Time-domain methods for quantifying dynamic cerebral blood flow autoregulation: Review and recommendations. A white paper from the Cerebrovascular Research Network (CARNet).

Cerebral Autoregulation (CA) is an important physiological mechanism stabilizing cerebral blood flow (CBF) in response to changes in cerebral perfusion pressure (CPP). By maintaining an adequate, relatively constant supply of blood flow, CA plays a critical role in brain function. Quantifying CA under different physiological and pathological states is crucial for understanding its implications. This knowledge may serve as a foundation for informed clinical decision-making, particularly in cases where CA may become impaired. The quantification of CA functionality typically involves constructing models that capture the relationship between CPP (or arterial blood pressure) and experimental measures of CBF. Besides describing normal CA function, these models provide a means to detect possible deviations from the latter. In this context, a recent white paper from the Cerebrovascular Research Network focused on Transfer Function Analysis (TFA), which obtains frequency domain estimates of dynamic CA. In the present paper, we consider the use of time-domain techniques as an alternative approach. Due to their increased flexibility, time-domain methods enable the mitigation of measurement/physiological noise and the incorporation of nonlinearities and time variations in CA dynamics. Here, we provide practical recommendations and guidelines to support researchers and clinicians in effectively utilizing these techniques to study CA.

Videoconference fatigue from a neurophysiological perspective: experimental evidence based on electroencephalography (EEG) and electrocardiography (ECG).

In the recent past, many organizations and people have substituted face-to-face meetings with videoconferences. Among others, tools like Zoom, Teams, and Webex have become the "new normal" of human social interaction in many domains (e.g., business, education). However, this radical adoption and extensive use of videoconferencing tools also has a dark side, referred to as videoconference fatigue (VCF). To date only self-report evidence has shown that VCF is a serious issue. However, based on self-reports alone it is hardly possible to provide a comprehensive understanding of a cognitive phenomenon like VCF. Against this background, we examined VCF also from a neurophysiological perspective. Specifically, we collected and analyzed electroencephalography (continuous and event-related) and electrocardiography (heart rate and heart rate variability) data to investigate whether VCF can also be proven on a neurophysiological level. We conducted a laboratory experiment based on a within-subjects design (N = 35). The study context was a university lecture, which was given in a face-to-face and videoconferencing format. In essence, the neurophysiological data-together with questionnaire data that we also collected-show that 50 min videoconferencing, if compared to a face-to-face condition, results in changes in the human nervous system which, based on existing literature, can undoubtedly be interpreted as fatigue. Thus, individuals and organizations must not ignore the fatigue potential of videoconferencing. A major implication of our study is that videoconferencing should be considered as a possible complement to face-to-face interaction, but not as a substitute.

Getting off track: Cortical feedback processing network modulated by continuous error signal during target-feedback mismatch.

Performance monitoring and feedback processing - especially in the wake of erroneous outcomes - represent a crucial aspect of everyday life, allowing us to deal with imminent threats in the short term but also promoting necessary behavioral adjustments in the long term to avoid future conflicts. Over the last thirty years, research extensively analyzed the neural correlates of processing discrete error stimuli, unveiling the error-related negativity (ERN) and error positivity (Pe) as two main components of the cognitive response. However, the connection between the ERN/Pe and distinct stages of error processing, ranging from action monitoring to subsequent corrective behavior, remains ambiguous. Furthermore, mundane actions such as steering a vehicle already transgress the scope of discrete erroneous events and demand fine-tuned feedback control, and thus, the processing of continuous error signals - a topic scarcely researched at present. We analyzed two electroencephalography datasets to investigate the processing of continuous erroneous signals during a target tracking task, employing feedback in various levels and modalities. We observed significant differences between correct (slightly delayed) and erroneous feedback conditions in the larger one of the two datasets that we analyzed, both in sensor and source space. Furthermore, we found strong error-induced modulations that appeared consistent across datasets and error conditions, indicating a clear order of engagement of specific brain regions that correspond to individual components of error processing.

Using linear parameter varying autoregressive models to measure cross frequency couplings in EEG signals.

For years now, phase-amplitude cross frequency coupling (CFC) has been observed across multiple brain regions under different physiological and pathological conditions. It has been suggested that CFC serves as a mechanism that facilitates communication and information transfer between local and spatially separated neuronal populations. In non-invasive brain computer interfaces (BCI), CFC has not been thoroughly explored. In this work, we propose a CFC estimation method based on Linear Parameter Varying Autoregressive (LPV-AR) models and we assess its performance using both synthetic data and electroencephalographic (EEG) data recorded during attempted arm/hand movements of spinal cord injured (SCI) participants. Our results corroborate the potentiality of CFC as a feature for movement attempt decoding and provide evidence of the superiority of our proposed CFC estimation approach compared to other commonly used techniques.

Point/counterpoint: We should not take the direction of blood pressure change into consideration for dynamic cerebral autoregulation quantification.

Over the past years, a wide range of studies have provided evidence of asymmetry in the response of static and dynamic cerebral autoregulation (CA) during increasing and decreasing pressure challenges. The main message is that CA is stronger during transient increases of arterial blood pressure rather than decreases. Here we do not argue against the presence of CA asymmetry but we seek to raise questions regarding the measurement of the effect and whether this effect needs to be taken into account, especially in clinical settings.

Measuring Spinal Cord Potentials and Cortico-Spinal Interactions After Wrist Movements Induced by Neuromuscular Electrical Stimulation.

Electroencephalographic (EEG) correlates of movement have been studied extensively over many years. In the present work, we focus on investigating neural correlates that originate from the spine and study their connectivity to corresponding signals from the sensorimotor cortex using multivariate autoregressive (MVAR) models. To study cortico-spinal interactions, we simultaneously measured spinal cord potentials (SCPs) and somatosensory evoked potentials (SEPs) of wrist movements elicited by neuromuscular electrical stimulation. We identified directional connections between spine and cortex during both the extension and flexion of the wrist using only non-invasive recording techniques. Our connectivity estimation results are in alignment with various studies investigating correlates of movement, i.e., we found the contralateral side of the sensorimotor cortex to be the main sink of information as well as the spine to be the main source of it. Both types of movement could also be clearly identified in the time-domain signals.

Corrigendum: Mental State Detection Using Riemannian Geometry on Electroencephalogram Brain Signals.

[This corrects the article DOI: 10.3389/fnhum.2021.746081.].

Mental State Detection Using Riemannian Geometry on Electroencephalogram Brain Signals.

The goal of this study was to implement a Riemannian geometry (RG)-based algorithm to detect high mental workload (MWL) and mental fatigue (MF) using task-induced electroencephalogram (EEG) signals. In order to elicit high MWL and MF, the participants performed a cognitively demanding task in the form of the letter n-back task. We analyzed the time-varying characteristics of the EEG band power (BP) features in the theta and alpha frequency band at different task conditions and cortical areas by employing a RG-based framework. MWL and MF were considered as too high, when the Riemannian distances of the task-run EEG reached or surpassed the threshold of the baseline EEG. The results of this study showed a BP increase in the theta and alpha frequency bands with increasing experiment duration, indicating elevated MWL and MF that impedes/hinders the task performance of the participants. High MWL and MF was detected in 8 out of 20 participants. The Riemannian distances also showed a steady increase toward the threshold with increasing experiment duration, with the most detections occurring toward the end of the experiment. To support our findings, subjective ratings (questionnaires concerning fatigue and workload levels) and behavioral measures (performance accuracies and response times) were also considered.

Assessment of dynamic cerebral autoregulation in humans: Is reproducibility dependent on blood pressure variability?

We tested the influence of blood pressure variability on the reproducibility of dynamic cerebral autoregulation (DCA) estimates. Data were analyzed from the 2nd CARNet bootstrap initiative, where mean arterial blood pressure (MABP), cerebral blood flow velocity (CBFV) and end tidal CO2 were measured twice in 75 healthy subjects. DCA was analyzed by 14 different centers with a variety of different analysis methods. Intraclass Correlation (ICC) values increased significantly when subjects with low power spectral density MABP (PSD-MABP) values were removed from the analysis for all gain, phase and autoregulation index (ARI) parameters. Gain in the low frequency band (LF) had the highest ICC, followed by phase LF and gain in the very low frequency band. No significant differences were found between analysis methods for gain parameters, but for phase and ARI parameters, significant differences between the analysis methods were found. Alternatively, the Spearman-Brown prediction formula indicated that prolongation of the measurement duration up to 35 minutes may be needed to achieve good reproducibility for some DCA parameters. We conclude that poor DCA reproducibility (ICC<0.4) can improve to good (ICC > 0.6) values when cases with low PSD-MABP are removed, and probably also when measurement duration is increased.

Cerebrovascular Pulsatility During Rest and Exercise Reflects Hemodynamic Impairment in Stroke and Cerebral Small Vessel Disease.

Although aerobic exercise is recommended as a core component of stroke rehabilitation, knowledge of acute cerebrovascular responses in patients is limited. This study tested the hypothesis that older adults with chronic stroke or cerebral small vessel disease (SVD) exhibit a greater increase in pulsatile hemodynamics during exercise compared with young and age-matched healthy adults. Middle cerebral artery blood flow velocity was acquired during 20 min of moderate intensity cycling in 51 participants from four groups (young, old, SVD and stroke). During rest, only the stroke group had a higher pulsatility index (PI) compared with the young group (1.02 ± 0.17 vs 0.83 ± 0.13; p = 0.038). During exercise, however, the SVD group exhibited a larger increase in PI (68 ± 20% relative to rest) than the young (47 ± 19%), old (45 ± 17%) and stroke (40 ± 25%) groups (p < 0.05, for each). The stress of aerobic exercise may reveal arterial dysfunction associated with latent and overt cerebrovascular disease.

Dynamic Cerebral Autoregulation Reproducibility Is Affected by Physiological Variability.

Parameters describing dynamic cerebral autoregulation (DCA) have limited reproducibility. In an international, multi-center study, we evaluated the influence of multiple analytical methods on the reproducibility of DCA. Fourteen participating centers analyzed repeated measurements from 75 healthy subjects, consisting of 5 min of spontaneous fluctuations in blood pressure and cerebral blood flow velocity signals, based on their usual methods of analysis. DCA methods were grouped into three broad categories, depending on output types: (1) transfer function analysis (TFA); (2) autoregulation index (ARI); and (3) correlation coefficient. Only TFA gain in the low frequency (LF) band showed good reproducibility in approximately half of the estimates of gain, defined as an intraclass correlation coefficient (ICC) of >0.6. None of the other DCA metrics had good reproducibility. For TFA-like and ARI-like methods, ICCs were lower than values obtained with surrogate data (p < 0.05). For TFA-like methods, ICCs were lower for the very LF band (gain 0.38 ± 0.057, phase 0.17 ± 0.13) than for LF band (gain 0.59 ± 0.078, phase 0.39 ± 0.11, p ≤ 0.001 for both gain and phase). For ARI-like methods, the mean ICC was 0.30 ± 0.12 and for the correlation methods 0.24 ± 0.23. Based on comparisons with ICC estimates obtained from surrogate data, we conclude that physiological variability or non-stationarity is likely to be the main reason for the poor reproducibility of DCA parameters.

A Novel Framework for Estimating Time-Varying Multivariate Autoregressive Models and Application to Cardiovascular Responses to Acute Exercise.

OBJECTIVE: We present a novel modeling framework for identifying time-varying (TV) couplings between time-series of biomedical relevance. METHODS: The proposed methodology is based on multivariate autoregressive (MVAR) models, which have been extensively used to study couplings between biosignals. Contrary to the standard estimation methods that assume time-invariant relationships, we propose a modified recursive Kalman filter (KF) to track changes in the model parameters. We perform model order selection and hyperparameter optimization simultaneously using Genetic Algorithms, greatly improving accuracy and computation time. In addition, we address the effect of residual heteroscedasticity, possibly associated with event-related changes or phase transitions during a given experimental protocol, on the TV-MVAR coupling measures by using Generalized Autoregressive Conditional Heteroskedasticity (GARCH) models to fit the TV-MVAR residuals. RESULTS: Using simulated data, we show that the proposed framework yields more accurate parameter estimates compared to the conventional KF, particularly when the true system parameters exhibit different rate of variations over time. Furthermore, by accounting for heteroskedasticity, we obtain more accurate estimates of the strength and directionality of the underlying couplings. We also use our approach to investigate TV hemodynamic interactions during exercise in young and old healthy adults, as well as individuals with chronic stroke. We extract TV coupling patterns that reflect well known exercise-induced effects on the underlying regulatory mechanisms with excellent time resolution. CONCLUSION AND SIGNIFICANCE: The proposed modeling framework can be used to efficiently quantify TV couplings between biosignals. It is fully automated and does not require prior knowledge of the system TV characteristics.

Reproducibility of dynamic cerebral autoregulation parameters: a multi-centre, multi-method study.

OBJECTIVE: Different methods to calculate dynamic cerebral autoregulation (dCA) parameters are available. However, most of these methods demonstrate poor reproducibility that limit their reliability for clinical use. Inter-centre differences in study protocols, modelling approaches and default parameter settings have all led to a lack of standardisation and comparability between studies. We evaluated reproducibility of dCA parameters by assessing systematic errors in surrogate data resulting from different modelling techniques. APPROACH: Fourteen centres analysed 22 datasets consisting of two repeated physiological blood pressure measurements with surrogate cerebral blood flow velocity signals, generated using Tiecks curves (autoregulation index, ARI 0-9) and added noise. For reproducibility, dCA methods were grouped in three broad categories: 1. Transfer function analysis (TFA)-like output; 2. ARI-like output; 3. Correlation coefficient-like output. For all methods, reproducibility was determined by one-way intraclass correlation coefficient analysis (ICC). MAIN RESULTS: For TFA-like methods the mean (SD; [range]) ICC gain was 0.71 (0.10; [0.49-0.86]) and 0.80 (0.17; [0.36-0.94]) for VLF and LF (p = 0.003) respectively. For phase, ICC values were 0.53 (0.21; [0.09-0.80]) for VLF, and 0.92 (0.13; [0.44-1.00]) for LF (p < 0.001). Finally, ICC for ARI-like methods was equal to 0.84 (0.19; [0.41-0.94]), and for correlation-like methods, ICC was 0.21 (0.21; [0.056-0.35]). SIGNIFICANCE: When applied to realistic surrogate data, free from the additional exogenous influences of physiological variability on cerebral blood flow, most methods of dCA modelling showed ICC values considerably higher than what has been reported for physiological data. This finding suggests that the poor reproducibility reported by previous studies may be mainly due to the inherent physiological variability of cerebral blood flow regulatory mechanisms rather than related to (stationary) random noise and the signal analysis methods.

Identification of Time-Varying Cortico-cortical and Cortico-Muscular Coherence during Motor Tasks with Multivariate Autoregressive Models.

Neural populations coordinate at fast subsecond time-scales during rest and task execution. As a result, functional brain connectivity assessed with different neuroimaging modalities (EEG, MEG, fMRI) may also change over different time scales. In addition to the more commonly used sliding window techniques, the General Linear Kalman Filter (GLFK) approach has been proposed to estimate time-varying brain connectivity. In the present work, we propose a modification of the GLFK approach to model timevarying connectivity. We also propose a systematic method to select the hyper-parameters of the model. We evaluate the performance of the method using MEG and EMG data collected from 12 young subjects performing two motor tasks (unimanual and bimanual hand grips), by quantifying time-varying cortico-cortical and corticomuscular coherence (CCC and CMC). The CMC results revealed patterns in accordance with earlier findings, as well as an improvement in both time and frequency resolution compared to sliding window approaches. These results suggest that the proposed methodology is able to unveil accurate time-varying connectivity patterns with an excellent time resolution.

Prediction of the Time to Syncope Occurrence in Patients Diagnosed with Vasovagal Syncope.

OBJECTIVE: In this study we aimed to predict the time to syncope occurrence (TSO) in patients with vasovagal syncope (VVS), solely based on measurements recorded during the supine position of the head-up tilt (HUT) testing protocol. METHODS: We extracted various time and frequency domain features related to morphological aspects of arterial blood pressure (ABP) and the electrocardiogram (ECG) raw signals as well as to dynamic interactions between beat-to-beat ABP, heart rate, and cerebral blood flow velocity. From these we identified the most predictive features related to TSO. RESULTS: Specifically, when no orthostatic stress is involved, TSO in VVS patients can be predicted with high accuracy from a set of only five ECG features.

Classification and Prediction of Clinical Improvement in Deep Brain Stimulation From Intraoperative Microelectrode Recordings.

We present a random forest (RF) classification and regression technique to predict, intraoperatively, the unified Parkinson's disease rating scale (UPDRS) improvement after deep brain stimulation (DBS). We hypothesized that a data-informed combination of features extracted from intraoperative microelectrode recordings (MERs) can predict the motor improvement of Parkinson's disease patients undergoing DBS surgery. We modified the employed RFs to account for unbalanced datasets and multiple observations per patient, and showed, for the first time, that only five neurophysiologically interpretable MER signal features are sufficient for predicting UPDRS improvement. This finding suggests that subthalamic nucleus (STN) electrophysiological signal characteristics are strongly correlated to the extent of motor behavior improvement observed in STN-DBS.

Dynamic cerebral autoregulation in young athletes following concussion.

The purpose of this study was to examine cerebral autoregulation (CA) in young athletes experiencing concussion. The subjects were monitored and repeatedly tested 72 hours, 2 weeks and 1 month post-injury. Mean arterial blood pressure (MABP), end-tidal partial pressure of carbon dioxide (PETCO2) and cerebral blood flow velocity (CBFV) in the middle and posterior cerebral arteries were monitored during mental activation paradigms. In order to characterize CA we employed autoregressive models with exogenous inputs (ARX) and impulse response models based on the Laguerre expansion technique (LET). By extracting gain and phase estimates from the obtained models we were able to detect disruptions in CA 72 hours following concussion and a slow recovery within a time period of one month.

GPU technology as a platform for accelerating physiological systems modeling based on Laguerre-Volterra networks.

The use of a GPGPU programming paradigm (running CUDA-enabled algorithms on GPU cards) in biomedical engineering and biology-related applications have shown promising results. GPU acceleration can be used to speedup computation-intensive models, such as the mathematical modeling of biological systems, which often requires the use of nonlinear modeling approaches with a large number of free parameters. In this context, we developed a CUDA-enabled version of a model which implements a nonlinear identification approach that combines basis expansions and polynomial-type networks, termed Laguerre-Volterra networks and can be used in diverse biological applications. The proposed software implementation uses the GPGPU programming paradigm to take advantage of the inherent parallel characteristics of the aforementioned modeling approach to execute the calculations on the GPU card of the host computer system. The initial results of the GPU-based model presented in this work, show performance improvements over the original MATLAB model.

Between-centre variability in transfer function analysis, a widely used method for linear quantification of the dynamic pressure-flow relation: the CARNet study.

Transfer function analysis (TFA) is a frequently used method to assess dynamic cerebral autoregulation (CA) using spontaneous oscillations in blood pressure (BP) and cerebral blood flow velocity (CBFV). However, controversies and variations exist in how research groups utilise TFA, causing high variability in interpretation. The objective of this study was to evaluate between-centre variability in TFA outcome metrics. 15 centres analysed the same 70 BP and CBFV datasets from healthy subjects (n=50 rest; n=20 during hypercapnia); 10 additional datasets were computer-generated. Each centre used their in-house TFA methods; however, certain parameters were specified to reduce a priori between-centre variability. Hypercapnia was used to assess discriminatory performance and synthetic data to evaluate effects of parameter settings. Results were analysed using the Mann-Whitney test and logistic regression. A large non-homogeneous variation was found in TFA outcome metrics between the centres. Logistic regression demonstrated that 11 centres were able to distinguish between normal and impaired CA with an AUC>0.85. Further analysis identified TFA settings that are associated with large variation in outcome measures. These results indicate the need for standardisation of TFA settings in order to reduce between-centre variability and to allow accurate comparison between studies. Suggestions on optimal signal processing methods are proposed.

Nonstationary multivariate modeling of cerebral autoregulation during hypercapnia.

We examined the time-varying characteristics of cerebral autoregulation and hemodynamics during a step hypercapnic stimulus by using recursively estimated multivariate (two-input) models which quantify the dynamic effects of mean arterial blood pressure (ABP) and end-tidal CO2 tension (PETCO2) on middle cerebral artery blood flow velocity (CBFV). Beat-to-beat values of ABP and CBFV, as well as breath-to-breath values of PETCO2 during baseline and sustained euoxic hypercapnia were obtained in 8 female subjects. The multiple-input, single-output models used were based on the Laguerre expansion technique, and their parameters were updated using recursive least squares with multiple forgetting factors. The results reveal the presence of nonstationarities that confirm previously reported effects of hypercapnia on autoregulation, i.e. a decrease in the MABP phase lead, and suggest that the incorporation of PETCO2 as an additional model input yields less time-varying estimates of dynamic pressure autoregulation obtained from single-input (ABP-CBFV) models.