Objective. Cardiorespiratory coupling (CRC) subsumes diverse mechanisms of reciprocal influence between cardiac and respiratory rhythms. Its most studied manifestation, the respiratory sinus arrhythmia (RSA), is thought to be under full vagal control. However, some studies on healthy subjects observed an enhancement of RSA following beta-adrenergic blockade. In the present study, we investigated the effects of habitual beta-blocker therapy on CRC using non-directional and directional measures.Approach.A retrospective analysis was performed on heart period (HP) variability and respiration (R) in a cohort of subjects with preserved left ventricular ejection fraction scheduled for cardiopulmonary exercise test subdivided into those under beta-blocker therapy (BB: 67 ± 9 yrs, 34 males, 21 females) and treatment-naïve participants (noBB: 63 ± 10 yrs, 22 males, 35 females). CRC was assessed through the RSA, estimated as the high frequency (HF) power of HP variability, a non-directional linear measure such as HP-R squared coherence (K2), and a directional model-free nonlinear cross-predictability (CP) approach opening the HP-R closed loop.Main results.Spectral analysis showed a significant increase of the HF power of HP variability in the BB group.K2did not show significant between-group differences, while the CP was higher in the BB cohort regardless of the time direction of the HP-R interactions.Significance.These findings support the hypothesis that CRC is not a pure vagal phenomenon but is also modulated by sympathetic activity. Furthermore, they highlight the importance of directional analysis to clarify the physiological pathways underlying CRC and their modulation by beta-adrenergic blockade.

The dynamic component of the cerebral autoregulation (CA) is characterized via the transfer function (TF) from mean arterial pressure (MAP) to mean cerebral blood velocity (MCBv), acquired noninvasively via transcranial Doppler device. TF analysis theoretically requires the significance of squared coherence (K2). However, the practical relevance of assessing the significance of K2 is unclear. The study compares K2, TF phase (TFP), and TF gain (TFG) assessed via a moving window approach over all the frames regardless of K2 and after exclusion of those frames with K2 below the significance threshold. The approach is based on the generation of uncoupled surrogate pairs that preserve distribution and power spectral density of the original series while being fully uncoupled. MAP and MCBv were recorded in 24 patients (age: 61 ± 14 yrs, 18 males, 6 females) scheduled for surgical aortic valve replacement (SAVR). Data was acquired at supine resting and during active standing the day before the procedure (PRE) and within 7 days after (POST). In SAVR population we found that: (i) the practical relevance of accounting for the significance of K2 to discriminate time points and experimental conditions is marginal especially at time scales typical of CA; (ii) CA is preserved in both PRE and POST and this conclusion holds irrespective of K2 and its significance. Cerebrovascular control is so complex that the concomitant action of multiple regulatory mechanisms might have reduced the efficacy of the application of the criterion based on K2 significance in SAVR population.

Objective: We investigated the effect of posture on the link between cerebral circulation and cortical activity without applying cognitive tasks. Methods: We computed the zero-lag mutual information (MI) between spontaneous variations of mean cerebral blood velocity (MCBv) and the series of spectral powers computed over electroencephalographic (EEG) channels in traditional frequency bands. Estimation of MI was performed according to a fully linear approach and to a technique able to describe nonlinear components of the relationship as well. Time-shifting surrogate approach was utilized to reject the null hypothesis of uncoupling. Experimental protocol: Analysis was carried out in 27 healthy young individuals (age: 33±8 yrs; 13 males; 14 females) at rest in supine position (REST) and during active standing (STAND). Results: Percentage of rejection of the null hypothesis of uncoupling peaked to 52% and did not vary across the MI estimates and experimental conditions. STAND did not affect MI regardless of the method utilized to its estimate. Results were consistent across brain areas and EEG frequency bands. Conclusion: In healthy young subjects in the absence of task-related activity, neurovascular coupling (NVC) can be assessed from spontaneous fluctuations of MCBv and EEG spectral powers, posture is not a confounding factor, and nonlinear components negligibly contribute to the information exchange between MCBv and resting-state brain activity. Significance: The significant values of MI suggest that NVC can be assessed from spontaneous variability of MCBv and EEG spectral power series and was not affected by orthostatic position.

Baroreflex regulation is directly influenced by the mechano-sensitive properties of the baroreceptors. The mechanical and dimensional properties of the aorta are affected in patients with thoracic aortic aneurysm (TAA). We hypothesize that the baroreflex sensitivity (BRS) is modified in TAA patients and that these modifications might be different when the TAA group is divided into syndromic (Synd) and non-syndromic (NonSynd) patients. The aim of the study is to evaluate autonomic and baroreflex control in patients with Synd and NonSynd TAAs. We enrolled 80 TAA patients and divided them into Synd (N = 46) and NonSynd (N = 34) groups. The two groups did not differ in either demographic factors or pharmacological therapy. Autonomic function and BRS, assessed from the heart period (HP) and systolic arterial pressure (SAP) variability, were compared to those of age- and gender-matched healthy controls (HCs, N = 28). Analyses were carried out in the low-frequency (LF, 0.04 Hz-0.15 Hz) and high-frequency (HF, 0.15 Hz-0.4 Hz) bands. The Synd and NonSynd subgroups did not show any significant differences in terms of autonomic control or BRS. We observed that, in the LF band, BRS was lower in TAA patients than in HCs during rest in the supine position (REST), while it was similar during active standing (STAND). STAND reduced the power of HP variability in the HF band and BRS in the LF band while increasing the power of SAP in the LF band in both HCs and TAA patients. Since BRS was lower at REST in both Synd and NonSynd TAA groups than in the HC group, we conclude that BRS is affected by either the dimensional or the mechanical properties of the aorta in relation to the pathology.

Background. Cerebral autoregulation (CA) is estimated by assessing the association between variations of mean cerebral blood velocity (MCBv) and mean arterial pressure (MAP). Recently, regional oxygen saturation (rSO2) has been tested as an alternative to MCBv for CA estimation.Objective. We propose a correlation-based method iterating the computation of the Pearson correlation coefficientrover short windows of MAP, MCBv and rSO2and testing on an individual basis the significance of the positive MCBv-MAP and rSO2-MAP association.Analysis. The rejection of the null hypothesis of zero or negative correlation was performed using a fast approach based on the classical t-test applied to the Pearson correlation coefficient and via a time-consuming approach based on surrogate series generation. The median ofrcomputed over segments rejecting the null hypothesis and their percentage was computed in 53 patients (age: 62 ± 11 years, 39 males, 14 females) scheduled for cardiac surgery acquired before (BASAL) and after induction of propofol-based general anesthesia (ANESTH). The method was compared to more traditional time-domain techniques.Main results.The percentage of positively correlated sequences and theirrdecreased during ANESTH and this result was valid regardless of the method utilized to reject the null hypothesis and the use of MCBv or rSO2. Since markers computed using MCBv and rSO2were uncorrelated, two approaches might unveil different CA aspects. Only results based on MCBv were significantly correlated with traditional time-domain indexes.Significance.The method should be considered for applications of CA monitoring in practical settings.

Background: Aperiodic $1/f-$like neural activity is thought to reflect fundamental properties of population-level excitation-inhibition balance, yet no existing framework provides directional causal inference between this component and neuroautonomic dynamics. Current brain-heart models also lack formulations accounting for both aperiodic and oscillatory spectral components. OBJECTIVES:To develop a mathematical framework for directional causal inference between time-resolved aperiodic ($1/f-$like) electroencephalographic (EEG) components and heartbeat dynamics. We also aim to extend the same formalism to periodic narrow-band EEG oscillations. METHODS:We introduce the directional causality for brain-heart interplay (DiCa-BHI) framework, a stochastic modelling approach in which each EEG spectral parameter is treated as a time-varying process governed by autoregressive dynamics with exogenous neuroautonomic inputs. Aperiodic exponent, offset, and oscillatory peak amplitudes are modelled within a parametric spectral representation, while heartbeat dynamics are characterized via an extended, stochastic integral pulse frequency modulation model. Directional causal coefficients are estimated using a Granger-predictive causal ARX formalism. Validation employed synchronized EEG-ECG recordings from 27 healthy adults undergoing supine rest, postural changes, and emotional video elicitation. Subject-specific estimations are performed and then compared across experimental conditions. RESULTS:The aperiodic $1/f-$-like EEG component exhibited predominant bottom-up heart-to-brain causality, attenuated during orthostasis but strengthened during emotional stimulation across widespread cortical regions. Conversely, periodic narrowband components showed strong top-down brain-to-heart dominance, exceeding 90% for vagal and 70% for sympathovagal contributions. CONCLUSIONS:DiCa-BHI provides a novel methodological framework for directional causal inference in the $1/f-$ aperiodic component of neural activity and generalizes seamlessly to narrow-band oscillatory components. SIGNIFICANCE:The framework advances mathematical modelling of the brain-heart axis and provides a quantitative tool for applications in cardiology, neurology, and psychophysiological research.

Symbolic analysis (SA) infers cardiac control from spontaneous stationary sequences of heart period (HP) by estimating the probability of symbolic pattern classes. Unfortunately, SA does not assess the fraction of HP variability associated with symbolic pattern families. This study proposes amplitude SA (ASA) accounting for absolute changes between consecutive HPs. ASA leverages uniform 6-bin quantization to symbolize HP, the delay embedding procedure to form length-3 symbolic patterns and a traditional strategy to group symbolic patterns into four classes families according to number and sign of variations between adjacent symbols. ASA computes the fraction of variance associated with symbolic pattern classes. ASA was applied to HP variability derived from: 1) healthy subjects during pharmacological challenges (n = 9; age: 25-46 yrs, 9 males); 2) healthy subjects during graded postural stimuli (n = 19; age: 21-48 yrs, 8 males); 3) Parkinson disease (PD) patients (n = 12; age: 55-79 yrs, 8 males) and matched healthy controls (n = 12; age: 58-72 yrs, 7 males). We computed both global and local ASA markers and we compared them with SA indexes. Over stationary HP series we found that: i) ASA provides a general method to decompose HP variance according to symbolic pattern classes; ii) ASA is useful to describe cardiac control; iii) ASA indexes are complementary to SA markers; iv) ASA emphasizes the link of HP variability markers expressed in absolute units with vagal control; v) global and local ASA approaches provide similar information. SA and ASA should be utilized concomitantly for a deeper characterization of cardiac control from spontaneous HP fluctuations.

Objective.Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH) is a rare condition characterized by unpredictable swelling attacks. Despite evidence of the involvement of the cardiac autonomic nervous system in the pathophysiology of HAE-C1INH, no studies have been conducted under real-life conditions.Approach.This study aims to investigate cardiac autonomic modulation in HAE-C1INH patients during attack-free period, via linear spectral and nonlinear complexity indexes (CIs) derived from 24 h Holter recordings of heart period variability in comparison with healthy controls (HCs).Main results.Twenty-five HAE-C1INH patients (13 males, age 43 ± 13 yrs) and 25 sex- and gender-matched HC (44 ± 15 yrs) were studied during a regular day. HAE-C1INH patients were divided into those who experience at least one HAE-C1INH attack in the last 6 months (ATT, n = 11, 6 males, 39 ± 14 yrs) and those who did not (NoATT,n= 14, 7 males, 47 ± 16 yrs). Power spectral indexes and markers of CIs estimated by sample entropy and twok-nearest-neighbour (KNN) techniques were derived during day-time (DAY) and night-time (NIGHT). All the calculated parameters showed a circadian rhythm and this time course was similar in HAE-C1INH and HC group. In HAE-C1INH patients, KNN complexity markers were significantly higher in ATT compared to NoATT during NIGHT.Significance.In HAE-C1INH patients, compared to HCs, cardiac autonomic modulation remains intact. However, in the ATT group, complexity analysis possibly suggests a more reactive vagal control compared to the NoATT one. Complexity indexes demonstrated superior sensitivity over traditional spectral measures in stratifying the risk of attack. The results are preliminary and need to be confirmed in larger samples.

Objective. The dynamic cerebral autoregulation (dCA) limits variability of mean cerebral blood velocity (MCBv) despite mean arterial pressure (MAP) variations through a myriad of nonlinear mechanisms. However, dCA operates in association with the flow-to-pressure pathway. This study aims at characterizing the closed loop MCBv-MAP relationship by separating the dependence of MAP on MCBv from that over the reverse pathway using different surrogate approaches.Approach.Analyses were carried out in 26 healthy controls (HCs, age: 43 ± 11 yr, 13 males, 13 females) and 48 severe aortic valve stenosis patients undergoing surgical aortic valve replacement (SAVR, age: 62 ± 14 yr; 35 males, 13 females) before and after surgery. Active standing (STAND) from supine resting (REST) was exploited to challenge dCA. A state space correspondence method based on model-free cross-predictability was exploited to estimate the degree of MCBv dependence on MAP and vice versa and two different types of surrogates destroying nonlinear components or preserving them as much as possible were utilized.Main results.We found that: i) STAND deteriorates dCA in HCs; ii) in SAVR patients STAND does not affect dCA either before or after surgery, but a pre-surgery activation of flow-to-pressure link is present at REST; iii) in HCs preserving nonlinear dynamics when testing the significance of the pressure-to-flow link provides results different from those derived while maintaining exclusively linear dynamics.Significance.Results stressed the pathophysiological relevance of applying a nonlinear directional approach to disentangle closed loop MCBv-MAP relationship and suggest that conclusions might depend on the strategy adopted to generate surrogates.

The brain–heart axis arises from a bidirectional systems interaction mediated by vagal and sympathetic pathways, together with mechanical and baroreflex feedback loops. Although these dynamics have been investigated using a range of signal-processing approaches, it remains unclear whether they synchronize through phase locking mechanisms. Here, we test the hypothesis that cortical and cardiovascular interactions display phase synchronization. To this end, electroencephalogram (EEG), electrocardiogram (ECG), and blood pressure (BP) signals were recorded from 27 healthy subjects during rest and upright conditions. Time-resolved EEG power series were derived for canonical frequency bands, while the series of intervals between two consecutive R waves (RR intervals) was obtained from the ECG. Dynamic EEG-RR and EEG-BP phase synchronization was quantified using mean phase coherence (MPC), and the estimates were validated through surrogate data analysis. Significant EEG-RR coupling was observed in the high-frequency band of heartbeat dynamics, reflecting parasympathetic modulation, especially in resting conditions. Changes in EEG-BP synchronization were mainly sustained by cardiovascular oscillations in the low-frequency band during standing, consistent with enhanced sympathetic and baroreflex activity. These results reveal frequency-dependent phase synchronization within a healthy central-autonomic brain network and demonstrate the dynamic integration of central and peripheral oscillations. Phase-locking values such as MPC provide a robust quantitative framework for characterizing physiological brain–heart-vascular networks and may serve as valuable tools for investigating pathophysiological states.

Cerebrovascular regulation, driven by mechanisms such as cerebral autoregulation and the Cushing's reflex, plays a critical role in maintaining cerebral blood flow (CBF) adequate despite changes in arterial pressure (AP), since a dampening of CBF can lead to serious brain pathologies. This study investigates the causal and self-predictable dynamics of cerebrovascular interactions in patients undergoing coronary artery bypass graft surgery, before and after propofol general anaesthesia. The dynamics of the pressure-to-flow and flow-to-pressure links between mean arterial pressure (MAP) and mean cerebral blood velocity (MCBv) is assessed using time-domain and frequency-domain measures of Granger Causality (GC) and Granger Autonomy (GA). The results indicate that while time-domain indices remain stable, frequency-domain measures reveal variations in the very-low-frequency, low-frequency, and high-frequency (HF) bands. The increased spectral GC in the HF band may be related to the effect of mechanical ventilation during anaesthesia. Additionally, a reduction in self-dependency of MCBv in the HF band reflects weakened internal regulatory mechanisms post-anaesthesia. In conclusion, propofol-induced suppression of sympathetic control and the effects of mechanical respiration increase the dependence of cerebral blood flow on arterial pressure in specific bands of cerebrovascular interest. These findings underscore the importance of frequency-domain analysis in detecting subtle cerebrovascular dynamics that time-domain measures may overlook.

Patients undergoing surgical aortic valve replacement (SAVR) are at risk of developing stroke after the intervention, usually detected via diffusion-weighted magnetic resonance imaging (DW-MRI). Previous studies suggested the maintenance of cerebral autoregulation (CA) as derived from time series analysis of mean arterial pressure (MAP) and mean cerebral blood velocity (MCBv) after SAVR, but the association of CA markers with the presence of recent ischemic lesions was not assessed so far. This study investigates closed-loop cerebrovascular control via causal cross-spectral analysis in 23 subjects (19 males, age 57±16 years) who recently underwent SAVR. Analyses were performing at rest in supine position (REST) and during an active standing test (STAND). Traditional MAP-MCBv coherence (K2) was computed as well as causal coherence (K2) was assessed from MAP to MCBv, i.e. along the pressure-to-flow arm, and from MCBv to MAP, i.e. along the flow-to-pressure arm, in the frequency bands typically used to describe CA. As detected via DW-MRI, 9 patients exhibited recent ischemic lesions (classified as STROKE) and 15 did not (noSTROKE). Results showed that STROKE patients showed an increased variability of MCBv during STAND and an inability to decouple MAP and MCBv variability series during STAND compared to REST, suggesting possible CA impairment. Trends in the coupling strength were observed in the high frequency band (0.15-0.4 Hz) regardless of the direction of the MAP-MCBv interactions. The proposed techniques allowed the investigation of the closed loop relationship between MAP and MCBv in association with damages of the brain microcirculation after SAVRClinical Relevance— Cerebral autoregulation might be reduced in patients exhibiting recent ischemic brain lesions after surgical aortic valve replacement.

Background/Objectives: Carotid artery stenosis (CAS) is one of the main causes of stroke, and the vulnerability of plaque has been proved to be a determinant. A joint analysis of shear wave elastography, a radiofrequency echo-based wall tracking technique for arterial stiffness evaluation, and of autonomic and baroreflex function is proposed to noninvasively, preoperatively assess plaque vulnerability in asymptomatic CAS patients scheduled for carotid endarterectomy. Methods: Elastographic markers of arterial stiffness were derived preoperatively in 78 CAS patients (age: 74.2 + 7.7 years, 27 females). Autonomic and baroreflex markers were also assessed by means of an analysis of the beat-to-beat fluctuations in heart period and systolic arterial pressure, derived at rest in supine position (REST) and during active standing. Postoperative analysis identified 36 patients with vulnerable plaque (VULN) and 42 with stable plaque (STABLE). Results: Baroreflex sensitivity (BRS) at a respiratory rate decreased during STAND only in VULN patients, being much higher at REST compared to STABLE levels. Autonomic indexes were not helpful in separating experimental conditions and/or populations. The Young’s modulus (YM) of the plaque was lower in the VULN group than in the STABLE one. Cardiovascular control and elastographic markers were significantly correlated only in VULN patients. A multivariate logistic regression model built combining YM and BRS at the respiratory rate improved the prediction of plaque vulnerability, reporting an area under the ROC curve of 0.694. Conclusions: Noninvasive techniques assessing shear wave elastography and baroreflex control could contribute to the early detection of plaque vulnerability in patients with asymptomatic CAS.

Cerebral vasomotion is modulated according to brain demands via neurovascular coupling (NVC). NVC can be evaluated noninvasively via the simultaneous recording of electroencephalogram (EEG) and mean cerebral blood velocity (MCBv) monitored via transcranial Doppler (TCD) device. We propose an approach for NVC estimation grounded on the assessment of the cross-correlation at zero lag between the beat-to-beat variability series of MCBv and EEG power assessed over typical frequency bands utilized in EEG analysis, namely δ, θ, α and β bands. A surrogate data approach was applied to test the null hypothesis of the absence of NVC. This methodology was tested in 20 right-handed healthy volunteers (9 males, 11 females; age: 31±4 yrs) in which MCBv was monitored via TCD device along with a 19-channel EEG. Recordings were performed at rest in supine position (REST) and during active standing (STAND). We found that the strength of NVC varies with frequency band, experimental condition and brain region. More specifically, NVC strength was significant at REST especially in the δ and α bands and in the occipital and parietal regions, while it was much weaker during STAND, especially in those brain areas where NVC was particularly strong at REST. This novel approach to the NVC characterization highlights the complexity of the interactions between cerebral vasomotion and brain activity even in absence of a definite cognitive task.

We test the hypothesis that amplitude permutation conditional entropy (APCE) is more powerful than permutation conditional entropy (PCE) when complexity of heart period (HP) dynamics is decreased by vagal blockade or withdrawal. We acquired HP variability in 9 healthy male physicians (age: 25-46 yrs) at baseline (B) and during administration of a high dose of atropine (AT) and in 15 healthy nonsmoking volunteers (age: 24-54 yrs, 9 males and 6 females) at rest in horizontal position (T0) and during 90° head-up tilt (T90). In addition to coarse-graining-free methods, like PCE and APCE, we computed coarse-graining-based k-nearest-neighbor conditional entropy (KNNCE) for comparison. Markers were computed over 256 consecutive HP values, thus targeting the complexity of short-term cardiac control. PCE was unable to detect the decrease of HP variability complexity during AT compared to B, while APCE and KNNCE could. All the conditional entropy markers found a decrease in HP variability complexity during T90 compared to T0. Only APCE was correlated with KNNCE in both protocols. We conclude that APCE is more reliable than PCE in assessing cardiac control complexity, likely due to the better ability of APCE in the presence of the low signal-to-noise ratio of HP dynamics observed during AT.

BackgroundCoronavirus disease 19 (COVID-19) patients might develop sequelae after apparent resolution of the infection. Autonomic dysfunction and baroreflex failure have been frequently reported. However, the long-term effect of COVID-19 on cardiorespiratory and cardiovascular neural controls has not been investigated with directional approaches able to open the closed-loop relationship between physiological variables.MethodsA model-based causal spectral approach, namely causal squared coherence (CK2), was applied to the beat-to-beat variability series of heart period (HP) and systolic arterial pressure (SAP), and to the respiratory signal (RESP) acquired at rest in supine position and during active standing (STAND) in COVID-19 survivors 9 months after their hospital discharge. Patients were categorized according to their need of ventilatory support during hospitalization as individuals that had no need of continuous positive airway pressure (noCPAP, n = 27), need of continuous positive airway pressure in sub-intensive care unit (CPAP, n = 14) and need of invasive mechanical ventilation in intensive care unit (IMV, n = 8).ResultsThe expected decrease of the strength of the HP-RESP dynamic interactions as well as the expected increase of the dependence of HP on SAP along baroreflex during STAND was not observed and this result held regardless of the severity of the disease, namely in noCPAP, CPAP and IMV cohorts. Regardless of the experimental condition, spectral causality markers did not vary across groups either.ConclusionsCK2 markers, in association with an orthostatic challenge, were able to characterize the impairment of cardiorespiratory control and baroreflex in COVID-19 patients long after acute infection resolution and could be exploited to monitor the evolution of the COVID-19 patients after hospital discharge.