cancer Patients.

Over 95% of breast cancer patients treated with radiation therapy (RT) undergo an adverse skin reaction known as radiation dermatitis (RD). Assessment of severity or grading of RD is clinically visual and hence subjective. Our objective is to determine sub-clinical tissue oxygenation (oxygen saturation) changes in response to RT in breast cancer patients using near-infrared spectroscopic imaging and correlate these changes to RD grading. A 4-8 week longitudinal pilot imaging study was carried out on 10 RT-treated breast cancer patients. Non-contact near-infrared spectroscopic (NIRS) imaging was performed on the irradiated ipsilateral and the contralateral breast/chest wall, axilla and lower neck regions before RT, across the weeks of RT, and during follow-up after RT ended. Significant changes (p < 0.05) in oxygen saturation (StO2) of irradiated and contralateral breast/chest wall and axilla regions were observed across weeks of RT. The overall drop in StO2 was negatively correlated to RD scaling (in 7 out of 9 cases) and was higher in the irradiated regions when compared to its contralateral region. Differences in the pre-RT StO2 between ipsilateral and contralateral chest wall is a potential predictor of the severity of RD. The subclinical recovery of StO2 to its original state was longer than the visual recovery in RD grading scale, as observed from the post-RT assessment of tissue oxygenation.

Development of a Smartphone-Based Optical Device to Measure Hemoglobin Concentration Changes for Remote Monitoring of Wounds.

Telemedicine (TM) can revolutionize the impact of diabetic wound care management, along with tools for remote patient monitoring (RPM). There are no low-cost mobile RPM devices for TM technology to provide comprehensive (visual and physiological) clinical assessments. Here, a novel low-cost smartphone-based optical imaging device has been developed to provide physiological measurements of tissues in terms of hemoglobin concentration maps. The device (SmartPhone Oxygenation Tool-SPOT) constitutes an add-on optical module, a smartphone, and a custom app to automate data acquisition while syncing a multi-wavelength near-infrared light-emitting diode (LED) light source (690, 810, 830 nm). The optimal imaging conditions of the SPOT device were determined from signal-to-noise maps. A standard vascular occlusion test was performed in three control subjects to observe changes in hemoglobin concentration maps between rest, occlusion, and release time points on the dorsal of the hand. Hemoglobin concentration maps were compared with and without applying an image de-noising algorithm, single value decomposition. Statistical analysis demonstrated that the hemoglobin concentrations changed significantly across the three-time stamps. Ongoing efforts are in imaging diabetic foot ulcers using the SPOT device to assess its potential as a smart health device for physiological monitoring of wounds remotely.

Multi-projection fluorescence optical tomography using a handheld-probe-based optical imager: phantom studies.

A handheld-probe-based optical imager has recently been developed toward three-dimensional tomography. In this study, the improvement of target depth recovery was demonstrated using a multi-projection technique on large slab phantoms using 0.45 cc fluorescing target(s) (with 1:0 contrast ratio) of 1.5 to 2.5 cm deep. Tomographic results using single- and multi- (here dual) projection measurements (with and without a priori information of target location) were compared. In all experimental cases, the use of multi-projection measurements along with a priori information recovered target depth and location closer to their true values, demonstrating its applicability for clinical translation.

Fluorescence tomographic imaging using a handheld-probe-based optical imager: extensive phantom studies.

Handheld-probe-based optical imagers are a popular approach toward breast imaging because of their potential portability and maximum patient comfort. A novel handheld-probe-based optical imager has been developed and its feasibility for three-dimensional fluorescence tomographic imaging demonstrated. Extensive tomography studies were performed on large slab phantoms (650 ml) to assess the performance limits of the handheld imager. Experiments were performed by using different target volumes (0.1-0.45 cm3), target depths (1-3 cm), and fluorescence (Indocyanine Green) absorption contrast ratios in a nonfluorescing (1:0) and constant fluorescing backgrounds (1000:1 to 5:1). The estimated sensitivity and specificity of the handheld imager are 43% and 95%, respectively.

Development and Validation of a Smartphone-Based Near-Infrared Optical Imaging Device to Measure Physiological Changes In-Vivo.

Smartphone-based technologies for medical imaging purposes are limited, especially when it involves the measurement of physiological information of the tissues. Herein, a smartphone-based near-infrared (NIR) imaging device was developed to measure physiological changes in tissues across a wide area and without contact. A custom attachment containing multiple multi-wavelength LED light sources (690, 800, and 840 nm; and <4 mW of optical power per LED), source driver, and optical filters and lenses was clipped onto a smartphone that served as the detector during data acquisition. The ability of the device to measure physiological changes was validated via occlusion studies on control subjects. Noise removal techniques using singular value decomposition algorithms effectively removed surface noise and distinctly differentiated the physiological changes in response to occlusion. In the long term, the developed smartphone-based NIR imaging device with capabilities to capture physiological changes will be a great low-cost alternative for clinicians and eventually for patients with chronic ulcers and bed sores, and/or in pre-screening for potential ulcers in diabetic subjects.

Breath-Hold Paradigm to Assess Variations in Oxygen Flow in Diabetic Foot Ulcers Using a Noncontact Near-Infrared Optical Scanner.

Objective: Diabetic foot ulcers (DFUs) occur in almost 25% of all patients with diabetes in their lifetime, with oxygen being the key limiting factor in healing. Identifying regions of compromised oxygenated flow can help clinicians cater the wound treatment process, possibly reducing wound healing time. Herein, a handheld, noncontact near-infrared optical scanner (NIROS) was developed and used to measure temporal changes in hemoglobin concentrations in response to a breath-hold (BH) paradigm. Approach: Noncontact imaging studies were carried out on DFU subjects and control subjects in response to a 20-s BH paradigm. Continuous-wave-based multiwavelength diffused reflective signals were acquired to generate effective oxy-hemoglobin, deoxy-hemoglobin, total hemoglobin, and oxygen saturation concentration maps using modified Beer-Lambert's law. Pearson's correlation analysis was carried out to determine variations in oxygen flow from hemoglobin concentration maps and the extent of variation observed in controls versus DFU subjects. Results: Temporal changes in hemoglobin concentration maps were observed in controls and DFU subjects. However, the oxygen flow in response to BH varied within 10% in all controls but significantly varied between wound and background regions in subjects with DFUs. Innovation: A method to assess variations in oxygen supply in and around DFUs was demonstrated using NIROS. This approach has potential to better cater DFU treatment process. Conclusion: Changes in all hemoglobin parameters due to 20 s of BH was observed. Pearson's analysis indicates that oxy-hemoglobin, deoxy-hemoglobin, and oxygen saturation fluctuations are synchronous in controls. In DFUs, changes are asynchronous with blood flow between the wound region and background region being significantly different.

Tissue Oxygenation Changes to Assess Healing in Venous Leg Ulcers Using Near-Infrared Optical Imaging.

Objective: Venous leg ulcers (VLUs) comprise 80% of leg ulcers. One of the key parameters that can promote healing of VLUs is tissue oxygenation. To date, clinicians have employed visual inspection of the wound site to determine the healing progression of a wound. Clinicians measure the wound size and check for epithelialization. Imaging for tissue oxygenation changes surrounding the wounds can objectively complement the subjective visual inspection approach. Herein, a handheld noncontact near-infrared optical scanner (NIROS) was developed to measure tissue oxygenation of VLUs during weeks of treatment. Approach: Continuous-wave-based diffuse reflectance measurements were processed using Modified Beer-Lambert's law to obtain changes in tissue oxygenation (in terms of oxy-, deoxy-, total hemoglobin, and oxygen saturation). The tissue oxygenation contrast obtained between the wound and surrounding tissue was longitudinally mapped across weeks of treatment of four VLUs (healing and nonhealing cases). Results: It was observed that wound to background tissue oxygenation contrasts in healing wounds diminished and/or stabilized, whereas in the nonhealing wounds it did not. In addition, in a very slow-healing wound, wound to background tissue oxygenation contrasts fluctuated and did not converge. Innovation: Near-infrared imaging of wounds to assess healing or nonhealing of VLUs from tissue oxygenation changes using a noncontact, handheld, and low-cost imager has been demonstrated for the first time. Conclusion: The tissue oxygenation changes in wound with respect to the surrounding tissue can provide an objective subclinical physiological assessment of VLUs during their treatment, along with the gold-standard visual clinical assessment.

Three-dimensional fluorescence-enhanced optical tomography using a hand-held probe based imaging system.

Hand-held based optical imaging systems are a recent development towards diagnostic imaging of breast cancer. To date, all the hand-held based optical imagers are used to perform only surface mapping and target localization, but are not capable of demonstrating tomographic imaging. Herein, a novel hand-held probe based optical imager is developed towards three-dimensional (3-D) optical tomography studies. The unique features of this optical imager, which primarily consists of a hand-held probe and an intensified charge coupled device detector, are its ability to; (i) image large tissue areas (5 x 10 sq. cm) in a single scan, (ii) perform simultaneous multiple point illumination and collection, thus reducing the overall imaging time; and (iii) adapt to varying tissue curvatures, from a flexible probe head design. Experimental studies are performed in the frequency domain on large slab phantoms (approximately 650 ml) using fluorescence target(s) under perfect uptake (1:0) contrast ratios, and varying target depths (1-2 cm) and X-Y locations. The effect of implementing simultaneous over sequential multiple point illumination towards 3-D tomography is experimentally demonstrated. The feasibility of 3-D optical tomography studies has been demonstrated for the first time using a hand-held based optical imager. Preliminary fluorescence-enhanced optical tomography studies are able to reconstruct 0.45 ml target(s) located at different target depths (1-2 cm). However, the depth recovery was limited as the actual target depth increased, since only reflectance measurements were acquired. Extensive tomography studies are currently carried out to determine the resolution and performance limits of the imager on flat and curved phantoms.

Assessing the Healing of Venous Leg Ulcers Using a Noncontact Near-Infrared Optical Imaging Approach.

Objective: Venous leg ulcers (VLUs) are one of the most common complications in lower extremity wounds. To date, clinicians employ visual inspection of the wound site during its healing process by monitoring surface granulation and reduction in wound size across weeks of treatment. In this study, a handheld near-infrared optical scanner (NIROS) has been developed at the Optical Imaging Laboratory to differentiate healing from nonhealing VLUs based on differences in blood flow to the wound and its surroundings. Approach: Noncontact near-infrared (NIR) area imaging of 12 VLUs have been carried out at two podiatric clinics. Diffuse reflectance images of the wounds were used to quantify optical contrasts between the wound and its surroundings. The variability in imaging conditions, analysis, and operator dependency were assessed to determine the robustness of the imaging approach. Results: Optical contrast obtained from diffuse reflectance images of VLUs were distinctly different for healing (positive contrast) and nonhealing (negative contrast) wounds, independent of the varying imaging and data analysis conditions. Innovation: NIR imaging of wounds to differentiate healing from nonhealing VLUs using a noncontact wide-area imager has been demonstrated for the first time. Conclusion: The application of a portable handheld imager to assess the healing or nonhealing nature of VLUs during weekly clinical treatment is significant since physiological changes, as observed using NIROS, manifest before visual reduction in wound size during the healing process.

Design and development of a hand-held optical probe toward fluorescence diagnostic imaging.

Near-infrared optical imaging is an emerging noninvasive technology toward breast cancer diagnosis. The optical imaging systems available to date are limited either by flexibility to image any given breast volume, patient comfort, or instrument portability. Here, a hand-held optical probe is designed and developed, 1. employing a unique measurement scheme of simultaneous multiple point illumination and collection for rapid data acquisition and minimal patient discomfort, and 2. employing a curved probe head such that it allows flexible imaging of tissue curvatures. Simulation studies are carried out on homogeneous slab phantoms (5x10x8 cc) to determine an appropriate source-detector configuration for the probe head. These design features are implemented in the development of the probe, which consisted of six simultaneous illuminating and 165 simultaneous collecting fibers, spaced 0.5 cm apart on a 5x10 sq-cm probe head. Simulation studies on 3-D slab and curved phantoms demonstrate an increase in the total area of predicted fluorescence amplitude and overall signal strength on using simultaneous multiple point sources over a single point source. The probe is designed and developed such that on coupling with a detection system in the future, the hand-held probe based imager can be clinically assessed toward cancer diagnostic imaging.

Fluorescence-enhanced three-dimensional lifetime imaging: a phantom study.

Near-infrared fluorescence optical imaging has the unique opportunity of differentiating diseased lesions from normal lesions based upon environmentally indicated changes in the lifetime of a fluorescent imaging agent. In this paper, we demonstrate three-dimensional lifetime tomography using the gradient-based penalty modified barrier function with simple bounds truncated Newton with trust region method to reconstruct lifetime maps in a clinically relevant, single breast-shaped ( approximately 1081 cm(3)) phantom from point-frequency-domain photon migration measurements at 100 MHz. A reverse differentiation technique is used to calculate the gradients. This algorithm is desirable because the storage benefit from the use of the truncated Newton method and the reverse differentiation technique increase the speed. Two fluorescent contrast agents, indocyanine green and 3-3'-diethylthiatricarbocyanine iodide which differed in their fluorescence lifetimes by 0.62 ns, were used. Images of targets at a depth of 2.0 cm and target-to-background ratios (T:B) of 212:1 and 70:1 in fluoroscence absorption and 1:2.1 and 2.1:1 in lifetimes are successfully reconstructed. Our results show that image reconstruction is possible when there is (i) a longer lifetime in a target than the background and (ii) a shorter lifetime in a target than the background.

Fluorescence-enhanced optical tomography of a large tissue phantom using point illumination geometries.

We demonstrate fluorescence-enhanced optical imaging of single and multiple fluorescent targets within a large (approximately 1081 cm3) phantom using frequency-domain photon migration measurements of fluorescence collected at individual points in response to illumination of excitation light at individual points on the boundary. The tissue phantom was filled with a 1% lipid solution with and without 0.01 microM Indocyanine Green (ICG) and targets consisted of vials filled with the 1% lipid containing 1-2.5 microM ICG. Measurements were acquired using a modulated intensified CCD imaging system under different experimental conditions. For 3-D image reconstruction, the gradient-based penalty modified barrier function (PMBF) method with simple bounds constrained truncated Newton with trust region method (CONTN) was used. Targets of 0.5, 0.6, and 1.0 cm3 at depths of 1.4-2.8 cm from the phantom surface were tomographically reconstructed. This work demonstrates the practicality of fluorescence-enhanced tomography in clinically relevant volumes.

Near-Infrared Fluorescence-Enhanced Optical Tomography.

Fluorescence-enhanced optical imaging using near-infrared (NIR) light developed for in vivo molecular targeting and reporting of cancer provides promising opportunities for diagnostic imaging. The current state of the art of NIR fluorescence-enhanced optical tomography is reviewed in the context of the principle of fluorescence, the different measurement schemes employed, and the mathematical tools established to tomographically reconstruct the fluorescence optical properties in various tissue domains. Finally, we discuss the recent advances in forward modeling and distributed memory parallel computation to provide robust, accurate, and fast fluorescence-enhanced optical tomography.