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

Revisiting the frequency domain: the multiple and partial coherence of cerebral blood flow velocity in the assessment of dynamic cerebral autoregulation

Despite advances in modelling dynamic autoregulation, only part of the variability of cerebral blood flow velocity (CBFV) in the low frequency range has been explained. We investigate whether a multivariate representation can be used for this purpose. Pseudorandom sequences were used to inflate thigh cuffs and to administer 5% CO2. Multiple and partial coherence were estimated, using arterial blood pressure (ABP), end-tidal CO2 (EtCO2) and resistance area product as input and CBFV as output variables. The inclusion of second and third input variables increased the amount of CBFV variability that can be accounted for (p  <  10−4 in both cases). Partial coherence estimates in the low frequency range (<0.07 Hz) were not influenced by the use of thigh cuffs, but CO2 administration had a statistically significant effect (p  <  10−4 in all cases). We conclude that the inclusion of additional inputs of a priori known physiological significance can help account for a greater amount of CBFV variability and may represent a viable alternative to more conventional non-linear modelling. The results of partial coherence analysis suggest that dynamic autoregulation and CO2 reactivity are likely to be the result of different physiological mechanisms

Detection of impaired cerebral autoregulation improves by increasing arterial blood pressure variability

Although the assessment of dynamic cerebral autoregulation (CA) based on measurements of spontaneous fluctuations in arterial blood pressure (ABP) and cerebral blood flow (CBF) is a convenient and much used method, there remains uncertainty about its reliability. We tested the effects of increasing ABP variability, provoked by a modification of the thigh cuff method, on the ability of the autoregulation index to discriminate between normal and impaired CA, using hypercapnia as a surrogate for dynamic CA impairment. In 30 healthy volunteers, ABP (Finapres) and CBF velocity (CBFV, transcranial Doppler) were recorded at rest and during 5% CO(2) breathing, with and without pseudo-random sequence inflation and deflation of bilateral thigh cuffs. The application of thigh cuffs increased ABP and CBFV variabilities and was not associated with a distortion of the CBFV step response estimates for both normocapnic and hypercapnic conditions (P=0.59 and P=0.96, respectively). Sensitivity and specificity of CA impairment detection were improved with the thigh cuff method, with the area under the receiver-operator curve increasing from 0.746 to 0.859 (P=0.031). We conclude that the new method is a safe, efficient, and appealing alternative to currently existing assessment methods for the investigation of the status of CA

Coherent averaging of pseudorandom binary stimuli: is the dynamic cerebral autoregulatory response symmetrical?

Objective: Previous studies on cerebral autoregulation have shown the existence of hemispheric symmetry, which may be altered in stroke and traumatic brain injury. There is a paucity of data however on whether the response is symmetrical between those disturbances that cause cerebral hyperperfusion, to those that cause hypoperfusion. Our aim was to investigate whether the responses of cerebral autoregulation to haemodynamic stimuli of different directions are symmetrical. &#13; Approach: Using a previously described assessment method, we employed coherent averaging of the cerebral blood flow velocity (CBFV) responses to thigh cuff inflation and deflation, as driven by pseudorandom binary sequences, whilst simultaneously altering the inspired CO2. The symmetry of the autoregulatory response was assessed with regards to two parameters, its speed and gain. Using the first harmonic method, critical closing pressure (CrCP) and resistance area product (RAP) were estimated, and the gain of the autoregulatory response was calculated by performing linear regression between the coherent averages of arterial blood pressure (ABP) and CBFV, ABP and CrCP and finally ABP and RAP. A two-way repeated measures ANOVA was used to assess for the effect of the direction of change in ABP and the method of CO2 administration. &#13; Main results: Our results suggest that whilst the direction of ABP change does not have a significant effect, the effect of CO2 administration method is highly significant (p&lt;10-4). &#13; Significance: This is the first report to report to demonstrate the symmetry of the autoregulatory response to stimuli of different directions as well as the short term dynamics of RAP and CrCP under intermittent and constant hypercapnia. As haemodynamic stimulus direction does not appear to have an influence, our findings validate previous work done using different assessment methods

Tissue Doppler imaging of carotid plaque wall motion: a pilot study

BACKGROUND: Studies suggest the physical and mechanical properties of vessel walls and plaque may be of clinical value in the diagnosis and treatment of cardiovascular atherosclerotic disease. The purpose of this pilot study was to investigate the potential clinical application of ultrasound Tissue Doppler Imaging (TDI) of Arterial Wall Motion (AWM) and to quantify simple wall motion indices in normal and diseased carotid arteries. METHODS: 224 normal and diseased carotid arteries (0–100% stenoses) were imaged in 126 patients (age 25–88 years, mean 68 ± 11). Longitudinal sections of the carotid bifurcation were imaged using a Philips HDI5000 scanner and L12-5 probe under optimized TDI settings. Temporal and spatial AWMs were analyzed to evaluate the vessel wall displacements and spatial gradients at peak systole averaged over 5 cardiac cycles. RESULTS: AWM data were successfully extracted in 91% of cases. Within the carotid bifurcation/plaque region, the maximum wall dilation at peak systole ranged from -100 to 750 microns, mean 335 ± 138 microns. Maximum wall dilation spatial gradients ranged 0–0.49, mean 0.14 ± 0.08. The AWM parameters showed a wide variation and had poor correlation with stenoses severity. Case studies illustrated a variety of pertinent qualitative and quantitative wall motion features related to the biophysics of arterial disease. CONCLUSION: Our clinical experience, using a challenging but realistic imaging protocol, suggests the use of simple quantitative AWM measures may have limitations due to high variability. Despite this, pertinent features of AWM in normal and diseased arteries demonstrate the potential clinical benefit of the biomechanical information provided by TDI

The Neurovascular Unit in Dementia: An Opinion on Current Research and Future Directions

Dementia is a burgeoning public health crisis, with 50 million people currently affected worldwide (Prince et al., 2015). As the population ages, this figure is set to rise dramatically by 40% over the next 12 years (Prince et al., 2015). Dementia is an umbrella term for several disorders which result in the progressive loss of memory or other cognitive functions (Scott and Barrett, 2007). It remains an incurable disease, and current therapeutics have limited efficacy at slowing disease progression for one third of patients (Rockwood et al., 2008). Of the dementia sub-types, Alzheimer's disease (AD) remains the most prevalent, accounting for ~60–70% cases (Alzheimer's-Society, 2016). Vascular dementia (VaD) is the second most common form and is responsible for ~20% of cases, with a further 10% being a combination of these two diseases (Alzheimer's-Society, 2016). However, in practise these distinctions are somewhat arbitrary given the significant overlap in altered vascular structure and function in both of these major sub-types (Kalaria and Ballard, 1999). At least 30% of patients with AD have evidence of cerebrovascular disease on post-mortem examination, and almost all have evidence of cerebral amyloid angiopathy, microvascular degeneration, and white matter lesions (Kalaria and Ballard, 1999). Similarly, one-third of patients with VaD exhibit pathology consistent with AD (e.g., hippocampal or temporal lobe atrophy) (Kalaria and Ballard, 1999). Longitudinal studies have demonstrated that vascular risk factors (e.g., hypertension), significantly increase the risk of both AD and VaD (Rius-Pérez et al., 2018). In genetically at-risk individuals positive for apolipoprotein E4 (APOE4), atherosclerosis can increase the risk of AD by three-fold (Hoffmann et al., 2010). This article provides an opinion on the current evidence on the role of the neurovascular unit in dementia, for further information, several recent reviews are available on this topic (Nelson et al., 2016; Kisler et al., 2017)

The INfoMATAS project: methods for assessing cerebral autoregulation in stroke

Cerebral autoregulation refers to the physiological mechanism that aims to maintain blood flow to the brain approximately constant when blood pressure changes. Impairment of this protective mechanism has been linked to a number of serious clinical conditions, including carotid stenosis, head trauma, subarachnoid haemorrhage and stroke. While the concept and experimental evidence is well established, methods for the assessment of autoregulation in individual patients remains an open challenge, with no gold-standard having emerged. In the current review paper, we will outline some of the basic concepts of autoregulation, as a foundation for experimental protocols and signal analysis methods used to extract indexes of cerebral autoregulation. Measurement methods for blood flow and pressure are discussed, followed by an outline of signal pre-processing steps. An outline of the data analysis methods is then provided, linking the different approaches through their underlying principles and rationale. The methods cover correlation based approaches (e.g. Mx) through Transfer Function Analysis to non-linear, multivariate and time-variant approaches. Challenges in choosing which method may be ‘best’ and some directions for ongoing and future research conclude this work