Biomedical subjects

David A Boas

Publications and source records attributed to David A Boas.

At least 19 recordsLinked to original sources

PubMed2007

Depth-resolved optical imaging and microscopy of vascular compartment dynamics during somatosensory stimulation.

The cortical hemodynamic response to somatosensory stimulus is investigated at the level of individual vascular compartments using both depth-resolved optical imaging and in-vivo two-photon microscopy. We utilize a new imaging and spatiotemporal analysis approach that exploits the different characteristic dynamics of responding arteries, arterioles, capillaries and veins to isolate their three-dimensional spatial extent within the cortex. This spatial delineation is validated using vascular casts. Temporal delineation is supported by in-vivo two-photon microscopy of the temporal dynamics and vascular mechanisms of the arteriolar and venous responses. Using these techniques we have been able to characterize the roles of the different vascular compartments in generating and controlling the hemodynamic response to somatosensory stimulus. We find that changes in arteriolar total hemoglobin concentration agree well with arteriolar dilation dynamics, which in turn correspond closely with changes in venous blood flow. For 4-s stimuli, we see only small changes in venous hemoglobin concentration, and do not detect measurable dilation or ballooning in the veins. Instead, we see significant evidence of capillary hyperemia. We compare our findings to historical observations of the composite hemodynamic response from other modalities including functional magnetic resonance imaging. Implications of our results are discussed with respect to mathematical models of cortical hemodynamics, and to current theories on the mechanisms underlying neurovascular coupling. We also conclude that our spatiotemporal analysis approach is capable of isolating and localizing signals from the capillary bed local to neuronal activation, and holds promise for improving the specificity of other hemodynamic imaging modalities.

Animals↗

PubMed2007

A multicompartment vascular model for inferring baseline and functional changes in cerebral oxygen metabolism and arterial dilation.

Functional hemodynamic responses are the composite results of underlying variations in cerebral oxygen consumption and the dilation of arterial vessels after neuronal activity. The development of biophysically based models of the cerebral vasculature allows the separation of the neuro-metabolic and neuro-vascular influences on measurable hemodynamic signals such as functional magnetic resonance imaging or optical imaging. We describe a multicompartment model of the vascular and oxygen transport dynamics associated with stimulus-driven neuronal activation. Our model offers several unique features compared with previous formulations such as the ability to estimate baseline blood flow, volume, and oxygen consumption from functional data. In addition, we introduce a capillary compliance model, arterial and venous oxygen permeability, and model the dynamics of extravascular tissue oxygenation. We apply this model to multimodal optical spectroscopic and laser speckle imaging of the rat somato-sensory cortex during nine conditions of whisker stimulation. By fitting the model using a psuedo-Bayesian framework to incorporate multimodal observations, we estimate baseline blood flow to be 94 (+/-15) mL/100 g min and baseline oxygen consumption to be 6.7 (+/-1.3) mL O(2)/100 g min. We calculate parametric, linear increases in arterial dilation (R(2)=0.96) and CMRO(2) (R(2)=0.87) responses over the nine conditions. Other parameters estimated by the model include vascular transit time and volume reserve, oxygen content, saturation, diffusivity rate constants, and partial pressure of oxygen in the vascular compartments and in the extravascular tissue. Finally, we compare this model to earlier work and find that the multicompartment model more accurately describes the observed oxygenation changes when compared with a single compartment version.

Arteries↗

PubMed2006

Diffuse optical tomography system to image brain activation with improved spatial resolution and validation with functional magnetic resonance imaging.

Although most current diffuse optical brain imaging systems use only nearest- neighbor measurement geometry, the spatial resolution and quantitative accuracy of the imaging can be improved through the collection of overlapping sets of measurements. A continuous-wave diffuse optical imaging system that combines frequency encoding with time-division multiplexing to facilitate overlapping measurements of brain activation is described. Phantom measurements to confirm the expected improvement in spatial resolution and quantitative accuracy are presented. Experimental results showing the application of this instrument for imaging human brain activation are also presented. The observed improvement in spatial resolution is confirmed by functional magnetic resonance imaging.

Brain↗

PubMed2006

Assessing infants' cortical response to speech using near-infrared spectroscopy.

Sensitivity to spoken language is an integral part of infants' formative development, yet relatively little is known about the neural mechanisms that underlie the emerging ability to perceive and process speech. This is in large part because there are a limited number of non-invasive techniques available to measure brain functioning in human infants. Near-infrared spectroscopy (NIRS), an optical imaging technique that estimates changes in neuronal activity by measuring changes in total hemoglobin concentration and oxygenation, may be a viable procedure for assessing the relation between speech processing and brain function in human infants. While auditory processing data have been gathered from newborn and preterm infants using NIRS, such data have not been collected from older infants. Many behavioral measures used to establish linguistic sensitivity in this population are accompanied by visual stimuli; however, it is unclear how coupling of auditory and visual stimuli influences neural processing. Here we studied cortical activity in infants aged 6-9 months, as measured by NIRS, during exposure to linguistic stimuli paired with visual stimuli and compared this to the activity observed in the same regions during exposure to visual stimuli alone. Results dissociate infants' hemodynamic responses to multimodal and unimodal stimuli, demonstrating the utility of NIRS for studying perceptual development in infants. In particular, these findings support the use of NIRS to study the neurobiology of language development in older infants, a task that is difficult to accomplish without the use of attention-getting visual stimuli.

Female↗

PubMed2006

Rho-kinase inhibition acutely augments blood flow in focal cerebral ischemia via endothelial mechanisms.

Rho-kinase is a serine threonine kinase that increases vasomotor tone via its effects on both endothelium and smooth muscle. Rho-kinase inhibition reduces cerebral infarct size in wild type, but not endothelial nitric oxide synthase deficient (eNOS-/-) mice. The mechanism may be related to Rho-kinase activation under hypoxic/ischemic conditions and impaired vasodilation because of downregulation of eNOS activity. To further implicate Rho-kinase in impaired vascular relaxation during hypoxia/ischemia, we exposed isolated vessels from rat and mouse to 60 mins of hypoxia, and showed that hypoxia reversibly abolished acetylcholine-induced eNOS-dependent relaxation, and that Rho-kinase inhibitor hydroxyfasudil partially preserved this relaxation during hypoxia. We, therefore, hypothesized that if hypoxia-induced Rho-kinase activation acutely impairs vasodilation in ischemic cortex, in vivo, then Rho-kinase inhibitors would acutely augment cerebral blood flow (CBF) as a mechanism by which they reduce infarct size. To test this, we studied the acute cerebral hemodynamic effects of Rho-kinase inhibitors in ischemic core and penumbra during distal middle cerebral artery occlusion (dMCAO) in wild-type and eNOS-/- mice using laser speckle flowmetry. When administered 60 mins before or immediately after dMCAO, Rho-kinase inhibitors hydroxyfasudil and Y-27632 reduced the area of severely ischemic cortex. However, hydroxyfasudil did not reduce the area of CBF deficit in eNOS-/- mice, suggesting that its effect on CBF within the ischemic cortex is primarily endothelium-dependent, and not mediated by its direct vasodilator effect on vascular smooth muscle. Our results suggest that Rho-kinase negatively regulates eNOS activity in acutely ischemic brain, thereby worsening the CBF deficit. Therefore, rapid nontranscriptional upregulation of eNOS activity by small molecule inhibitors of Rho-kinase may be a viable therapeutic approach in acute stroke.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed2006

Effective scattering coefficient of the cerebral spinal fluid in adult head models for diffuse optical imaging.

An efficient computation of the time-dependent forward solution for photon transport in a head model is a key capability for performing accurate inversion for functional diffuse optical imaging of the brain. The diffusion approximation to photon transport is much faster to simulate than the physically correct radiative transport equation (RTE); however, it is commonly assumed that scattering lengths must be much smaller than all system dimensions and all absorption lengths for the approximation to be accurate. Neither of these conditions is satisfied in the cerebrospinal fluid (CSF). Since line-of-sight distances in the CSF are small, of the order of a few millimeters, we explore the idea that the CSF scattering coefficient may be modeled by any value from zero up to the order of the typical inverse line-of-sight distance, or approximately 0.3 mm(-1), without significantly altering the calculated detector signals or the partial path lengths relevant for functional measurements. We demonstrate this in detail by using a Monte Carlo simulation of the RTE in a three-dimensional head model based on clinical magnetic resonance imaging data, with realistic optode geometries. Our findings lead us to expect that the diffusion approximation will be valid even in the presence of the CSF, with consequences for faster solution of the inverse problem.

Adult↗

PubMed2005

Fluorescence-lifetime-based tomography for turbid media.

We derive a novel algorithm to recover the in vivo distributions of fluorophores based on an asymptotic life-time analysis of time-domain fluorescence measurements with turbid tissue. We experimentally demonstrate the advantage offered by this method in localizing fluorophores with distinct lifetimes. This algorithm has wide applicability for diagnostic fluorescence imaging in the presence of several-centimeter-thick biological tissue, since fluorescence lifetime is a sensitive indicator of local tissue environment and interactions at the molecular level.

Algorithms↗

PubMed2005

Vasoconstrictive neurovascular coupling during focal ischemic depolarizations.

Ischemic depolarizing events, such as repetitive spontaneous periinfarct spreading depolarizations (PIDs), expand the infarct size after experimental middle cerebral artery (MCA) occlusion. This worsening may result from increased metabolic demand, exacerbating the mismatch between cerebral blood flow (CBF) and metabolism. Here, we present data showing that anoxic depolarization (AD) and PIDs caused vasoconstriction and abruptly reduced CBF in the ischemic cortex in a distal MCA occlusion model in mice. This reduction in CBF during AD increased the area of cortex with 20% or less residual CBF by 140%. With each subsequent PID, this area expanded by an additional 19%. Drugs that are known to inhibit cortical spreading depression (CSD), such as N-methyl-D-aspartate receptor antagonists MK-801 and 7-chlorokynurenic acid, and sigma-1 receptor agonists dextromethorphan and carbetapentane, did not reduce the frequency of PIDs, but did diminish the severity of episodic hypoperfusions, and prevented the expansion of severely hypoperfused cortex, thus improving CBF during 90 mins of acute focal ischemia. In contrast, AMPA receptor antagonist NBQX, which does not inhibit CSD, did not impact the deterioration in CBF. When measured 24 h after distal MCA occlusion, infarct size was reduced by MK-801, but not by NBQX. Our results suggest that AD and PIDs expand the CBF deficit, and by so doing negatively impact lesion development in ischemic mouse brain. Mitigating the vasoconstrictive neurovascular coupling during intense ischemic depolarizations may provide a novel hemodynamic mechanism of neuroprotection by inhibitors of CSD.

Animals↗

PubMed2005

Dynamic physiological modeling for functional diffuse optical tomography.

Diffuse optical tomography (DOT) is a noninvasive imaging technology that is sensitive to local concentration changes in oxy- and deoxyhemoglobin. When applied to functional neuroimaging, DOT measures hemodynamics in the scalp and brain that reflect competing metabolic demands and cardiovascular dynamics. The diffuse nature of near-infrared photon migration in tissue and the multitude of physiological systems that affect hemodynamics motivate the use of anatomical and physiological models to improve estimates of the functional hemodynamic response. In this paper, we present a linear state-space model for DOT analysis that models the physiological fluctuations present in the data with either static or dynamic estimation. We demonstrate the approach by using auxiliary measurements of blood pressure variability and heart rate variability as inputs to model the background physiology in DOT data. We evaluate the improvements accorded by modeling this physiology on ten human subjects with simulated functional hemodynamic responses added to the baseline physiology. Adding physiological modeling with a static estimator significantly improved estimates of the simulated functional response, and further significant improvements were achieved with a dynamic Kalman filter estimator (paired t tests, n=10, P<0.05). These results suggest that physiological modeling can improve DOT analysis. The further improvement with the Kalman filter encourages continued research into dynamic linear modeling of the physiology present in DOT. Cardiovascular dynamics also affect the blood-oxygen-dependent (BOLD) signal in functional magnetic resonance imaging (fMRI). This state-space approach to DOT analysis could be extended to BOLD fMRI analysis, multimodal studies and real-time analysis.

Blood Pressure↗

PubMed2005

Evidence that cerebral blood volume can provide brain activation maps with better spatial resolution than deoxygenated hemoglobin.

With the aim of evaluating the relative performance of hemodynamic contrasts for mapping brain activity, the spatio-temporal response of oxy-, deoxy-, and total-hemoglobin concentrations were imaged with diffuse optical tomography during electrical stimulation of the rat somatosensory cortex. For both 6-s and 30-s stimulus durations, total hemoglobin images provided smaller activation areas than oxy- or deoxy-hemoglobin images. In addition, analysis of regions of interest near the sagittal sinus vein show significantly greater contrast in both oxy- and deoxy-relative to total hemoglobin, suggesting that oximetric contrasts have larger draining vein contributions compared to total hemoglobin contrasts under the given stimulus conditions. These results indicate that total hemoglobin and cerebral blood volume may have advantages as hemodynamic mapping contrasts, particularly for large amplitude, longer duration stimulus paradigms.

Algorithms↗

PubMed2005

A haemodynamic response function model in spatio-temporal diffuse optical tomography.

Diffuse optical tomography (DOT) is a new and effective technique for functional brain imaging. It can detect local changes in both oxygenated and deoxygenated haemoglobin concentrations in tissue based on differential absorption at multiple wavelengths. Traditional methods in spatio-temporal analysis of haemoglobin concentrations in diffuse optical tomography first reconstruct the spatial distribution at different time instants independently, then look at the temporal dynamics on each pixel, without incorporating any temporal information as a prior in the image reconstruction. In this work, we present a temporal haemodynamic response function model described by a basis function expansion, in a joint spatio-temporal DOT reconstruction of haemoglobin concentration changes during simulated brain activation. In this joint framework, we simultaneously employ spatial regularization, spectral information and temporal assumptions. We also present an efficient algorithm for solving the associated large-scale systems. The expected improvements in spatial resolution and contrast-to-noise ratio are illustrated with simulations of human brain activation.

Algorithms↗

PubMed2005

Spatial extent of oxygen metabolism and hemodynamic changes during functional activation of the rat somatosensory cortex.

The spatial extent of the changes in oxy-hemoglobin (HbO), deoxy-hemoglobin (HbR), total hemoglobin concentration (HbT), cerebral blood flow (CBF), and the cerebral metabolic rate of oxygen (CMRO(2)) in response to forepaw and whisker stimulation were compared in the rat somatosensory cortex using a combination of multi-wavelength reflectance imaging and laser speckle contrast imaging of cerebral blood flow. The spatial extents of the response of each hemodynamic parameter and CMRO(2) were found to be comparable at the time of peak response, and at early times following stimulation onset, the spatial extent of the change in HbR was smaller than that of HbO, HbT, CBF, and CMRO(2). In addition, a slight spatial dependence was found in the power law coefficient relating changes in CBF and HbT. Although the CMRO(2) response is a metabolic measure and thus expected to have a more localized response than the hemodynamic parameters, the results presented here suggest that this may not be the case in general, possibly due to the increased sensitivity of optical imaging techniques to superficial cortical layers where the lateral extent of the metabolic and neuronal activation is larger compared to that in layer IV. In addition, we found that the measured spatial extent of the CMRO(2) changes was insensitive to assumptions made in the calculation of the CMRO(2) changes such as baseline hemoglobin concentrations, vascular weighting constants, and wavelength dependence of tissue scattering. Multi-parameter full field imaging of the functional response provides a more complete picture of the hemodynamic response to functional activation including the spatial and temporal estimation of CMRO(2) changes.

Algorithms↗

PubMed2005

Quantitative spectroscopic diffuse optical tomography of the breast guided by imperfect a priori structural information.

Spectroscopic diffuse optical tomography (DOT) can directly image the concentrations of physiologically significant chromophores in the body. This information may be of importance in characterizing breast tumours and distinguishing them from benign structures. This paper studies the accuracy with which lesions can be characterized given a physiologically realistic situation in which the background architecture of the breast is heterogeneous yet highly structured. Specifically, in simulation studies, we assume that the breast is segmented into distinct glandular and adipose regions. Imaging with a high-resolution imaging modality, such as magnetic resonance imaging, in conjunction with a segmentation by a clinical expert, allows the glandular/adipose boundary to be determined. We then apply a two-step approach in which the background chromophore concentrations of each region are estimated in a nonlinear fashion, and a more localized lesion is subsequently estimated using a linear perturbational approach. In addition, we examine the consequences which errors in the breast segmentation have on estimating both the background and inhomogeneity chromophore concentrations.

Algorithms↗

PubMed2005

Determination of optimal exposure time for imaging of blood flow changes with laser speckle contrast imaging.

Laser speckle contrast imaging is becoming an established method for full-field imaging of cerebral blood flow dynamics in animal models. The sensitivity and noise in the measurement of blood flow changes depend on the camera exposure time. The relation among sensitivity, noise, and camera exposure time was investigated experimentally by imaging the speckle contrast changes in the brain after electrical forepaw stimulation in rats. The sensitivity to relative changes in speckle contrast was found to increase at longer exposure times and to reach a plateau for exposure times greater than approximately 2 ms. However, the speckle contrast noise also increases with exposure time and thus the contrast-to-noise ratio was found to peak at an exposure time of approximately 5 ms. Our results suggests that approximately 5 ms is an optimal exposure time for imaging of stimulus-induced changes in cerebral blood flow in rodents.

Algorithms↗

PubMed2005

Optimal linear inverse solution with multiple priors in diffuse optical tomography.

A general framework for incorporating single and multiple priors in diffuse optical tomography is described. We explore the use of this framework for simultaneously utilizing spatial and spectral priors in the context of imaging breast cancer. The utilization of magnetic resonance images of water and lipid content as a statistical spatial prior for the diffuse optical image reconstructions is also discussed. Simulations are performed to demonstrate the significant improvement in image quality afforded by combining spatial and spectral priors.

Algorithms↗

PubMed2005

Simulation study of magnetic resonance imaging-guided cortically constrained diffuse optical tomography of human brain function.

Diffuse optical imaging can measure brain activity noninvasively in humans through the scalp and skull by measuring the light intensity modulation arising from localized-activity-induced absorption changes within the cortex. Spatial resolution and localization accuracy are currently limited by measurement geometry to approximately 3 cm in the plane parallel to the scalp. Depth resolution is a more significant challenge owing to the limited angle tomography permitted by reflectance-only measurements. We combine previously established concepts for improving image quality and demonstrate, through simulation studies, their application for improving the image quality of adult human brain function. We show in a three-dimensional human head model that localization accuracy is significantly improved by the addition of measurements that provide overlapping samples of brain tissue. However, the reconstructed absorption contrast is significantly underestimated because its depth is underestimated. We show that the absorption contrast amplitude accuracy can be significantly improved by providing a cortical spatial constraint in the image reconstruction to obtain a better depth localization. The cortical constraint makes physiological sense since the brain-activity-induced absorption changes are occurring in the cortex and not in the scalp, skull, and cerebral spinal fluid. This spatial constraint is provided by segmentation of coregistered structural magnetic resonance imaging (MRI). However, the absorption contrast deep within the cortex is reconstructed superficially, resulting in an underestimation of the absorption contrast. The synthesis of techniques described here indicates that multimodality imaging of brain function with diffuse optical imaging and MRI has the potential to provide more quantitative estimates of the total and deoxyhemoglobin response to brain activation, which is currently not provided by either method independently. However, issues of depth resolution within the cortex remain to be resolved.

Algorithms↗

PubMed2005

Coupling of the cortical hemodynamic response to cortical and thalamic neuronal activity.

Accurate interpretation of functional MRI (fMRI) signals requires knowledge of the relationship between the hemodynamic response and the neuronal activity that underlies it. Here we address the question of coupling between pre- and postsynaptic neuronal activity and the hemodynamic response in rodent somatosensory (Barrel) cortex in response to single-whisker deflection. Using full-field multiwavelength optical imaging of hemoglobin oxygenation and electrophysiological recordings of spiking activity and local field potentials, we demonstrate that a point hemodynamic measure is influenced by neuronal activity across multiple cortical columns. We demonstrate that the hemodynamic response is a spatiotemporal convolution of the neuronal activation. Therefore, positive hemodynamic response in one cortical column might be explained by neuronal activity not only in that column but also in the neighboring columns. Thus, attempts at characterizing the neurovascular relationship based on point measurements of electrophysiology and hemodynamics may yield inconsistent results, depending on the spatial extent of neuronal activation. The finding that the hemodynamic signal observed at a given location is a function of electrophysiological activity over a broad spatial region helps explain a previously observed increase of local vascular response beyond the saturation of local neuronal activity. We also demonstrate that the oxy- and total-hemoglobin hemodynamic responses can be well approximated by space-time separable functions with an antagonistic center-surround spatial pattern extending over several millimeters. The surround "negative" hemodynamic activity did not correspond to observable changes in neuronal activity. The complex spatial integration of the hemodynamic response should be considered when interpreting fMRI data.

Animals↗

PubMed2005

Physiological system identification with the Kalman filter in diffuse optical tomography.

Algorithms↗