Joseph P. Culver

Diffuse Optical Tomography of Cerebral Blood Flow, Oxygenation, and Metabolism in Rat during Focal Ischemia

Diffuse optical tomography (DOT) is an attractive approach for evaluating stroke physiology. It provides hemodynamic and metabolic imaging with unique potential for continuous noninvasive bedside imaging in humans. To date there have been few quantitative spatial-temporal studies of stroke pathophysiology based on diffuse optical signatures. The authors report DOT images of hemodynamic and metabolic contrasts using a rat middle cerebral artery occlusion (MCAO) stroke model. This study used a novel DOT device that concurrently obtains coregistered images of relative cerebral blood volume (rCBV), tissue-averaged hemoglobin oxygen saturation (Sto2), and relative cerebral blood flow (rCBF). The authors demonstrate how these hemodynamic measures can be synthesized to calculate an index of the oxygen extraction fraction (OEF) and the cerebral metabolic rate of oxygen consumption (CMRo2). Temporary (60-minute) MCAO was performed on five rats. Ischemic changes, averaged over the 60 minutes of occlusion, were as follows: rCBF = 0.42 ± 0.04, rCBV = 1.02 ± 0.04, ΔSto2 = −11 ± 2%, rOEF = 1.39 ± 0.06 and rCMRo2 = 0.59 ± 0.07. Although rOEF increased in response to decreased blood flow, rCMRo2 decreased. The sensitivity of this method of DOT analysis is discussed in terms of assumptions about baseline physiology, and the diffuse optical results are compared with positron emission tomography, magnetic resonance imaging, and histology observations in the literature.

In vivo cerebrovascular measurement combining diffuse near-infrared absorption and correlation spectroscopies

We combine two near-infrared diffuse optical techniques to study variations of blood flow, haemoglobin concentration, and blood oxygen saturation in the functioning rat brain. Diffuse correlation spectroscopy (or flowmetry) monitors changes in the cerebral blood flow, without the use of the principles of tracer clearance, by measuring the optical phase-shifts caused by moving blood cells. Near-infrared absorption spectroscopy concurrently measures tissue absorption at two wavelengths to determine haemoglobin concentration and blood oxygen saturation in this same tissue volume. This optical probe is non-invasive and was employed through the intact skull. The utility of the technique is demonstrated in vivo by measuring the temporal changes in the regional vascular dynamics of rat brain during hypercapnia. Temporal and spatial variations of cerebral blood flow, haemoglobin concentration and blood oxygen saturation during hypercapnia are compared with other measurements in the literature, and a quantitative analysis demonstrating the self-consistency of our combined observations of vascular response is presented.

Hemodynamic evoked response of the sensorimotor cortex measured noninvasively with near-infrared optical imaging

We have performed a noninvasive bilateral optical imaging study of the hemodynamic evoked response to unilateral finger opposition task, finger tactile, and electrical median nerve stimulation in the human sensorimotor cortex. This optical study shows the hemoglobin-evoked response to voluntary and nonvoluntary stimuli. We performed measurements on 10 healthy volunteers using block paradigms for motor, sensory, and electrical stimulations of the right and left hands separately. We analyzed the spatial/temporal features and the amplitude of the optical signal induced by cerebral activation during these three paradigms. We consistently found an increase (decrease) in the cerebral concentration of oxy-hemoglobin (deoxy-hemoglobin) at the cortical side contralateral to the stimulated side. We observed an optical response to activation that was larger in size and amplitude during voluntary motor task compared to the other two stimulations. The ipsilateral response was consistently smaller than the contralateral response, and even reversed (i.e., a decrease in oxy-hemoglobin, and an increase in deoxy-hemoglobin) in the case of the electrical stimulation. We observed a systemic contribution to the optical signal from the increase in the heart rate increase during stimulation, and we made a first attempt to subtract it from the evoked hemoglobin signal. Our findings based on optical imaging are in agreement with results in the literature obtained with positron emission tomography and functional magnetic resonance imaging.

Volumetric diffuse optical tomography of brain activity

We present three-dimensional diffuse optical tomography of the hemodynamic response to somatosensory stimulation in a rat. These images show the feasibility of volumetrically imaging the functional response to brain activity with diffuse light. A combination of positional optode calibration and contrast-to-noise ratio weighting was found to improve imaging performance.

Reconstructing chromosphere concentration images directly by continuous-wave diffuse optical tomography

We present an algorithm to reconstruct chromosphere concentration images directly rather than following the traditional two-step process of reconstructing wavelength-dependent absorption coefficient images and then calculating chromosphere concentration images. This procedure imposes prior spectral information into the image reconstruction that results in a dramatic improvement in the image contrast-to-noise ratio of better than 100%. We demonstrate this improvement with simulations and a dynamic blood phantom experiment.

Temporal comparison of functional brain imaging with diffuse optical tomography and fMRI during rat forepaw stimulation

The time courses of oxyhaemoglobin ([HbO2]), deoxyhaemoglobin ([HbR]) and total haemoglobin ([HbT]) concentration changes following cortical activation in rats by electrical forepaw stimulation were measured using diffuse optical tomography (DOT) and compared to similar measurements performed previously with fMRI at 2.0 T and 4.7 T. We also explored the qualitative effects of varying stimulus parameters on the temporal evolution of the hemodynamic response. DOT images were reconstructed at a depth of 1.5 mm over a 1 cm square area from 2 mm anterior to bregma to 8 mm posterior to bregma. The measurement set included 9 sources and 16 detectors with an imaging frame rate of 10 Hz. Both DOT [HbR] and [HbO2] time courses were compared to the fMRI BOLD time course during stimulation, and the DOT [HbT] time course was compared to the fMRI cerebral plasma volume (CPV) time course. We believe that DOT and fMRI can provide similar temporal information for both blood volume and deoxyhaemoglobin changes, which helps to cross-validate these two techniques and to demonstrate that DOT can be useful as a complementary modality to fMRI for investigating the hemodynamic response to neuronal activity.

Singular-value analysis and optimization of experimental parameters in fluorescence molecular tomography

The advent of specific molecular markers and probes employing optical reporters has encouraged the application of in vivo diffuse tomographic imaging at greater spatial resolutions and hence data-set volumes. This study applied singular-value analysis (SVA) of the fluorescence tomographic problem to determine optimal source and detector distributions that result in data sets that are balanced between information content and size. Weight matrices describing the tomographic forward problem were constructed for a range of source and detector distributions and fields of view and were decomposed into their associated singular values. These singular-value spectra were then compared so that we could observe the effects of each parameter on imaging performance. The findings of the SVA were then confirmed by examining reconstructions of simulated and experimental data acquired with the same optode distributions as examined by SVA. It was seen that for a 20-mm target width, which is relevant to the small-animal imaging situation, the source and detector fields of view should be set at approximately 30 mm. Equal numbers of sources and detectors result in the best imaging performance in the parallel-plate geometry and should be employed when logistically feasible. These data provide guidelines for the design of small-animal diffuse optical tomographic imaging systems and demonstrate the utility of SVA as a simple and efficient means of optimizing experimental parameters in problems for which a forward model of the data collection process is available.

Robust inference of baseline optical properties of the human head with three-dimensional segmentation from magnetic resonance imaging

We model the capability of a small (6-optode) time-resolved diffuse optical tomography (DOT) system to infer baseline absorption and reduced scattering coefficients of the tissues of the human head (scalp, skull, and brain). Our heterogeneous three-dimensional diffusion forward model uses tissue geometry from segmented magnetic resonance (MR) data. Handling the inverse problem by use of Bayesian inference and introducing a realistic noise model, we predict coefficient error bars in terms of detected photon number and assumed model error. We demonstrate the large improvement that a MR-segmented model can provide: 2-10% error in brain coefficients (for 2 x 10(6) photons, 5% model error). We sample from the exact posterior and show robustness to numerical model error. This opens up the possibility of simultaneous DOT and MR for quantitative cortically constrained functional neuroimaging.

Optode positional calibration in diffuse optical tomography

Although diffuse optical tomography is a highly promising technique used to noninvasively image blood volume and oxygenation, the reconstructed data are sensitive to systemic difference between the forward model and the actual experimental conditions. In particular, small changes in optode location or in the optode-tissue coupling coefficient significantly degrade the quality of the reconstruction images. Accurate system calibration therefore is an essential part of any experimental protocol. We present a technique for simultaneously calibrating optode positions and reconstructing images that significantly improves image quality, as we demonstrate with simulations and phantom experiments.

Refractive index matching of tissue components as a new technology for correlation and diffusing-photon spectroscopy and imaging

The refractive index matching of components of highly scattering tissue has a strong influence on its transmittance and reflectance what can be considered as a new tool for imaging within relatively thick tissues. We present experimental data on various solutions, gels and oils influence on optical properties of in vivo human eye and in vivo human skin. The dynamics of tissue optical properties depending on matter diffusion rate within tissue is studied. The possible application of refractive index matching effect for diffusing-photon imaging is discussed.