Kristen T. Tgavalekos

Cerebral autoregulation in the microvasculature measured with near-infrared spectroscopy.

Cerebral autoregulation (CA) is the mechanism that allows the brain to maintain a stable blood flow despite changes in blood pressure. Dynamic CA can be quantified based on continuous measurements of systemic mean arterial pressure (MAP) and global cerebral blood flow. Here, we show that dynamic CA can be quantified also from local measurements that are sensitive to the microvasculature. We used near-infrared spectroscopy (NIRS) to measure temporal changes in oxy- and deoxy-hemoglobin concentrations in the prefrontal cortex of 11 human subjects. A novel hemodynamic model translates those changes into changes of cerebral blood volume and blood flow. The interplay between them is described by transfer function analysis, specifically by a high-pass filter whose cutoff frequency describes the autoregulation efficiency. We have used pneumatic thigh cuffs to induce MAP perturbation by a fast release during rest and during hyperventilation, which is known to enhance autoregulation. Based on our model, we found that the autoregulation cutoff frequency increased during hyperventilation in comparison to normal breathing in 10 out of 11 subjects, indicating a greater autoregulation efficiency. We have shown that autoregulation can reliably be measured noninvasively in the microvasculature, opening up the possibility of localized CA monitoring with NIRS.

Cerebral blood flow and autoregulation: current measurement techniques and prospects for noninvasive optical methods

Abstract. Cerebral blood flow (CBF) and cerebral autoregulation (CA) are critically important to maintain proper brain perfusion and supply the brain with the necessary oxygen and energy substrates. Adequate brain perfusion is required to support normal brain function, to achieve successful aging, and to navigate acute and chronic medical conditions. We review the general principles of CBF measurements and the current techniques to measure CBF based on direct intravascular measurements, nuclear medicine, X-ray imaging, magnetic resonance imaging, ultrasound techniques, thermal diffusion, and optical methods. We also review techniques for arterial blood pressure measurements as well as theoretical and experimental methods for the assessment of CA, including recent approaches based on optical techniques. The assessment of cerebral perfusion in the clinical practice is also presented. The comprehensive description of principles, methods, and clinical requirements of CBF and CA measurements highlights the potentially important role that noninvasive optical methods can play in the assessment of neurovascular health. In fact, optical techniques have the ability to provide a noninvasive, quantitative, and continuous monitor of CBF and autoregulation.

Blood-pressure-induced oscillations of deoxy- and oxyhemoglobin concentrations are in-phase in the healthy breast and out-of-phase in the healthy brain

Abstract. We present a near-infrared spectroscopy (NIRS) study of local hemodynamics in the breast and the brain (prefrontal cortex) of healthy volunteers in a protocol involving periodic perturbations to the systemic arterial blood pressure. These periodic perturbations were achieved by cyclic inflation (to a pressure of 200 mmHg) and deflation (at frequencies of 0.046, 0.056, 0.063, 0.071, and 0.083 Hz) of two pneumatic cuffs wrapped around the subject’s thighs. As a result of these systemic perturbations, the concentrations of deoxy- and oxyhemoglobin in tissue (D and O, respectively) oscillate at the set frequency. We found that the oscillations of D and O in breast tissue are in-phase at all frequencies considered, a result that we attribute to dominant contributions from blood volume oscillations. In contrast, D and O oscillations in brain tissue feature a frequency-dependent phase difference, which we attribute to significant contributions from cerebral blood flow oscillations. Frequency-resolved measurements of D and O oscillations are exploited by the technique of coherent hemodynamics spectroscopy for the assessment of cerebrovascular parameters and cerebral autoregulation. We show the relevant physiological information content of NIRS measurements of oscillatory hemodynamics, which have qualitatively distinct features in the healthy breast and healthy brain.

Non-invasive assessment of cerebral microcirculation with diffuse optics and coherent hemodynamics spectroscopy

We describe the general principles and initial results of coherent hemodynamics spectroscopy (CHS), which is a new technique for the quantitative assessment of cerebral hemodynamics on the basis of dynamic near-infrared spectroscopy (NIRS) measurements. The two components of CHS are (1) dynamic measurements of coherent cerebral hemodynamics in the form of oscillations at multiple frequencies (frequency domain) or temporal transients (time domain), and (2) their quantitative analysis with a dynamic mathematical model that relates the concentration and oxygen saturation of hemoglobin in tissue to cerebral blood volume (CBV), cerebral blood flow (CBF), and cerebral metabolic rate of oxygen (CMRO2). In particular, CHS can provide absolute measurements and dynamic monitoring of CBF, and quantitative measures of cerebral autoregulation. We report initial results of CBF measurements in hemodialysis patients, where we found a lower CBF (54 ± 16 ml/(100 g-min)) compared to a group of healthy controls (95 ± 11 ml/(100 g-min)). We also report CHS measurements of cerebral autoregulation, where a quantitative index of autoregulation (its cutoff frequency) was found to be significantly greater in healthy subjects during hyperventilation (0.034 ± 0.005 Hz) than during normal breathing (0.017 ± 0.002 Hz). We also present our approach to depth resolved CHS, based on multi-distance, frequency-domain NIRS data and a two-layer diffusion model, to enhance sensitivity to cerebral tissue. CHS offers a potentially powerful approach to the quantitative assessment and continuous monitoring of local brain perfusion at the microcirculation level, with prospective brain mapping capabilities of research and clinical significance.

Coherent Hemodynamics Spectroscopy: A New Technique to Characterize the Dynamics of Blood Perfusion and Oxygenation in Tissue

Hemodynamic-based neuroimaging techniques such as near-infrared spectroscopy (NIRS) and functional magnetic resonance imaging (fMRI) are directly sensitive to the blood volume fraction and oxygen saturation of blood in the probed tissue. The ability to translate such hemodynamic and oxygenation measurements into physiological quantities is critically important to enhance the effectiveness of NIRS and fMRI in a broad range of applications aimed at medical diagnostic or functional assessment. Coherent hemodynamics spectroscopy (CHS) is a novel technique based on the measurement (with techniques such as NIRS or fMRI) and quantitative analysis (with a novel mathematical model) of coherent hemodynamics in living tissues. Methods to induce coherent hemodynamics in humans include controlled perturbations to the mean arterial pressure by paced breathing or by timed inflations of pneumatic cuffs wrapped around the subject’s legs. A mathematical model recently outlined translates coherent hemodynamics into physiological measures of the capillary and venous blood transit times, cerebral autoregulation, and cerebral blood flow. A typical method to analyze the optical signal from non-invasive NIRS measurements of the human brain is the modified Beer-Lambert law (mBLL), which does not allow the discrimination of hemodynamics taking place in the scalp and skull from those occurring in the brain cortex. A hybrid method using continuous wave NIRS (with the mBLL) together with frequency-domain NIRS (with a two-layer diffusion model) was successfully used to discriminate oscillatory hemodynamics in the superficial (extracerebral) tissue layer from that in deeper, cerebral tissue.

Measurements of coherent hemodynamics to enrich the physiological information provided by near-infrared spectroscopy (NIRS) and functional MRI

Hemodynamic-based neuroimaging techniques such as functional magnetic resonance imaging (fMRI) and near-infrared spectroscopy (NIRS) sense hemoglobin concentration in cerebral tissue. The local concentration of hemoglobin, which is differentiated into oxy- and deoxy-hemoglobin by NIRS, features spontaneous oscillations over time scales of 10-100 s in response to a number of local and systemic physiological processes. If one of such processes becomes the dominant source of cerebral hemodynamics, there is a high coherence between this process and the associated hemodynamics. In this work, we report a method to identify such conditions of coherent hemodynamics, which may be exploited to study and quantify microvasculature and microcirculation properties. We discuss how a critical value of significant coherence may depend on the specific data collection scheme (for example, the total acquisition time) and the nature of the hemodynamic data (in particular, oxy- and deoxy-hemoglobin concentrations measured with NIRS show an intrinsic level of correlation that must be taken into account). A frequency-resolved study of coherent hemodynamics is the basis for the new technique of coherent hemodynamics spectroscopy (CHS), which aims to provide measures of cerebral blood flow and cerebral autoregulation. While these concepts apply in principle to both fMRI and NIRS data, in this article we focus on NIRS data.

Coherent hemodynamics spectroscopy: initial applications in the neurocritical care unit

We used coherent hemodynamics spectroscopy (CHS) and near-infrared spectroscopy (NIRS) to measure the absolute cerebral blood flow (CBF) and cerebral autoregulation efficiency of a patient with intraventricular hemorrhage in the neurocritical care unit. Mean arterial pressure oscillations were induced with cyclic thigh cuff inflations at a super-systolic pressure. The oscillations in oxyhemoglobin ([HbO2]) and deoxyhemoglobin ([Hb]) cerebral concentrations were used to compute CHS amplitude and phase spectra that were fit with the frequency-domain equations of our hemodynamic model. From the fitted parameters, we obtained measures of local autoregulation efficiency (cutoff frequency: 0.07 ± 0.02 Hz) and absolute regional CBF (33 ± 9 ml/100g/min). We introduce a new approach for computing CHS spectra using coherence criteria and time-varying transfer function analysis. We show that with this approach we can maximize the number of frequency points in the CHS spectra for more effective fitting with our hemodynamic model. Finally, we show how absolute measurements of the cerebral concentrations of [HbO2] and [Hb] at baseline can be used to further enhance the fitting procedure.

Induced and spontaneous hemodynamic oscillations in cerebral and extracerebral tissue for coherent hemodynamics spectroscopy

We report preliminary results of a study for investigating the spatial homogeneity of induced and spontaneous oscillations in the concentration of oxyhemoglobin on the scalp/skull layer of two human subjects. Hemodynamic oscillations were induced by modulation of arterial blood pressure, which triggers the cerebral autoregulation mechanism. Induced hemodynamic oscillations are used in coherent hemodynamics spectroscopy to derive physiological parameters of interest for medical diagnostics. For example, our dedicated mathematical model translates typical near-infrared spectroscopy observables, like the amplitude and phase relationship of the oscillations of oxy- and deoxyhemoglobin concentrations into capillary and venous blood transit times, cutoff frequency of the autoregulation process, and other parameters related to microvascular blood volume. In this study, we focused on the phase relationship between the oscillations of oxyhemoglobin concentrations in three optical channels, two of which feature a short (5 mm) source-detector separation (sampling the scalp/skull only) and the third one features a long (30 mm) source-detector separation (sampling both extracerebral and cerebral tissues). The two main goals of the study were: a) to compare the coherence of induced and spontaneous oscillations; b) to assess if induced and spontaneous oscillations may be assumed to be uniform in the extracerebral layer. This was assessed by studying the phase relationship of oscillations in oxyhemoglobin concentration at the two short source-detector separations. About point a) we verified that induced oscillations have a higher incidence of coherence than spontaneous oscillations: 74% for induced oscillations, and 30% for spontaneous oscillations. About point b) the results show an overall trend for both spontaneous and induced oscillations to be homogeneous or “quasi-homogeneous” in the extracerebral tissue; however, we observed cases where a significant non-zero phase difference was measured, indicating spatial heterogeneity. We propose a method for taking into account the possible inhomogeneous behavior of the oscillations in the scalp/skull in order to increase the accuracy of measurements of cerebral hemodynamic oscillations.

Depth resolution in coherent hemodynamics spectroscopy

Coherent hemodynamics spectroscopy (CHS) is a novel method based on the frequency-resolved study of induced hemodynamic oscillations in living tissues. Approaches to induce hemodynamic oscillations in human subjects include paced breathing and cyclic thigh cuff inflation. Such induced hemodynamic oscillations result in coherent oscillations of oxy-, deoxy-, and total hemoglobin concentrations in tissue, which can be measured with near-infrared spectroscopy (NIRS). The novel aspect of CHS is to induce hemodynamic oscillations at multiple frequencies in order to obtain frequency-resolved spectra of coherent hemodynamics. A dedicated mathematical model recently developed by our group, can translate the phase and amplitude spectra of these hemodynamic oscillations into physiological parameters such as capillary and venous transit times, and the autoregulation cutoff frequency. A typical method used in near-infrared tissue spectroscopy to measure oscillations of hemoglobin concentrations is based on the modified Beer-Lambert law, which does not allow for the discrimination of hemodynamic oscillations occurring in the scalp from those occurring in the brain cortex. In this work, we show preliminary results obtained by using diffusion theory for a two-layered medium, so that the hemodynamic oscillations obtained for the first and second layer are assigned to hemodynamic oscillations occurring in the scalp/skull and brain cortex tissues, respectively.

Depth-resolved optical measurements of cerebral hemodynamics

We apply a two-layer diffusion model to multi-distance optical data collected on the forehead of a human subject for depth-resolved measurements of the cerebral hemodynamic perturbations induced by a fast release of thigh cuffs.