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Cognitive paradigms induce changes in cerebral blood flow (CBF) associated with increased metabolic demand, namely neurovascular coupling (NVC). We tested the hypothesis that the effect of complexity and duration of cognitive paradigms will either enhance or inhibit the NVC response. Bilateral CBF velocity (CBFV) in the middle cerebral arteries (MCAs) via transcranial Doppler ultrasound (TCD), blood pressure (BP), electrocardiogram (ECG) and end-tidal CO 2 (EtCO 2 ) of 16 healthy participants (aged 21–71 years) were simultaneously recorded at rest and during randomized paradigms of different complexities (naming words beginning with P-,R-,V- words and serial subtractions of 100–2,100–7,1000–17), and durations (5s, 30s and 60s). CBFV responses were population mean normalized from a 30-s baseline period prior to task initiation. A significant increase in bilateral CBFV response was observed at the start of all paradigms and provided a similar pattern in most responses, irrespective of complexity or duration. Although significant inter-hemispherical differences were found during performance of R-word and all serial subtraction paradigms, no lateralisation was observed in more complex naming word tasks. Also, the effect of duration was manifested at late stages of 100–7, but not for other paradigms. CBFV responses could not distinguish different levels of complexity or duration with a single presentation of the cognitive paradigm. Further studies of the ordinal scalability of the NVC response are needed with more advanced modelling techniques, or different types of neural stimulation.

Septic shock, a life-threatening condition, can result in cerebral dysfunction and heightened mortality rates. In these patients, disturbances in cerebral hemodynamics, as reflected by impairment of myogenic cerebral autoregulation (CA), metabolic regulation, expressed by critical closing pressure (CrCP) and reductions in intracranial compliance (ICC), can adversely impact septic shock outcomes. The general recommendation is to maintain a target mean arterial pressure (MAP) of 65 mmHg but the effect of different MAP targets on cerebral hemodynamics in these patients is not clear and optimal targets might be dependent on the status of CA. This protocol aims to assess the cerebral hemodynamics profile at different pressure targets in septic shock patients. Prospective, non-randomized, single-center trial, which will study cerebral hemodynamics in patients with septic shock within 48 hours of its onset. Patients will be studied at their baseline MAP and at three MAP targets (T1: 65, T2: 75, T3: 85 mmHg). Cerebral hemodynamics will be assessed by transcranial Doppler (TCD) and a skull micro-deformation sensor (B4C). Dynamic CA will be expressed by the autoregulation index (ARI), calculated by transfer function analysis, using fluctuations of MAP as input and corresponding oscillations in cerebral blood velocity (CBv). The instantaneous relationship between arterial blood pressure and CBv will be used to estimate CrCP and resistance-area product (RAP) for each cardiac cycle using the first harmonic method. The B4C will access ICC by intracranial pressure waveforms (P2/P1). The primary aim is to assess cerebral hemodynamics (ARI, CrCP, RAP, and P2/P1) at different targets of MAP in septic shock patients. Our secondary objective is to assess cerebral hemodynamics at 65mmHg (target recommended by guidelines). In addition, we will assess the correlation between markers of organ dysfunction (such as lactate levels, vasoactive drugs usage, SOFA score, and delirium) and CA. The results of this study may help to understand the effect of the recommended MAP and variations in blood pressure in patients with septic shock and impaired CA and ICC. Furthermore, the results can assist large trials in establishing new hypotheses about neurological management in this group of patients. Approval was obtained from the local Ethics Committee (28134720.1.0000.0048). It is anticipated that the results of this study will be presented at national and international conferences and will be published in peer-reviewed journals in 2024 and 2025. Trial registration number: NCT05833607. https://clinicaltrials.gov/study/NCT05833607.

Transcranial Doppler ultrasound (TCD) can measure cerebral blood flow velocity in the main intracranial vessels non-invasively and with high accuracy. Combined with the availability of non-invasive devices for continuous measurement of arterial blood pressure, the relatively low cost, ease-of-use, and excellent temporal resolution of TCD have stimulated the development of new techniques to assess cerebral autoregulation in the laboratory or bedside using a dynamic approach, instead of the more classical ‘static’ method. Clinical applications have shown consistent results in certain conditions such as severe head injury and carotid artery disease. Studies in syncopal patients revealed a more complex pattern due to aetiological non-homogeneity and methodological limitations mainly due to inadequate sample-size. Different analytical models to quantify autoregulatory performance have also contributed to the diversity of results in the literature. The review concludes with specific recommendations for areas where further validation and research are needed to improve the reliability and usefulness of TCD in clinical practice.

[...]the lack of efficacy for amyloid-based targets may suggest amyloid is a by-product rather than causative agent of the disease process. [...]the potential efficacy in a sub-group of early AD (Tolar et al., 2020) suggests that amyloid is a late occurrence in the disease process, at which stage irrevocable damage and cognitive decline has ensued. [...]amyloid deposition damages the cerebrovasculature, both structurally and functionally, therefore worsening hypoperfusion in a cyclical fashion (Nelson et al., 2016). [...]deficiencies occurring in one or more components of the NVU threaten this tightly coordinated system.

Despite careful patient selection, successful recanalization in intravenous thrombolysis is only achieved in approximately 50% of cases. Understanding changes in cerebral autoregulation during and following successful recanalization in acute ischemic stroke patients who receive intravenous thrombolysis, may inform the management of common physiological perturbations, including blood pressure, in turn reducing the risk of reperfusion injury. Cerebral blood velocity (Transcranial Doppler), blood pressure (Finometer) and end-tidal carbon dioxide (capnography) were continuously recorded in 11 acute ischemic stroke patients who received intravenous thrombolysis (5 female, mean ± SD age 68±12 years) over 4-time points, during and at the following time intervals after intravenous thrombolysis: 23.9±2.6 hrs, 18.1±7.0 days and 89.6±4.2 days. Reductions in blood pressure (p = 0.04) were observed during intravenous thrombolysis. Reductions in heart rate (p<0.005) and critical closing pressure [Affected hemisphere (p = 0.02) and non-affected hemisphere (p<0.005)] were observed post intravenous thrombolysis. End-tidal CO2 increased during the sub-acute and chronic stages (p = 0.028). Reduction in affected hemisphere phase at low frequency was observed during intravenous thrombolysis (p = 0.021) and at subsequent visits (p = 0.048). No changes were observed in cerebral blood velocity, coherence, gain and Autoregulation Index during the follow-up period. Intravenous thrombolysis in acute ischemic stroke patients induced changes in affected hemisphere phase and other key hemodynamic parameters, but not Autoregulation Index. Further investigation of cerebral autoregulation is warranted in a larger acute ischemic stroke cohort to inform its potential role in individualized management plans.

The ability to discriminate between normal and impaired dynamic cerebral autoregulation (CA), based on measurements of spontaneous fluctuations in arterial blood pressure (BP) and cerebral blood flow (CBF), has considerable clinical relevance. We studied 45 normal subjects at rest and under hypercapnia induced by breathing a mixture of carbon dioxide and air. Non-linear models with BP as input and CBF velocity (CBFV) as output, were implemented with support vector machines (SVM) using separate recordings for learning and validation. Dynamic SVM implementations used either moving average or autoregressive structures. The efficiency of dynamic CA was estimated from the model's derived CBFV response to a step change in BP as an autoregulation index for both linear and non-linear models. Non-linear models with recurrences (autoregressive) showed the best results, with CA indexes of 5.9 ± 1.5 in normocapnia, and 2.5 ± 1.2 for hypercapnia with an area under the receiver-operator curve of 0.955. The high performance achieved by non-linear SVM models to detect deterioration of dynamic CA should encourage further assessment of its applicability to clinical conditions where CA might be impaired.

Short-term regulation of cerebral blood flow (CBF) is controlled by myogenic, metabolic and neurogenic mechanisms, which maintain flow within narrow limits, despite large changes in arterial blood pressure (ABP). Static cerebral autoregulation (CA) represents the steady-state relationship between CBF and ABP, characterized by a plateau of nearly constant CBF for ABP changes in the interval 60–150 mmHg. The transient response of the CBF–ABP relationship is usually referred to as dynamic CA and can be observed during spontaneous fluctuations in ABP or from sudden changes in ABP induced by thigh cuff deflation, changes in posture and other manoeuvres. Modelling the dynamic ABP–CBFV relationship is an essential step to gain better insight into the physiology of CA and to obtain clinically relevant information from model parameters. This paper reviews the literature on the application of CA models to different clinical conditions. Although mathematical models have been proposed and should be pursued, most studies have adopted linear input–output (‘black-box’) models, despite the inherently non-linear nature of CA. The most common of these have been transfer function analysis (TFA) and a second-order differential equation model, which have been the main focus of the review. An index of CA (ARI), and frequency-domain parameters derived from TFA, have been shown to be sensitive to pathophysiological changes in patients with carotid artery disease, stroke, severe head injury, subarachnoid haemorrhage and other conditions. Non-linear dynamic models have also been proposed, but more work is required to establish their superiority and applicability in the clinical environment. Of particular importance is the development of multivariate models that can cope with time-varying parameters, and protocols to validate the reproducibility and ranges of normality of dynamic CA parameters extracted from these models.

The population is ageing worldwide, thus increasing the burden of common age-related disorders to the individual, society and economy. Cerebrovascular diseases (stroke, dementia) contribute a significant proportion of this burden and are associated with high morbidity and mortality. Thus, understanding and promoting healthy vascular brain ageing are becoming an increasing priority for healthcare systems. In this review, we consider the effects of normal ageing on two major physiological processes responsible for vascular brain function: Cerebral autoregulation (CA) and neurovascular coupling (NVC). CA is the process by which the brain regulates cerebral blood flow (CBF) and protects against falls and surges in cerebral perfusion pressure, which risk hypoxic brain injury and pressure damage, respectively. In contrast, NVC is the process by which CBF is matched to cerebral metabolic activity, ensuring adequate local oxygenation and nutrient delivery for increased neuronal activity. Healthy ageing is associated with a number of key physiological adaptations in these processes to mitigate age-related functional and structural declines. Through multiple different paradigms assessing CA in healthy younger and older humans, generating conflicting findings, carbon dioxide studies in CA have provided the greatest understanding of intrinsic vascular anatomical factors that may mediate healthy ageing responses. In NVC, studies have found mixed results, with reduced, equivalent and increased activation of vascular responses to cognitive stimulation. In summary, vascular and haemodynamic changes occur in response to ageing and are important in distinguishing “normal” ageing from disease states and may help to develop effective therapeutic strategies to promote healthy brain ageing.

The brain is a fundamental organ for the human body to function properly, for which it needs to receive a continuous flow of blood, which explains the existence of control mechanisms that act to maintain this flow as constant as possible in a process known as cerebral autoregulation. One way to obtain information on how the levels of oxygen supplied to the brain vary is through of BOLD (Magnetic Resonance) images, which have the advantage of greater spatial resolution than other forms of measurement, such as transcranial Doppler. However, they do not provide good temporal resolution nor allow for continuous prolonged examination. Thus, it is of great importance to find a method to detect regional differences from short BOLD signals. One of the existing alternatives is complexity measures that can detect changes in the variability and temporal organisation of a signal that could reflect different physiological states. The so-called statistical complexity, created to overcome the shortcomings of entropy alone to explain the concept of complexity, has shown potential with haemodynamic signals. The aim of this study is to determine by using statistical complexity whether it is possible to find differences between physiologically distinct brain areas in healthy individuals. The data set includes BOLD images of 10 people obtained at the University Hospital of Leicester NHS Trust with a 1.5 Tesla magnetic resonance imaging scanner. The data were captured for 180 s at a frequency of 1 Hz. Using various combinations of statistical complexities, no differences were found between hemispheres. However, differences were detected between grey matter and white matter, indicating that these measurements are sensitive to differences in brain tissues.

We hypothesized that knowledge of cerebral autoregulation (CA) status during recanalization therapies could guide further studies aimed at neuroprotection targeting penumbral tissue, especially in patients that do not respond to therapy. Thus, we assessed CA status of patients with acute ischemic stroke (AIS) during intravenous r-tPA therapy and associated CA with response to therapy. AIS patients eligible for intravenous r-tPA therapy were recruited. Cerebral blood flow velocities (transcranial Doppler) from middle cerebral artery and blood pressure (Finometer) were recorded to calculate the autoregulation index (ARI, as surrogate for CA). National Institute of Health Stroke Score was assessed and used to define responders to therapy (improvement of ≥ 4 points on NIHSS measured 24–48 h after therapy). CA was considered impaired if ARI < 4. In 38 patients studied, compared to responders, non-responders had significantly lower ARI values (affected hemisphere: 5.0 vs. 3.6; unaffected hemisphere: 5.4 vs. 4.4, p  = 0.03) and more likely to have impaired CA (32% vs. 62%, p  = 0.02) during thrombolysis. In conclusion, CA during thrombolysis was impaired in patients who did not respond to therapy. This variable should be investigated as a predictor of the response to therapy and to subsequent neurological outcome.