An important protective feature of the cerebral circulation is its ability to maintain sufficient cerebral blood flow and oxygen supply in accordance with the energy demands of the brain despite variations in a number of external factors such as arterial blood pressure, heart rate and respiration rate. If cerebral autoregulation is impaired, abnormally low or high CBF can lead to cerebral ischemia, intracranial hypertension or even capillary damage, thus contributing to the onset of cerebrovascular events. The control and regulation of cerebral blood flow is a dynamic, multivariate phenomenon. Sensitive techniques are required to monitor and process experimental data concerning cerebral blood flow and metabolic rate in a clinical setting. This thesis presents a model simulation study and 4 related signal processing studies concerned with CBF regulation. The first study models the regulation of the cerebral vasculature to systemic changes in blood pressure, dissolved blood gas concentration and neural activation in a integrated haemodynamic system. The model simulations show that the three pathways which are generally thought to be independent (pressure, CO₂ and activation) greatly influence each other, it is vital to consider parallel changes of unmeasured variability when performing a single pathway study. The second study shows how simultaneously measured blood gas concentration fluctuations can improve the accuracy of an existing frequency domain technique for recovering cerebral autoregulation dynamics from spontaneous fluctuations in blood pressure and cerebral blood flow velocity. The third study shows how the continuous wavelet transform can recover both time and frequency information about dynamic autoregulation, including the contribution of blood gas concentration. The fourth study shows how the discrete wavelet transform can be used to investigate frequency-dependent coupling between cerebral and systemic cardiovascular dynamics. The final study then uses these techniques to investigate the systemic effects on resting BOLD variability. The general approach taken in this thesis is a combined analysis of both modelling and data analysis. Physiologically-based models encapsulate hypotheses about features of CBF regulation, particularly those features that may be difficult to recover using existing analysis methods, and thus provide the motivation for developing both new analysis methods and criteria to evaluate these methods. On the other hand, the statistical features extracted directly from experimental data can be used to validate and improve the model.

A hypothetical causal link between ventilatory regulation of carbon dioxide anddevelopment of syncope during orthostatic challenges is reduction in arterial partialpressure of carbon dioxide and resultant reduction in cerebral blood flow. We performedtwo experiments to investigate the ventilatory sensitivity to carbon dioxide and factorsaffecting cerebral autoregulation (CA). We also studied the nonlinear phase couplingbetween cardio-respiratory parameters before syncope.For experiment one, in 30 healthy adults, we stimulated chemo and baro reflexesby breathing either room-air or room-air with 5 percent carbon dioxide in a pseudorandom binary sequence during supine and 70 degree head up tilt (HUT). Six subjectsdeveloped presyncope during tilt.To determine whether changes in ventilatory control contribute to the observeddecrease in PaCO2 during HUT, we assessed ventilatory dynamic sensitivity to changesin PaCO2 during supine and 70 degrees HUT. The sensitivity of the ventilatory controlsystem to perturbations in end tidal carbon dioxide increased during tilt.To investigate nonlinear phase coupling between cardio-respiratory parametersbefore syncope, bispectra were estimated and compared between presyncopal andnon-presyncopal subjects. Our results indicate that preceding presyncope, nonlinearphase coupling is altered by perturbations to baro and chemo reflexes.To investigate the effects of gender in CA, we selected 10 men and 10age-matched women and used spectral analysis to compare differences in CA betweenmen and women. Our results showed that gender-related differences in CA did exist andgender may need to be considered as a factor in investigating CA.To investigate the influence of induced hypocapnia on CA in absence ofventilatory variability, we performed experiment two in which subjects were randomlyassigned to a Control (under normocapnia) or Treatment (under hypocapnia) group. Bothgroups voluntarily controlled their breathing pattern yet two groups breathed in air withdifferent levels of carbon dioxide. Our results show that changes in mean blood pressureat middle cerebral artery level were less transferred into mean cerebral blood flow in theTreatment group than in the Control group, suggesting better CA under hypocapniarelative to under normocapnia.

The Circle of Willis (CoW) is a ring-like arterial structure forming the major anastomotic connection between arterial supply systems in the brain, and is responsible for the distribution of oxygenated blood throughout the cerebral mass. Among the general population, only approximately 50% have a complete CoW, where absent or hypoplastic vessels are common among a multitude of possible anatomical variations, reducing the degree to which blood may be rerouted. While an individual with one of these variations may under normal circumstances suffer no ill effects, there are certain pathological conditions which can present a risk to the person's health and increase the possibility of suffering an ischaemic stroke when compounded with an anatomical variation. This body of work presents techniques for generating 3D models of the cerebral vasculature using magnetic resonance imaging (MRI) and performing computational fluid dynamics (CFD) simulations in order to simulate the flow patterns throughout a circle of Willis. Incorporated with the simulations is a mathematical model of the cerebral autoregulation mechanism, simulating the ability of the smaller arteries and arterioles in the brain to either constrict or dilate in response to alterations in cerebral blood flow, thereby altering the cerebrovascular resistance of each major brain territory and regulating the amount of blood flow within a physiological range of cerebral perfusion pressure. The CFD simulations have the ability to predict the amount of collateral flow rerouted via the communicating arteries in response to a stenosis or occlusion, and the major objective of this study has been the investigation of how anatomical variations of the circle of Willis affect the capacity to provide this collateral flow. Initial work began with the development of three idealized models of common anatomical variations, created using computer aided design software (CAD) and based on the results of MRI scans. The research then shifted to developing a technique whereby patient specific models of the circle of Willis could be directly segmented from the MRI data. As a result of this shift, an interactive GUI-based tool was developed for the processing of the MRI datasets, allowing for rapid data enhancement and creation of a surface topology representing the arterial wall of the circle of Willis, suitable for a CFD simulation. The results of both sets of simulations illustrate that there exist a number of variables associated with a patients circle of Willis geometry, such as cerebral blood flow and combinations and degrees of stenosis, implying that the initial goal of drawing generalized conclusions was perhaps flawed. Instead, a crucial outcome of this body of work is that the future research should be directed toward extending the physiological complexity of both the geometry and the autoregulation model, with the intention of a patient specific application rather than producing large datasets with which to make broad generalizations.

Altered cerebral hemodynamics contributes to mechanisms of unexplained syncope. Wecompared dynamic interaction between respiration and cerebral autoregulation in two groups ofsubjects from 28 healthy adults. Based on development of tilt-induced presyncope, subjects wereclassified as Non-Presyncopals (n=23) and Presyncopals (n=5). Airflow, CO2, Doppler cerebralblood flow velocity (CBF), ECG and blood pressure (BP) were recorded. To determine whetherinfluences of mean BP (MBP) and systolic BP (SBP) on CBF were altered in Presyncopals, thecoherencies and transfer functions between these variables and mean and peak CBF (CBFm andCBFp) were estimated. To determine influence of end-tidal CO2 (ETCO2) on CBF, relative CO2reactivity was calculated. The two primary findings were, during tilt in Presyncopals: (1) Inrespiratory frequency region, coherence between SBP and CBFp (p=0.02) and transfer functiongain between BP and CBFm was higher (MBP, p=0.01, and SBP, p=0.01) than in Non-Presyncopals. (2) In the last 3 minutes prior to presyncope, Presyncopals had a reduced relativeCO2 reactivity (p=0.005). Thus the relationship of CBF with systemic BP was more pronouncedor cerebral autoregulation was less effective preceding presyncope. This decreasedautoregulation, secondary to decreased ETCO2, may contribute in the cascade of events leadingto unexplained syncope.

Introduction Cerebral autoregulation (CA) refers to the physiological mechanisms in the brain to maintain constant blood flow despite changes in cerebral perfusion pressure (CPP). It plays an important protective role against the danger of ischaemia or oedema of the brain. Over the years, various methods for CA assessment have been proposed, while most commonly used parameters include the autoregulation index (ARI), which grades CA into ten levels; transfer function (TF) analysis, describing CA as a high pass filter; the mean flow index (Mx), that estimates CA through the correlation coefficient between slow waves of mean cerebral blood flow velocity (CBFV) and CPP; and pressure reactivity index (PRx), calculated as a moving correlation coefficient between mean arterial blood pressure (ABP) and intracranial pressure (ICP). However, until now, how these parameters are related with each other is still not clear. A comprehensive investigation of the relationship between all these parameters is therefore needed. In addition, the methods mentioned above mostly assume the system being analysed is linear and the signals are stationary, with the announcement of non-stationary characteristic of CA, a more robust method, in particular suitable for non-stationary signal analysis, needs to be explored. Objectives and Methods This thesis addresses three primary questions: 1. What are the relationships between currently widely used CA parameters, i.e. Mx, ARI, TF parameters, from theoretical and practical point of view? 2. It there an effective method that can be introduced to assess CA, which is suitable for analyses of non-stationary signals? 3. How can bedside monitoring of cerebral autoregulation be improved in traumatic brain injury patients? These general aims have been translated into a series of experiments, retrospective analyses and background studies that are presented in different chapters of this thesis. Results and Conclusions This PhD project carefully scrutinised currently used CA assessment methodologies in TBI patients, demonstrating significant relationships between ARI, Mx and TF phase. A new introduced wavelet-transform-based method, wPRx was validated and showed more stable result for CA assessment than the well-established parameter, PRx. A multi-window approach with weighting system for optimal CPP estimation was described. The result showed a significant improvement in the continuity and stability of CPPopt estimation, which made it possible to be applied in the future clinical management of TBI patients.

The human brain acts as an intelligent sensor by helping in effective signal communication and execution of logical functions and instructions, thus, coordinating all functions of the human body. More importantly, it shows the potential to combine prior knowledge with adaptive learning, thus ensuring constant improvement. These qualities help the brain to interact efficiently with both, the body (brain-body) as well as the environment (brain-environment). This dissertation attempts to apply the brain-body-environment interactions (BBEI) to elevate human existence and enhance our day-to-day experiences. For instance, when one stepped out of the house in the past, one had to carry keys (for unlocking), money (for purchasing), and a phone (for communication). With the advent of smartphones, this scenario changed completely and today, it is often enough to carry just one's smartphone because all the above activities can be performed with a single device. In the future, with advanced research and progress in BBEI interactions, one will be able to perform many activities by dictating it in one's mind without any physical involvement. This dissertation aims to shift the paradigm of existing brain-computer-interfaces from just ‘control' to ‘monitor, control, enhance, and restore' in three main areas - healthcare, transportation safety, and cryptography. In healthcare, measures were developed for understanding brain-body interactions by correlating cerebral autoregulation with brain signals. The variation in estimated blood flow of brain (obtained through EEG) was detected with evoked change in blood pressure, thus, enabling EEG metrics to be used as a first hand screening tool to check impaired cerebral autoregulation. To enhance road safety, distracted drivers' behavior in various multitasking scenarios while driving was identified by significant changes in the time-frequency spectrum of the EEG signals. A distraction metric was calculated to rank the severity of a distraction task that can be used as an intuitive measure for distraction in people - analogous to the Richter scale for earthquakes. In cryptography, brain-environment interactions (BBEI) were qualitatively and quantitatively modeled to obtain cancelable biometrics and cryptographic keys using brain signals. Two different datasets were used to analyze the key generation process and it was observed that neurokeys established for every subject-task combination were unique, consistent, and can be revoked and re-issued in case of a breach. This dissertation envisions a future where humans and technology are intuitively connected by a seamless flow of information through ‘the most intelligent sensor', the brain.

Intracranial monitoring after severe traumatic brain injury offers the possibility for early detection and amelioration of physiological insults. In this thesis, I explore cerebral insults due raised intracranial pressure, decreased cerebral perfusion pressure and impaired cerebral pressure reactivity after traumatic brain injury. In chapter 2, the importance of intracranial pressure, cerebral perfusion pressure and pressure reactivity in regulating the cerebral circulation is elucidated along with a summary of the existing evidence supporting intracranial monitoring in traumatic brain injury. In chapter 4, intracranial pressure, cerebral perfusion pressure, and pressure reactivity insults are demonstrated to be common, prognostically important, and responsive to long-term changes in management policies. Further, while these insults often occur independently, coexisting insults portend worse prognosis. In chapter 5, I examine possible imaging antecedents of raised intracranial pressure and demonstrate that initial subarachnoid haemorrhage is associated with the subsequent development of elevated intracranial pressure. In addition, elevated glucose during the intensive care stay is associated with worse pressure reactivity. Cortical blood flow and brain tissue oxygenation are demonstrated to be sensitive to increases in intracranial pressure in chapter 6. In chapter 7, a method is proposed to estimate the cerebral perfusion pressure limits of reactivity in real-time, which may allow for more nuanced intensive care treatment. Finally, I explore a recently developed visualisation technique for intracranial physiological insults and apply it to the cerebral perfusion pressure limits of reactivity. Taken together, this thesis outlines the scope, risk factors and consequences of intracranial insults after severe traumatic brain injury. Novel signal processing applications are presented that may serve to facilitate a physiological, personalised and precision approach to patient therapy.

The role of CEA for stroke prevention in the presence of symptomatic carotid artery stenosis is well established. In order to maximize the benefit of surgery, several perioperative processes of care have been under scrutiny, of which one is the choice of anaesthetic method. The differing effects of GA vs. LA on the cerebral circulation after CEA may be of significance, since changes in the cerebral circulation post-CEA may give rise to cerebral hyperperfusion and intracerebral haemorrhage. This work assessed the effect of GA vs. LA on cerebral haemodynamic control after CEA using transcranial Doppler (TCD) techniques, and correlated these changes with serum markers of cerebral injury. Subjects undergoing CEA had perioperative TCD monitoring of middle cerebral artery blood flow velocity (MCAV). Pre- and postoperative (within 48 hours of surgery) testing of cerebral autoregulation [CA] (tilt-testing) and cerebral vasoreactivity to CO2 [CVR] (rebreathing expired air) was conducted. Cerebral haemodynamic parameters and clinical outcome were correlated with changes in jugular venous and peripheral levels of protein S100β and neurone-specific enolase (NSE).The change in CA and CVR was not different between GA (n=16) and LA (n=20). Overall, CA and CVR improved significantly within 48 hours of CEA for patients with preoperative impairment of these parameters, although some patients with normal baseline CA and CVR exhibited postoperative impairment. Increase of MCAV >100% from baseline after restoration of carotid blood flow was observed in patients with impaired CVR, but resolved by the first postoperative day. Transient elevation in jugular venous (but not peripheral) S100β during surgery was seen. Both jugular and peripheral NSE levels dropped during surgery. Neither anaesthetic method nor CA or CVR status had any effect on changes in serum S100β or NSE. Cerebral autoregulatory parameters thus improve rapidly after CEA, but appear unaffected by anaesthetic technique. This supports the concept that cerebral hyperperfusion is dependent on factors in addition to impaired CA or CVR. Changes in serum S100β or NSE do not reflect cerebral haemodynamic changes. However, the variability encountered between patients warrants further investigation. The implications for clinical practice and directions for further research are discussed.

Cerebral autoregulation is an intrinsic physiological response that maintains a constant cerebral blood flow (CBF) despite dynamic changes in the systemic blood pressure. Autoregulation is achieved through changes in the resistance of the small blood vessels in the brain through reflexive vasodilatation and vasoconstriction. Cerebrovascular reactivity (CVR) is a measure of this response. CVR is defined as a change in CBF in response to a given vasodilatory stimulus. CVR therefore potentially reflects the vasodilatory reserve capacity of the cerebral vasculature to maintain a constant cerebral blood flow. A decrease in CVR (which is interpreted as a reduction in the vasodilatory reserve capacity) in the vascular territory downstream of a larger stenosed supply artery correlates strongly with the risk of a hemodynamic stroke. As a result, the use of CVR studies to evaluate the state of the cerebral autoregulatory capacity has clinical utility. Application of CVR studies in the clinical scenario depends on a thorough understanding of the normal response. The goal of this thesis therefore was to map CVR throughout the brain in normal healthy individuals using Blood Oxygen Level Dependant functional Magnetic Resonance Imaging (BOLD MRI) as an index to CBF and precisely controlled changes in end-tidal partial pressure of carbon dioxide (PETCO2) as the global flow stimulus.

Cerebral autoregulation is an intrinsic physiological response that maintains a constant cerebral blood flow (CBF) despite dynamic changes in the systemic blood pressure. Autoregulation is achieved through changes in the resistance of the small blood vessels in the brain through reflexive vasodilatation and vasoconstriction. Cerebrovascular reactivity (CVR) is a measure of this response. CVR is defined as a change in CBF in response to a given vasodilatory stimulus. CVR therefore potentially reflects the vasodilatory reserve capacity of the cerebral vasculature to maintain a constant cerebral blood flow. A decrease in CVR (which is interpreted as a reduction in the vasodilatory reserve capacity) in the vascular territory downstream of a larger stenosed supply artery correlates strongly with the risk of a hemodynamic stroke. As a result, the use of CVR studies to evaluate the state of the cerebral autoregulatory capacity has clinical utility. Application of CVR studies in the clinical scenario depends on a thorough understanding of the normal response. The goal of this thesis therefore was to map CVR throughout the brain in normal healthy individuals using Blood Oxygen Level Dependant functional Magnetic Resonance Imaging (BOLD MRI) as an index to CBF and precisely controlled changes in end-tidal partial pressure of carbon dioxide (PETCO2) as the global flow stimulus.