Jonathan T. Elliott

Comparison of time-resolved and continuous-wave near-infrared techniques for measuring cerebral blood flow in piglets.

A primary focus of neurointensive care is monitoring the injured brain to detect harmful events that can impair cerebral blood flow (CBF), resulting in further injury. Since current noninvasive methods used in the clinic can only assess blood flow indirectly, the goal of this research is to develop an optical technique for measuring absolute CBF. A time-resolved near-infrared (TR-NIR) apparatus is built and CBF is determined by a bolus-tracking method using indocyanine green as an intravascular flow tracer. As a first step in the validation of this technique, CBF is measured in newborn piglets to avoid signal contamination from extracerebral tissue. Measurements are acquired under three conditions: normocapnia, hypercapnia, and following carotid occlusion. For comparison, CBF is concurrently measured by a previously developed continuous-wave NIR method. A strong correlation between CBF measurements from the two techniques is revealed with a slope of 0.79±0.06, an intercept of -2.2±2.5 ml∕100 g∕min, and an R2 of 0.810±0.088. Results demonstrate that TR-NIR can measure CBF with reasonable accuracy and is sensitive to flow changes. The discrepancy between the two methods at higher CBF could be caused by differences in depth sensitivities between continuous-wave and time-resolved measurements.

Quantitative measurement of cerebral blood flow in a juvenile porcine model by depth-resolved near-infrared spectroscopy

Nearly half a million children and young adults are affected by traumatic brain injury each year in the United States. Although adequate cerebral blood flow (CBF) is essential to recovery, complications that disrupt blood flow to the brain and exacerbate neurological injury often go undetected because no adequate bedside measure of CBF exists. In this study we validate a depth-resolved, near-infrared spectroscopy (NIRS) technique that provides quantitative CBF measurement despite significant signal contamination from skull and scalp tissue. The respiration rates of eight anesthetized pigs (weight: 16.2+/-0.5 kg, age: 1 to 2 months old) are modulated to achieve a range of CBF levels. Concomitant CBF measurements are performed with NIRS and CT perfusion. A significant correlation between CBF measurements from the two techniques is demonstrated (r(2)=0.714, slope=0.92, p<0.001), and the bias between the two techniques is -2.83 mL min(-1)100 g(-1) (CI(0.95): -19.63 mL min(-1)100 g(-1)-13.9 mL min(-1)100 g(-1)). This study demonstrates that accurate measurements of CBF can be achieved with depth-resolved NIRS despite significant signal contamination from scalp and skull. The ability to measure CBF at the bedside provides a means of detecting, and thereby preventing, secondary ischemia during neurointensive care.

A broadband continuous-wave multichannel near-infrared system for measuring regional cerebral blood flow and oxygen consumption in newborn piglets.

Near-infrared spectroscopy (NIRS) is a promising technique for assessing brain function in newborns, particularly due to its portability and sensitivity to cerebral hemodynamics and oxygenation. Methods for measuring cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO(2)) have been developed based on broadband continuous-wave NIRS. However, broadband NIRS apparatus typically have only one detection channel, which limits their applicability to measuring regional CBF and CMRO(2). In this study, a relatively simple multiplexing approach based on electronically controlled mechanical shutters is proposed to expand the detection capabilities from one to eight channels. The tradeoff is an increase in the sampling interval; however, this has negligible effects on CBF measurements for intervals less than or equal to 1 s. The ability of the system to detect focal brain injury was demonstrated in piglets by injecting endothelin-1 (ET-1) into the cerebral cortex. For validation, CBF was independently measured by computed tomography (CT) perfusion. The average reduction in CBF from the source-detector pair that interrogated the injured region was 51%+/-9%, which was in good agreement with the CBF reduction measured by CT perfusion (55%+/-5%). No significant changes in regional CMRO(2) were observed. The average regional differential pathlength prior to ET-1 injection was 8.4+/-0.2 cm (range of 7.1-9.6 cm) and did not significantly change after the injury.

Broadband continuous-wave technique to measure baseline values and changes in the tissue chromophore concentrations

We present a broad-band, continuous-wave spectral approach to quantify the baseline optical properties of tissue and changes in the concentration of a chromophore, which can assist to quantify the regional blood flow from dynamic contrast-enhanced near-infrared spectroscopy data. Experiments were conducted on phantoms and piglets. The baseline optical properties of tissue were determined by a multi-parameter wavelength-dependent data fit of a photon diffusion equation solution for a homogeneous medium. These baseline optical properties were used to find the changes in Indocyanine green concentration time course in the tissue. The changes were obtained by fitting the dynamic data at the peak wavelength of the chromophore absorption, which were used later to estimate the cerebral blood flow using a bolus tracking method.

Depth resolution and multiexponential lifetime analyses of reflectance-based time-domain fluorescence data

Time-domain fluorescence imaging is a powerful new technique that adds a rich amount of information to conventional fluorescence imaging. Specifically, time-domain fluorescence can be used to remove autofluorescence from signals, resolve multiple fluorophore concentrations, provide information about tissue microenvironments, and, for reflectance-based imaging systems, resolve inclusion depth. The present study provides the theory behind an improved method of analyzing reflectance-based time-domain data that is capable of accurately recovering mixed concentration ratios of multiple fluorescent agents while also recovering the depth of the inclusion. The utility of the approach was demonstrated in a number of simulations and in tissuelike phantom experiments using a short source-detector separation system. The major findings of this study were (1) both depth of an inclusion and accurate ratios of two-fluorophore concentrations can be recovered accurately up to depths of approximately 1 cm with only the optical properties of the medium as prior knowledge, (2) resolving the depth and accounting for the dispersion effects on fluorescent lifetimes is crucial to the accuracy of recovered ratios, and (3) ratios of three-fluorophore concentrations can be resolved at depth but only if the lifetimes of the three fluorophores are used as prior knowledge. By accurately resolving the concentration ratios of two to three fluorophores, it may be possible to remove autofluorescence or carry out quantitative techniques, such as reference tracer kinetic modeling or ratiometric approaches, to determine receptor binding or microenvironment parameters in point-based time-domain fluorescence applications.

Reconstruction of cerebral hemodynamics with dynamic contrast- enhanced time-resolved near-infrared measurements before and during ischemia

We present a dynamic contrast-enhanced near-infrared (DCE-NIR) technique that is capable of non-invasive quantification of cerebral hemodynamics in adults. The challenge of removing extracerebral contamination is overcome through the use of multi-distance time-resolved DCE-NIR combined with the kinetic deconvolution optical reconstruction (KDOR) analytical method. As proof-of-principle, cerebral blood flow, cerebral blood volume and mean transit time recovered with DCE-NIR are compared with CT perfusion values in an adult pig during normocapnia, hypocapnia, and ischemia. Measurements of blood flow acquired with DCE-NIR were compared against concomitant measurements using CT Perfusion.

Kinetic DOT Reconstruction of Contrast-Enhanced Optical Mammography Data for Reader-Independent Lesion Detection

A unified kinetic and diffuse optical tomography reconstruction approach was applied to ICG bolus enhanced, fast optical mammography data for automatic lesion localization based on local enhanced flow and tissue leakage in the tumour region.

Towards Non-Invasive Bedside Monitoring of Cerebral Blood Flow and Oxygen Metabolism in Brain-Injured Patients with Near-Infrared Spectroscopy

Monitoring the injured brain to detect and treat harmful events that can cause secondary injury during the acute recovery period is a central part of neurointensive care. The most basic monitoring tool is the neurological examination, such as the Glasgow Coma Score; however, a large component of this scale involves verbal communication and braininjured patents are often comatose, mechanically ventilated or sedated. As well, symptoms of neurological deterioration detected by examination often occur at late stages of brain injury. Since the brain is extremely vulnerable to ischemia, a more direct indicator of potential brain injury is detecting impaired cerebral blood flow (CBF). Multiple factors following brain injury can cause ischemia, including systemic hypotension, cerebral hemorrhage, and edema – all of which independently worsen survival (Helmy et al., 2007). This focus has lead to the recognition that continuous monitoring of CBF in patients with, or at risk of, brain injury could improve outcome by providing the ability to detect and prevent cerebral ischemia. Imaging techniques, such as magnetic resonance imaging (MRI) and computed tomography (CT), are critical to the management of brain-injured patients as they provide detailed structural and functional information of the brain when patients are admitted to an emergency department (Gallagher et al., 2007). CT is the modality of choice because it is widely available and examination times are relatively short. Furthermore, techniques for measuring CBF have been developed on these imaging modalities (Wintermark et al., 2005) and subsequently used to identify CBF abnormalities following brain injury (DeWitt & Prough, 2003; Gowda et al., 2006; Soustiel et al., 2008). Despite these promising advances, conventional imaging modalities suffer from serious disadvantages regarding cerebral monitoring. First, they require transferring patients to imaging facilities which represents a significant risk factor when dealing with critically ill patients. Second, they only provide a single time-point measurement and, therefore, suffer from the possibility of missing flow abnormalities that occur at different times during intensive care. Clearly, effective cerebral monitoring requires bedside techniques.

Depth-resolved quantitative measurement of cerebral blood flow using broad-band near infrared spectroscopy and a two-layer head model

We propose an algorithm based on a two-layer optical model to quantify CBF from dynamic contrast-enhanced near-infrared data acquired with a two-channel broadband system. The key novel aspect of the algorithm is the ability to separate the contrast agent concentration, indocyanine green (ICG), in extracerebral (EC) tissue and cerebral cortex by representing the (EC) tissue as the top optical layer and the brain as the bottom optical layer. Experiments were conducted on a juvenile pig model. Broadband near-infrared spectra were acquired at source-detectors distances of 1 and 3 cm. The first step of the algorithm was to find the baseline optical properties of the layers by a multi-parameter wavelength-dependent data fit of a photon diffusion equation solution for a two-layer media. The second step was to use the baseline optical properties to separate the ICG concentration time course in brain from the ICG time course in EC tissue. The final step was to calculate CBF from the cerebral ICG time course. The resulting CBF measurements were in good agreement with concurrent measurements acquired by computed tomography, which a difference of 20%.