Optimising the assessment of cerebral autoregulation from black box models

Cerebral autoregulation (CA) mechanisms maintain blood flow approximately stable despite changes in arterial blood pressure. Mathematical models that characterise this system have been used extensively in the quantitative assessment of function/impairment of CA. Using spontaneous fluctuations in arterial blood pressure (ABP) as input and cerebral blood flow velocity (CBFV) as output, the autoregulatory mechanism can be modelled using linear and non-linear approaches, from which indexes can be extracted to provide an overall assessment of CA. Previous studies have considered a single – or at most a couple of measures, making it difficult to compare the performance of different CA parameters. We compare the performance of established autoregulatory parameters and propose novel measures. The key objective is to identify which model and index can best distinguish between normal and impaired CA. To this end 26 recordings of ABP and CBFV from normocapnia and hypercapnia (which temporarily impairs CA) in 13 healthy adults were analysed. In the absence of a ‘gold’ standard for the study of dynamic CA, lower inter- and intra-subject variability of the parameters in relation to the difference between normo- and hypercapnia were considered as criteria for identifying improved measures of CA. Significantly improved performance compared to some conventional approaches was achieved, with the simplest method emerging as probably the most promising for future studies

Adaptive feedback analysis and control of programmable stimuli for assessment of cerebrovascular function

The assessment of cerebrovascular regulatory mechanisms often requires flexibly controlled and precisely timed changes in arterial blood pressure (ABP) and/or inspired CO2. In this study, a new system for inducing variations in mean ABP was designed, implemented and tested using programmable sequences and programmable controls to induce pressure changes through bilateral thigh cuffs. The system is also integrated with a computer-controlled switch to select air or a CO2/air mixture to be provided via a face mask. Adaptive feedback control of a pressure generator was required to meet stringent specifications for fast changes, and accuracy in timing and pressure levels applied by the thigh cuffs. The implemented system consists of a PC-based signal analysis/control unit, a pressure control unit and a CO2/air control unit. Initial evaluations were carried out to compare the cuff pressure control performances between adaptive and non-adaptive control configurations. Results show that the adaptive control method can reduce the mean error in sustaining target pressure by 99.57 % and reduce the transient time in pressure increases by 45.21 %. The system has proven a highly effective tool in ongoing research on brain blood flow control

Linear and Nonlinear Modeling of Cerebral Flow Autoregulation Using Principal Dynamic Modes

Cerebral Flow Autoregulation (CFA) is the dynamic process by which cerebral blood flow is maintained within physiologically acceptable bounds during fluctuations of cerebral perfusion pressure. The distinction is made with “static” flow autoregulation under steady-state conditions of perfusion pressure, described by the celebrated “autoregulatory curve” with a homeostatic plateau. This paper studies the dynamic CFA during changes in perfusion pressure, which attains critical clinical importance in patients with stroke, traumatic brain injury and neurodegenerative disease with a cerebrovascular component. Mathematical and computational models have been used to advance our quantitative understanding of dynamic CFA and to elucidate the underlying physiological mechanisms by analyzing the relation between beat-to-beat data of mean arterial blood pressure (viewed as input) and mean cerebral blood flow velocity(viewed as output) of a putative CFA system. Although previous studies have shown that the dynamic CFA process is nonlinear, most modeling studies to date have been linear. It has also been shown that blood CO2 tension affects the CFA process. This paper presents a nonlinear modeling methodology that includes the dynamic effects of CO2 tension (or its surrogate, end-tidal CO2) as a second input and quantifies CFA from short data-records of healthy human subjects by use of the modeling concept of Principal Dynamic Modes (PDMs). The PDMs improve the robustness of the obtained nonlinear models and facilitate their physiological interpretation. The results demonstrate the importance of including the CO2 input in the dynamic CFA study and the utility of nonlinear models under hypercapnic or hypocapnic conditions

Separating vascular and neuronal effects of age on fMRI BOLD signals.

Accurate identification of brain function is necessary to understand the neurobiology of cognitive ageing, and thereby promote well-being across the lifespan. A common tool used to investigate neurocognitive ageing is functional magnetic resonance imaging (fMRI). However, although fMRI data are often interpreted in terms of neuronal activity, the blood oxygenation level-dependent (BOLD) signal measured by fMRI includes contributions of both vascular and neuronal factors, which change differentially with age. While some studies investigate vascular ageing factors, the results of these studies are not well known within the field of neurocognitive ageing and therefore vascular confounds in neurocognitive fMRI studies are common. Despite over 10 000 BOLD-fMRI papers on ageing, fewer than 20 have applied techniques to correct for vascular effects. However, neurovascular ageing is not only a confound in fMRI, but an important feature in its own right, to be assessed alongside measures of neuronal ageing. We review current approaches to dissociate neuronal and vascular components of BOLD-fMRI of regional activity and functional connectivity. We highlight emerging evidence that vascular mechanisms in the brain do not simply control blood flow to support the metabolic needs of neurons, but form complex neurovascular interactions that influence neuronal function in health and disease. This article is part of the theme issue 'Key relationships between non-invasive functional neuroimaging and the underlying neuronal activity'.This work is supported by the British Academy (PF160048), the Guarantors of Brain (G101149), the Wellcome Trust (103838), the Medical Research Council (SUAG/051 G101400; and SUAG/046 G101400), European Union’s Horizon 2020 (732592) and the Cambridge NIHR Biomedical Research Centre

Nonlinear, multiple-input modeling of cerebral autoregulation using Volterra Kernel estimation

Autoregulation refers to the automatic adjustment of blood flow to supply the required oxygen and glucose and remove waste, in proportion to the tissue’s requirement at any instant of time. For the brain, cerebral autoregulation is an active process by which cerebral blood flow is controlled at an approximately steady level despite changes in the arterial blood pressure. Robust assessment of the cerebral autoregulation by a model that characterizes this system has been the goal of many studies, searching for techniques that can be used in clinical scenarios to detect potentially dangerous impairment of control. Multiple input, single output (MISO) models can be used to assess autoregulation, and system parameters can be estimated from spontaneous beat-to-beat variations in arterial blood pressure (ABP) and breath-by-breath end-tidal carbon dioxide (PETCO2) as inputs, and cerebral blood flow velocity (CBFV) as the output .In this study a non-linear, multivariate approach, based on Volterra-type kernel estimation models is employed. The results are compared with linear models as well as nonlinear single-input single-output (SISO) models. The normalized mean squared error was used as the criteria of performance of each model in assessing cerebral autoregulation. Our simulation results indicate that for relatively short signals (around 300 sec), nonlinear, multiple-input models based on Volterra systems performed best, though the benefit varied considerably between subjects. When using a fixed model for all recordings, a linear SISO model with ABP as input provided the smallest average modeling error.Keywords- Cerebral Autoregulation, Non-linear analysis, physiological systems, Blood pressure, CO2, Blood flow, Volterra Kernel Models, Laguerre- Volterra networks (LVNs)

CARDIO-RESPIRATORY INTERACTION AND ITS CONTRIBUTION IN SYNCOPE

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

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