High-Resolution Time-Frequency Analysis Of Neurovascular Responses To Ischemic Challenges

The identification and delineation of oscillatory patterns of blood flow associated with cerebral autoregulation mechanisms is the focus of three specific aims. 1) Identify a superior spectral analysis method for the identification of activity due to cholinergic oscillatory control of the microvasculature (COCmicvasc) and compare the effectiveness of the Hilbert-Huang transform (HHT), the smoothed pseudo Wigner-Ville (SPWV) distribution, and the variable-frequency complex demodulation (VFCDM) method to detect such activity. 2) Determine if changes in forehead microcirculation as monitored by noninvasive laser Doppler flowmetry may provide a reliable indication of the adequacy of cerebral blood flow during progressive simulated hypovolemia. 3) Identify changes in forehead microvascular activity that is due to parasympathetic activity associated with the onset of mental status changes and show a lack of coherence with potential confounding variables. The lower body negative pressure (LBNP) protocol is a noninvasive technique that can induce a hypovolemic state through blood pooling in the lower extremities by a portion of the circulating blood volume. Increasing degrees of LBNP is applied to healthy volunteers being monitored with noninvasive laser Doppler (LD) flowmetry to assess levels of forehead perfusion and vascular resistance. MATLAB is utilized as the primary tool for the development of custom mathematical algorithms to analyze this data in the time-frequency-energy domain. Utilizing the VFCDM technique to analyze forehead laser Doppler data offers greater insight into the identification and understanding of cerebral autoregulatory mechanisms than using other available methods. Techniques to identify COCmicvasc activity in the forehead and distinguish it from respiration, a potential confounder, are discussed. Presented data provides evidence that the observed COCmicvasc activity is due to a locally induced autoregulatory mechanism in the forehead that is unrelated to passive transmission of the mechanical effects of respiration. The close relationship of the forehead vasculature to that of the brain (i.e. part of the forehead is fed by a branch of the internal carotid artery with the remainder from the external carotid artery) suggests that the observed autoregulatory processes in the forehead microvasculature may be the same mechanisms responsible for autoregulation of the brain and other vital organs. This conclusion is also supported by the correlation between changes in mental status (i.e. lightheadedness) and forehead COCmicvasc activity

Multimodal Pressure-Flow Method to Assess Dynamics of Cerebral Autoregulation in Stroke and Hypertension

Background: This study evaluated the effects of stroke on regulation of cerebral blood flow in response to fluctuations in systemic blood pressure (BP). The autoregulatory dynamics are difficult to assess because of the nonstationarity and nonlinearity of the component signals. Methods: We studied 15 normotensive, 20 hypertensive and 15 minor stroke subjects (48.0 ± 1.3 years). BP and blood flow velocities (BFV) from middle cerebral arteries (MCA) were measured during the Valsalva maneuver (VM) using transcranial Doppler ultrasound. Results: A new technique, multimodal pressure-flow analysis (MMPF), was implemented to analyze these short, nonstationary signals. MMPF analysis decomposes complex BP and BFV signals into multiple empirical modes, representing their instantaneous frequency-amplitude modulation. The empirical mode corresponding to the VM BP profile was used to construct the continuous phase diagram and to identify the minimum and maximum values from the residual BP (BPR) and BFV (BFVR) signals. The BP-BFV phase shift was calculated as the difference between the phase corresponding to the BPR and BFVR minimum (maximum) values. BP-BFV phase shifts were significantly different between groups. In the normotensive group, the BFVR minimum and maximum preceded the BPR minimum and maximum, respectively, leading to large positive values of BP-BFV shifts. Conclusion: In the stroke and hypertensive groups, the resulting BP-BFV phase shift was significantly smaller compared to the normotensive group. A standard autoregulation index did not differentiate the groups. The MMPF method enables evaluation of autoregulatory dynamics based on instantaneous BP-BFV phase analysis. Regulation of BP-BFV dynamics is altered with hypertension and after stroke, rendering blood flow dependent on blood pressure

Experimental investigations of two-phase flow measurement using ultrasonic sensors

This thesis presents the investigations conducted in the use of ultrasonic technology to measure two-phase flow in both horizontal and vertical pipe flows which is important for the petroleum industry. However, there are still key challenges to measure parameters of the multiphase flow accurately. Four methods of ultrasonic technologies were explored. The Hilbert-Huang transform (HHT) was first applied to the ultrasound signals of air-water flow on horizontal flow for measurement of the parameters of the two- phase slug flow. The use of the HHT technique is sensitive enough to detect the hydrodynamics of the slug flow. The results of the experiments are compared with correlations in the literature and are in good agreement. Next, experimental data of air-water two-phase flow under slug, elongated bubble, stratified-wavy and stratified flow regimes were used to develop an objective flow regime classification of two-phase flow using the ultrasonic Doppler sensor and artificial neural network (ANN). The classifications using the power spectral density (PSD) and discrete wavelet transform (DWT) features have accuracies of 87% and 95.6% respectively. This is considerably more promising as it uses non-invasive and non-radioactive sensors. Moreover, ultrasonic pulse wave transducers with centre frequencies of 1MHz and 7.5MHz were used to measure two-phase flow both in horizontal and vertical flow pipes. The liquid level measurement was compared with the conductivity probes technique and agreed qualitatively. However, in the vertical with a gas volume fraction (GVF) higher than 20%, the ultrasound signals were attenuated. Furthermore, gas-liquid and oil-water two-phase flow rates in a vertical upward flow were measured using a combination of an ultrasound Doppler sensor and gamma densitometer. The results showed that the flow gas and liquid flow rates measured are within ±10% for low void fraction tests, water-cut measurements are within ±10%, densities within ±5%, and void fractions within ±10%. These findings are good results for a relatively fast flowing multiphase flow

A Nonlinear Dynamic Approach Reveals a Long-Term Stroke Effect on Cerebral Blood Flow Regulation at Multiple Time Scales

Cerebral autoregulation (CA) is an important vascular control mechanism responsible for relatively stable cerebral blood flow despite changes of systemic blood pressure (BP). Impaired CA may leave brain tissue unprotected against potentially harmful effects of BP fluctuations. It is generally accepted that CA is less effective or even inactive at frequencies >∼0.1 Hz. Without any physiological foundation, this concept is based on studies that quantified the coupling between BP and cerebral blood flow velocity (BFV) using transfer function analysis. This traditional analysis assumes stationary oscillations with constant amplitude and period, and may be unreliable or even invalid for analysis of nonstationary BP and BFV signals. In this study we propose a novel computational tool for CA assessment that is based on nonlinear dynamic theory without the assumption of stationary signals. Using this method, we studied BP and BFV recordings collected from 39 patients with chronic ischemic infarctions and 40 age-matched non-stroke subjects during baseline resting conditions. The active CA function in non-stroke subjects was associated with an advanced phase in BFV oscillations compared to BP oscillations at frequencies from ∼0.02 to 0.38 Hz. The phase shift was reduced in stroke patients even at > = 6 months after stroke, and the reduction was consistent at all tested frequencies and in both stroke and non-stroke hemispheres. These results provide strong evidence that CA may be active in a much wider frequency region than previously believed and that the altered multiscale CA in different vascular territories following stroke may have important clinical implications for post-stroke recovery. Moreover, the stroke effects on multiscale cerebral blood flow regulation could not be detected by transfer function analysis, suggesting that nonlinear approaches without the assumption of stationarity are more sensitive for the assessment of the coupling of nonstationary physiological signals

Doppler imaging with dual-detection full-range frequency domain optical coherence tomography

Most of full-range techniques for Frequency Domain Optical Coherence Tomography (FD-OCT) reported to date utilize the phase relation between consecutive axial lines to reconstruct a complex interference signal and hence may exhibit degradation in either mirror image suppression performance or detectable velocity dynamic range or both when monitoring a moving sample such as flow activity. We have previously reported a technique of mirror image removal by simultaneous detection of the quadrature components of a complex spectral interference called a Dual-Detection Frequency Domain OCT (DD-FD-OCT) [Opt. Lett. 35, 1058-1060 (2010)]. The technique enables full range imaging without any loss of acquisition speed and is intrinsically less sensitive to phase errors generated by involuntary movements of the subject. In this paper, we demonstrate the application of the DD-FD-OCT to a phase-resolved Doppler imaging without degradation in either mirror image suppression performance or detectable velocity dynamic range that were observed in other full-range Doppler methods. In order to accommodate for Doppler imaging, we have developed a fiber-based DD-FD-OCT that more efficiently utilizes the source power compared with the previous free-space DD-FD-OCT. In addition, the velocity sensitivity of the phase-resolved DD-FD-OCT was investigated, and the relation between the measured Doppler phase shift and set flow velocity of a flow phantom was verified. Finally, we demonstrate the Doppler imaging using the DD-FD-OCT in a biological sample

Development Of Optical Coherence Tomography For Tissue Diagnostics

Microvasculature can be found in almost every part of the human body, including the internal organs. Importantly, abnormal changes in microvasculature are usually related to pathological development of the tissue cells. Monitoring of changes in blood flow properties in microvasculature, therefore, provides useful diagnostic information about pathological conditions in biological tissues as exemplified in glaucoma, diabetes, age related macular degeneration, port wine stains, burn-depth, and potentially skin cancer. However, the capillary network is typically only one cell in wall thickness with 5 to 10 microns in diameter and located in the dermis region of skin. Therefore, a non-invasive flow imaging technique that is capable of depth sectioning at high resolution and high speed is demanded. Optical coherence tomography (OCT), particularly after its advancement in frequency domain OCT (FD-OCT), is a promising tool for non-invasive high speed, high resolution, and high sensitivity depth-resolved imaging of biological tissues. Over the last ten years, numerous efforts have been paid to develop OCTbased flow imaging techniques. An important effort is the development of phase-resolved Doppler OCT (PR-DOCT). Phase-resolved Doppler imaging using FD-OCT is particularly of interest because of the direct access to the phase information of the depth profile signal. Furthermore, the high speed capability of FD-OCT is promising for real time flow monitoring as well as 3D flow segmentation applications. However, several challenges need to be addressed; 1) Flow in biological samples exhibits a wide dynamic range of flow velocity caused by, for example, the iv variation in the flow angles, flow diameters, and functionalities. However, the improvement in imaging speed of FD-OCT comes at the expense of a reduction in sensitivity to slow flow information and hence a reduction in detectable velocity range; 2) A structural ambiguity socalled \u27mirror image\u27 in FD-OCT prohibits the use of maximum sensitivity and imaging depth range; 3) The requirement of high lateral resolution to resolve capillary vessels requires the use of an imaging optics with high numerical aperture (NA) that leads to a reduction in depth of focus (DOF) and hence the imaging depth range (i.e. less than 100 microns) unless dynamic focusing is performed. Nevertheless, intrinsic to the mechanism of FD-OCT, dynamic focusing is not possible. In this dissertation, the implementation of PR-DOCT in a high speed swept-source based FD-OCT is investigated and optimized. An acquisition scheme as well as a processing algorithm that effectively extends the detectable velocity dynamic range of the PR-DOCT is presented. The proposed technique increased the overall detectable velocity dynamic range of PR-DOCT by about five times of that achieved by the conventional method. Furthermore, a novel technique of mirror image removal called ‘Dual-Detection FD-OCT’ (DD-FD-OCT) is presented. One of the advantages of DD-FD-OCT to Doppler imaging is that the full-range signal is achieved without manipulation of the phase relation between consecutive axial lines. Hence the full-range DD-FDOCT is fully applicable to phase-resolved Doppler detection without a reduction in detectable velocity dynamic range as normally encountered in other full-range techniques. In addition, PRDOCT can utilize the maximum SNR provided by the full-range capability. This capability is particularly useful for imaging of blood flow that locates deep below the sample surface, such as v blood flow at deep posterior human eye and blood vessels network in the dermis region of human skin. Beside high speed and functional imaging capability, another key parameter that will open path for optical diagnostics using OCT technology is high resolution imaging (i.e. in a regime of a few microns or sub-micron). Even though the lateral resolution of OCT can be independently improved by opening the NA of the imaging optics, the high lateral resolution is maintained only over a short range as limited by the depth of focus that varies inversely and quadratically with NA. Recently developed by our group, ‘Gabor-Domain Optical Coherence Microscopy’ (GD-OCM) is a novel imaging technique capable for invariant resolution of about 2-3 m over a 2 mm cubic field-of-view. This dissertation details the imaging protocol as well as the automatic data fusion method of GD-OCM developed to render an in-focus high-resolution image throughout the imaging depth of the sample in real time. For the application of absolute flow measurement as an example, the precise information about flow angle is required. GDOCM provides more precise interpretation of the tissue structures over a large field-of-view, which is necessary for accurate mapping of the flow structure and hence is promising for diagnostic applications particularly when combined with Doppler imaging. Potentially, the ability to perform high resolution OCT imaging inside the human body is useful for many diagnostic applications, such as providing an accurate map for biopsy, guiding surgical and other treatments, monitoring the functional state and/or the post-operative recovery process of internal organs, plaque detection in arteries, and early detection of cancers in the gastrointestinal tract. Endoscopic OCT utilizes a special miniature probe in the sample arm to vi access tubular organs inside the human body, such as the cardiovascular system, the lung, the gastrointestinal tract, the urinary tract, and the breast duct. We present an optical design of a dynamic focus endoscopic probe that is capable of about 4 to 6 m lateral resolution over a large working distance (i.e. up to 5 mm from the distal end of the probe). The dynamic focus capability allows integration of the endoscopic probe to GD-OCM imaging to achieve high resolution endoscopic tomograms. We envision the future of this developing technology as a solution to high resolution, minimally invasive, depth-resolved imaging of not only structure but also the microvasculature of in vivo biological tissues that will be useful for many clinical applications, such as dermatology, ophthalmology, endoscopy, and cardiology. The technology is also useful for animal study applications, such as the monitoring of an embryo’s heart for the development of animal models and monitoring of changes in blood circulation in response to external stimulus in small animal brains