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

Hemodynamic variability and cerebrovascular control after transient cerebral ischemia

We investigated if hemodynamic variability, cerebral blood flow (CBF) regulation, and their interrelationships differ between patients with transient ischemic attack (TIA) and controls. We recorded blood pressure (BP) and bilateral middle cerebral artery flow velocity (MCAv) in a cohort of TIA patients (n = 17), and age?matched controls (n = 15). Spontaneous fluctuations in BP and MCAv were characterized by spectral power analysis, and CBF regulation was assessed by wavelet phase synchronization analysis in the very low? (0.02–0.07 Hz), low? (0.07–0.20 Hz), and high?frequency (0.20–0.40 Hz) ranges. Furthermore, cerebrovascular CO2 reactivity was assessed as a second metric of CBF regulation by inducing hypercapnia with 8% CO2 inhalation followed by hyperventilation driven hypocapnia. We found that TIA was associated with higher BP power (group effect, P < 0.05), but not MCAv power (P = 0.11). CBF regulation (assessed by wavelet phase synchronization and CO2 reactivity) was intact in patients (all P ? 0.075) across both hemispheres (all P ? 0.51). Pooled data (controls and affected hemisphere of patients) showed that BP and MCAv power were positively correlated at all frequency ranges (R2 = 0.20–0.80, all P < 0.01). Furthermore, LF phase synchronization index was a significant determinant of MCAv power (P < 0.05), while VLF and HF phase synchronization index, and TIA were not (all P ? 0.50). These results indicate that CBF stability and control is maintained in TIA patients, but BPV is markedly elevated. BPV attenuation may be an important therapeutic strategy for enhancing secondary stroke prevention in patients who suffer a TIA

MRI-based cerebrovascular reactivity using transfer function analysis reveals temporal group differences between patients with sickle cell disease and healthy controls

AbstractObjectivesCerebrovascular reactivity (CVR) measures the ability of cerebral blood vessels to change their diameter and, hence, their capacity to regulate regional blood flow in the brain. High resolution quantitative maps of CVR can be produced using blood-oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) in combination with a carbon dioxide stimulus, and these maps have become a useful tool in the clinical evaluation of cerebrovascular disorders. However, conventional CVR analysis does not fully characterize the BOLD response to a stimulus as certain regions of the brain are slower to react to the stimulus than others, especially in disease. Transfer function analysis (TFA) is an alternative technique that can account for dynamic temporal relations between signals and has recently been adapted for CVR computation. We investigated the application of TFA in data on children with sickle cell disease (SCD) and healthy controls, and compared them to results derived from conventional CVR analysis.Materials and methodsData from 62 pediatric patients with SCD and 34 age-matched healthy controls were processed using conventional CVR analysis and TFA. BOLD data were acquired on a 3Tesla MRI scanner while a carbon dioxide stimulus was quantified by sampling the end-tidal partial pressures of each exhaled breath. In addition, T1 weighted structural imaging was performed to identify grey and white matter regions for analysis. The TFA method generated maps representing both the relative magnitude change of the BOLD signal in response to the stimulus (Gain), as well as the BOLD signal speed of response (Phase) for each subject. These were compared to CVR maps calculated from conventional analysis. The effect of applying TFA on data from SCD patients versus controls was also examined.ResultsThe Gain measures derived from TFA were significantly higher than CVR values based on conventional analysis in both SCD patients and healthy controls, but the difference was greater in the SCD data. Moreover, while these differences were uniform across the grey and white matter regions of controls, they were greater in white matter than grey matter in the SCD group. Phase was also shown to be significantly correlated with the amount that TFA increases CVR estimates in both the grey and white matter.ConclusionsWe demonstrated that conventional CVR analysis underestimates vessel reactivity and this effect is more prominent in patients with SCD. By using TFA, the resulting Gain and Phase measures more accurately characterize the BOLD response as it accounts for the temporal dynamics responsible for the CVR underestimation. We suggest that the additional information offered through TFA can provide insight into the mechanisms underlying CVR compromise in cerebrovascular diseases

Modeling the dynamics of cerebrovascular reactivity to carbon dioxide in fMRI under task and resting-state conditions

Conventionally, cerebrovascular reactivity (CVR) is estimated as the amplitude of the hemodynamic response to vascular stimuli, most commonly carbon dioxide (CO(2)). While the CVR amplitude has established clinical utility, the temporal characteristics of CVR (dCVR) have been increasingly explored and may yield even more pathology-sensitive parameters. This work is motivated by the current need to evaluate the feasibility of dCVR modeling in various experimental conditions. In this work, we present a comparison of several recently published/utilized model-based deconvolution (response estimation) approaches for estimating the CO(2) response function h(t), including maximum a posteriori likelihood (MAP), inverse logit (IL), canonical correlation analysis (CCA), and basis expansion (using Gamma and Laguerre basis sets). To aid the comparison, we devised a novel simulation framework that incorporates a wide range of SNRs, ranging from 10 to -7 dB, representative of both task and resting-state CO(2) changes. In addition, we built ground-truth h(t) into our simulation framework, overcoming the conventional limitation that the true h(t) is unknown. Moreover, to best represent realistic noise found in fMRI scans, we extracted noise from in-vivo resting-state scans. Furthermore, we introduce a simple optimization of the CCA method (CCA(opt)) and compare its performance to these existing methods. Our findings suggest that model-based methods can accurately estimate dCVR even amidst high noise (i.e. resting-state), and in a manner that is largely independent of the underlying model assumptions for each method. We also provide a quantitative basis for making methodological choices, based on the desired dCVR parameters, the estimation accuracy and computation time. The BEL method provided the highest accuracy and robustness, followed by the CCA(opt) and IL methods. Of the three, the CCA(opt) method has the lowest computational requirements. These findings lay the foundation for wider adoption of dCVR estimation in CVR mapping

Hybrid Optical System for Studying the Dynamic Regulation of Blood Flow/Metabolism in the Adult Brain

Cerebral blood flow (CBF) and oxygen delivery are tightly controlled to meet neuronal energy demands; however, studying dynamic neurovascular coupling in the human brain is challenging due to the lack of methods that can measure rapid changes in CBF and tissue oxygenation. This report presents an in-house-developed hybrid time-resolved near-infrared spectroscopy/diffuse correlation spectroscopy (TR-NIRS/DCS) device and its use to track dynamic CBF and tissue oxygen saturation (StO2) responses simultaneously with sub-second resolution following a vasodilatory stimulus (i.e., a hypercapnic challenge). Cerebrovascular reactivity (CVR) experiments were performed on 10 healthy participants (mean age: 27 years) using a computer-controlled gas delivery system to manipulate breath-to-breath inspired CO2 levels. TR-NIRS and DCS data were acquired continuously at a sampling frequency of 3 Hz to capture dynamic CBF and oxygenation responses. CVR measurements derived from oxyhemoglobin and deoxyhemoglobin concentrations were 3.4 ± 2.6 and 3.0 ± 1.9 %/mmHg, respectively. Their dynamic component, a fitted exponential coefficient that defines the speed of the response as per the hemodynamic response function, was estimated to be 32 ± 16 and 33 ± 28 seconds. The corresponding CVR value and dynamic component derived from CBF was 3.5 ± 3.6 %/mmHg and 33 ± 18 seconds. These experiments demonstrated that the optical system had sufficient temporal resolution to capture the dynamics of the oxygenation and CBF responses to a vasodilatory stimulus

A stochastic delay differential model of cerebral autoregulation

Mathematical models of the cardiovascular system and of cerebral autoregulation (CAR) have been employed for several years in order to describe the time course of pressures and flows changes subsequent to postural changes. The assessment of the degree of efficiency of cerebral auto regulation has indeed importance in the prognosis of such conditions as cerebro-vascular accidents or Alzheimer. In the quest for a simple but realistic mathematical description of cardiovascular control, which may be fitted onto non-invasive experimental observations after postural changes, the present work proposes a first version of an empirical Stochastic Delay Differential Equations (SDDEs) model. The model consists of a total of four SDDEs and two ancillary algebraic equations, incorporates four distinct delayed controls from the brain onto different components of the circulation, and is able to accurately capture the time course of mean arterial pressure and cerebral blood flow velocity signals, reproducing observed auto-correlated error around the expected drift

Cerebral blood flow autoregulation is impaired in schizophrenia

Patients with schizophrenia have a higher risk of cardiovascular diseases and higher mortality from them than does the general population; however, the underlying mechanism remains unclear. Impaired cerebral autoregulation is associated with cerebrovascular diseases and their mortality. Increased or decreased cerebral blood flow in different brain regions has been reported in patients with schizophrenia, which implies impaired cerebral autoregulation. This study investigated the cerebral autoregulation in 21 patients with schizophrenia and 23 age- and sex-matched healthy controls. None of the participants had a history of cardiovascular diseases, hypertension, or diabetes. All participants underwent 10-min blood pressure and cerebral blood flow recording through finger plethysmography and Doppler ultrasonography, respectively. Cerebral autoregulation was assessed by analyzing two autoregulation indices: the mean blood pressure and cerebral blood flow correlation coefficient (Mx), and the phase shift between the waveforms of blood pressure and cerebral blood flow determined using transfer function analysis. Compared with the controls, the patients had a significantly higher Mx (0.257 vs. 0.399, p = 0.036) and lower phase shift (44.3° vs. 38.7° in the 0.07–0.20 Hz frequency band, p = 0.019), which indicated impaired maintenance of constant cerebral blood flow and a delayed cerebrovascular autoregulatory response. Impaired cerebral autoregulation may be caused by schizophrenia and may not be an artifact of coexisting medical conditions. The mechanism underlying impaired cerebral autoregulation in schizophrenia and its probable role in the development of cerebrovascular diseases require further investigation

Aerospace medicine and biology: A continuing bibliography with indexes (supplement 349)

This bibliography lists 149 reports, articles and other documents introduced into the NASA Scientific and Technical Information System during April, 1991. Subject coverage includes: aerospace medicine and psychology, life support systems and controlled environments, safety equipment, exobiology and extraterrestrial life, and flight crew behavior and performance

Advanced MRI in cerebral small vessel disease

Cerebral small vessel disease (cSVD) is a major cause of stroke and dementia. This review summarizes recent developments in advanced neuroimaging of cSVD with a focus on clinical and research applications. In the first section, we highlight how advanced structural imaging techniques, including diffusion magnetic resonance imaging (MRI), enable improved detection of tissue damage, including characterization of tissue appearing normal on conventional MRI. These techniques enable progression to be monitored and may be useful as surrogate endpoint in clinical trials. Quantitative MRI, including iron and myelin imaging, provides insights into tissue composition on the molecular level. In the second section, we cover how advanced MRI techniques can demonstrate functional or dynamic abnormalities of the blood vessels, which could be targeted in mechanistic research and early-stage intervention trials. Such techniques include the use of dynamic contrast enhanced MRI to measure blood–brain barrier permeability, and MRI methods to assess cerebrovascular reactivity. In the third section, we discuss how the increased spatial resolution provided by ultrahigh field MRI at 7 T allows imaging of perforating arteries, and flow velocity and pulsatility within them. The advanced MRI techniques we describe are providing novel pathophysiological insights in cSVD and allow improved quantification of disease burden and progression. They have application in clinical trials, both in assessing novel therapeutic mechanisms, and as a sensitive endpoint to assess efficacy of interventions on parenchymal tissue damage. We also discuss challenges of these advanced techniques and suggest future directions for research

Blood oxygenation-level dependent cerebrovascular reactivity imaging as strategy to monitor CSF-hemoglobin toxicity

Objectives: Cell-free hemoglobin in the cerebrospinal fluid (CSF-Hb) may be one of the main drivers of secondary brain injury after aneurysmal subarachnoid hemorrhage (aSAH). Haptoglobin scavenging of CSF-Hb has been shown to mitigate cerebrovascular disruption. Using digital subtraction angiography (DSA) and blood oxygenation-level dependent cerebrovascular reactivity imaging (BOLD-CVR) the aim was to assess the acute toxic effect of CSF-Hb on cerebral blood flow and autoregulation, as well as to test the protective effects of haptoglobin. Methods: DSA imaging was performed in eight anesthetized and ventilated sheep (mean weight: 80.4 kg) at baseline, 15, 30, 45 and 60 minutes after infusion of hemoglobin (Hb) or co-infusion with haptoglobin (Hb:Haptoglobin) into the left lateral ventricle. Additionally, 10 ventilated sheep (mean weight: 79.8 kg) underwent BOLD-CVR imaging to assess the cerebrovascular reserve capacity. Results: DSA imaging did not show a difference in mean transit time or cerebral blood flow. Whole-brain BOLD-CVR compared to baseline decreased more in the Hb group after 15 minutes (Hb vs Hb:Haptoglobin: -0.03 ± 0.01 vs -0.01 ± 0.02) and remained diminished compared to Hb:Haptoglobin group after 30 minutes (Hb vs Hb:Haptoglobin: -0.03 ± 0.01 vs 0.0 ± 0.01), 45 minutes (Hb vs Hb:Haptoglobin: -0.03 ± 0.01 vs 0.01 ± 0.02) and 60 minutes (Hb vs Hb:Haptoglobin: -0.03 ± 0.02 vs 0.01 ± 0.01). Conclusion: It is demonstrated that CSF-Hb toxicity leads to rapid cerebrovascular reactivity impairment, which is blunted by haptoglobin co-infusion. BOLD-CVR may therefore be further evaluated as a monitoring strategy for CSF-Hb toxicity after aSAH