A comprehensive longitudinal study of magnetic resonance imaging identifies novel features of the Mecp2 deficient mouse brain.

Rett syndrome (RTT) is a X-linked neurodevelopmental disorder which represents the leading cause of severe incurable intellectual disability in females worldwide. The vast majority of RTT cases are caused by mutations in the X-linked MECP2 gene, and preclinical studies on RTT largely benefit from the use of mouse models of Mecp2, which present a broad spectrum of symptoms phenocopying those manifested by RTT patients. Neurons represent the core targets of the pathology; however, neuroanatomical abnormalities that regionally characterize the Mecp2 deficient mammalian brain remain ill-defined. Neuroimaging techniques, such as MRI and MRS, represent a key approach for assessing in vivo anatomic and metabolic changes in brain. Being non-invasive, these analyses also permit to investigate how the disease progresses over time through longitudinal studies. To foster the biological comprehension of RTT and identify useful biomarkers, we have performed a thorough in vivo longitudinal study of MRI and MRS in Mecp2 deficient mouse brains. Analyses were performed on both genders of two different mouse models of RTT, using an automatic atlas-based segmentation tool that permitted to obtain a detailed and unbiased description of the whole RTT mouse brain. We found that the most robust alteration of the RTT brain consists in an overall reduction of the brain volume. Accordingly, Mecp2 deficiency generally delays brain growth, eventually leading, in heterozygous older animals, to stagnation and/or contraction. Most but not all brain regions participate in the observed deficiency in brain size; similarly, the volumetric defect progresses diversely in different brain areas also depending on the specific Mecp2 genetic lesion and gender. Interestingly, in some regions volumetric defects anticipate overt symptoms, possibly revealing where the pathology originates and providing a useful biomarker for assessing drug efficacy in pre-clinical studies.

Influence of the Tikhonov Regularization Parameter on the Accuracy of the Inverse Problem in Electrocardiography.

The electrocardiogram (ECG) is the standard method in clinical practice to non-invasively analyze the electrical activity of the heart, from electrodes placed on the body's surface. The ECG can provide a cardiologist with relevant information to assess the condition of the heart and the possible presence of cardiac pathology. Nonetheless, the global view of the heart's electrical activity given by the ECG cannot provide fully detailed and localized information about abnormal electrical propagation patterns and corresponding substrates on the surface of the heart. Electrocardiographic imaging, also known as the inverse problem in electrocardiography, tries to overcome these limitations by non-invasively reconstructing the heart surface potentials, starting from the corresponding body surface potentials, and the geometry of the torso and the heart. This problem is ill-posed, and regularization techniques are needed to achieve a stable and accurate solution. The standard approach is to use zero-order Tikhonov regularization and the L-curve approach to choose the optimal value for the regularization parameter. However, different methods have been proposed for computing the optimal value of the regularization parameter. Moreover, regardless of the estimation method used, this may still lead to over-regularization or under-regularization. In order to gain a better understanding of the effects of the choice of regularization parameter value, in this study, we first focused on the regularization parameter itself, and investigated its influence on the accuracy of the reconstruction of heart surface potentials, by assessing the reconstruction accuracy with high-precision simultaneous heart and torso recordings from four dogs. For this, we analyzed a sufficiently large range of parameter values. Secondly, we evaluated the performance of five different methods for the estimation of the regularization parameter, also in view of the results of the first analysis. Thirdly, we investigated the effect of using a fixed value of the regularization parameter across all reconstructed beats. Accuracy was measured in terms of the quality of reconstruction of the heart surface potentials and estimation of the activation and recovery times, when compared with ground truth recordings from the experimental dog data. Results show that values of the regularization parameter in the range (0.01-0.03) provide the best accuracy, and that the three best-performing estimation methods (L-Curve, Zero-Crossing, and CRESO) give values in this range. Moreover, a fixed value of the regularization parameter could achieve very similar performance to the beat-specific parameter values calculated by the different estimation methods. These findings are relevant as they suggest that regularization parameter estimation methods may provide the accurate reconstruction of heart surface potentials only for specific ranges of regularization parameter values, and that using a fixed value of the regularization parameter may represent a valid alternative, especially when computational efficiency or consistency across time is required.

Incidence, prevalence, and trajectories of repetitive conduction patterns in human atrial fibrillation.

AIMS: Repetitive conduction patterns in atrial fibrillation (AF) may reflect anatomical structures harbouring preferential conduction paths and indicate the presence of stationary sources for AF. Recently, we demonstrated a novel technique to detect repetitive patterns in high-density contact mapping of AF. As a first step towards repetitive pattern mapping to guide AF ablation, we determined the incidence, prevalence, and trajectories of repetitive conduction patterns in epicardial contact mapping of paroxysmal and persistent AF patients. METHODS AND RESULTS: A 256-channel mapping array was used to record epicardial left and right AF electrograms in persistent AF (persAF, n = 9) and paroxysmal AF (pAF, n = 11) patients. Intervals containing repetitive conduction patterns were detected using recurrence plots. Activation movies, preferential conduction direction, and average activation sequence were used to characterize and classify conduction patterns. Repetitive patterns were identified in 33/40 recordings. Repetitive patterns were more prevalent in pAF compared with persAF [pAF: median 59%, inter-quartile range (41-72) vs. persAF: 39% (0-51), P < 0.01], larger [pAF: = 1.54 (1.15-1.96) vs. persAF: 1.16 (0.74-1.56) cm2, P < 0.001), and more stable [normalized preferentiality (0-1) pAF: 0.38 (0.25-0.50) vs. persAF: 0.23 (0-0.33), P < 0.01]. Most repetitive patterns were peripheral waves (87%), often with conduction block (69%), while breakthroughs (9%) and re-entries (2%) occurred less frequently. CONCLUSION: High-density epicardial contact mapping in AF patients reveals frequent repetitive conduction patterns. In persistent AF patients, repetitive patterns were less frequent, smaller, and more variable than in paroxysmal AF patients. Future research should elucidate whether these patterns can help in finding AF ablation targets.

Improving Prediction of Favourable Outcome After 6 Months in Patients with Severe Traumatic Brain Injury Using Physiological Cerebral Parameters in a Multivariable Logistic Regression Model.

BACKGROUND/OBJECTIVE: Current severe traumatic brain injury (TBI) outcome prediction models calculate the chance of unfavourable outcome after 6 months based on parameters measured at admission. We aimed to improve current models with the addition of continuously measured neuromonitoring data within the first 24 h after intensive care unit neuromonitoring. METHODS: Forty-five severe TBI patients with intracranial pressure/cerebral perfusion pressure monitoring from two teaching hospitals covering the period May 2012 to January 2019 were analysed. Fourteen high-frequency physiological parameters were selected over multiple time periods after the start of neuromonitoring (0-6 h, 0-12 h, 0-18 h, 0-24 h). Besides systemic physiological parameters and extended Corticosteroid Randomisation after Significant Head Injury (CRASH) score, we added estimates of (dynamic) cerebral volume, cerebral compliance and cerebrovascular pressure reactivity indices to the model. A logistic regression model was trained for each time period on selected parameters to predict outcome after 6 months. The parameters were selected using forward feature selection. Each model was validated by leave-one-out cross-validation. RESULTS: A logistic regression model using CRASH as the sole parameter resulted in an area under the curve (AUC) of 0.76. For each time period, an increased AUC was found using up to 5 additional parameters. The highest AUC (0.90) was found for the 0-6 h period using 5 parameters that describe mean arterial blood pressure and physiological cerebral indices. CONCLUSIONS: Current TBI outcome prediction models can be improved by the addition of neuromonitoring bedside parameters measured continuously within the first 24 h after the start of neuromonitoring. As these factors might be modifiable by treatment during the admission, testing in a larger (multicenter) data set is warranted.

The electrocardiogram as a predictor of successful pharmacological cardioversion and progression of atrial fibrillation.

Aims: Non-invasive characterization of atrial fibrillation (AF) substrate complexity based on the electrocardiogram (ECG) may improve outcome prediction in patients receiving rhythm control therapies for AF. Multiple parameters to assess AF complexity and predict treatment outcome have been suggested. A comparative study of the predictive performance of complexity parameters on response to therapy and progression of AF in a large patient population is needed to standardize non-invasive analysis of AF. Methods and results: A large variety of ECG complexity parameters were systematically compared in patients with recent onset AF undergoing pharmacological cardioversion (PCV) with flecainide. Parameters were computed on 10-s 12-lead ECGs of 221 patients before drug administration. The ability of ECG parameters to predict successful PCV and progression to persistent AF (mean follow-up 49 months) was evaluated and compared with common clinical predictors. Optimal prediction performance of successful PCV using only one ECG parameter was low, using dominant atrial frequency [lead II, receiver operating area under curve (AUC) 0.66, 95% confidence interval [0.64-0.67]], but the optimal combination of several ECG parameters strongly improved predictive performance (AUC 0.78 [0.76-0.79]). While predictive value of the optimal combination of clinical predictors was low (AUC 0.68 [0.66-0.70], using right atrial volume and weight), adding ECG parameters strongly increased performance (AUC 0.81 [0.79-0.82], P < 0.001). Interestingly, higher dominant frequency and higher f-wave amplitude were associated with increased risk of progression to persistent AF during follow-up. Conclusion: Assessment of AF complexity from 12-lead ECGs significantly improves prediction of successful PCV and progression to persistent AF compared with common clinical and echocardiographic predictors.

Systematic comparison of non-invasive measures for the assessment of atrial fibrillation complexity: a step forward towards standardization of atrial fibrillation electrogram analysis.

AIMS: To present a comparison of electrocardiogram-based non-invasive measures of atrial fibrillation (AF) substrate complexity computed on invasive animal recordings to discriminate between short-term and long-term AF. The final objective is the selection of an optimal sub-set of measures for AF complexity assessment. METHODS AND RESULTS: High-density epicardial direct contact mapping recordings (234 leads) were acquired from the right and the left atria of 17 goats in which AF was induced for 3 weeks (short-term AF group, N = 10) and 6 months (long-term AF group, N = 7). Several non-invasive measures of AF organization proposed in the literature in the last decade were investigated to assess their power in discriminating between the short-term and long-term group. The best performing measures were identified, which when combined attained a correct classification rate of 100%. Their ability to predict standard invasive AF complexity measures was also tested, showing an average R(2) of 0.73 ± 0.04. CONCLUSION: An optimal set of measures of the AF substrate complexity was identified out of the set of non-invasive measures analysed in this study. These measures may contribute to improve patient-tailored diagnosis and therapy of sustained AF.

Standardized 2D atrial mapping and its clinical applications.

The visualization and comparison of electrophysiological information in the atrium among different patients could be facilitated by a standardized 2D atrial mapping. However, due to the complexity of the atrial anatomy, unfolding the 3D geometry into a 2D atrial mapping is challenging. In this study, we aim to develop a standardized approach to achieve a 2D atrial mapping that connects the left and right atria, while maintaining fixed positions and sizes of atrial segments across individuals. Atrial segmentation is a prerequisite for the process. Segmentation includes 19 different segments with 12 segments from the left atrium, 5 segments from the right atrium, and two segments for the atrial septum. To ensure consistent and physiologically meaningful segment connections, an automated procedure is applied to open up the atrial surfaces and project the 3D information into 2D. The corresponding 2D atrial mapping can then be utilized to visualize different electrophysiological information of a patient, such as activation time patterns or phase maps. This can in turn provide useful information for guiding catheter ablation. The proposed standardized 2D maps can also be used to compare more easily structural information like fibrosis distribution with rotor presence and location. We show several examples of visualization of different electrophysiological properties for both healthy subjects and patients affected by atrial fibrillation. These examples show that the proposed maps provide an easy way to visualize and interpret intra-subject information and perform inter-subject comparison, which may provide a reference framework for the analysis of the atrial fibrillation substrate before treatment, and during a catheter ablation procedure.

High-density and high-coverage composite atrial activation maps: an in-silico validation study.

OBJECTIVE: Repetitive atrial activation patterns (RAAPs) during complex atrial tachycardia could be associated with localized mechanisms that can be targeted. Clinically available electroanatomical mapping systems are limited by either the spatial coverage or electrode density of the mapping catheters, preventing the adequate visualization of transiently occurring RAAPs. This work proposes a technique to overcome this shortcoming by stitching spatially overlapping conduction patterns together to a larger image- called a composite map. METHODS: Simulated stable mechanisms and meandering reentries are sequentially mapped (4x4 grid, 3mm spacing) and then reconstructed back to the original sizes with the proposed recurrence plot-based algorithm. RESULTS: The reconstruction of single linear waves presents minimal errors (local activation time (LAT) difference: 3.2 [1.6-4.9] ms, conduction direction difference: 5.2 [2.3-8.0] degrees). Errors significantly increase (p<0.05) for more complex patterns, being the highest with unstable reentries (LAT difference: 10.3 [3.5-16.2] ms, conduction direction difference: 18.2 [6.7-29.7] deg). In a second part of the analysis, 111 meandering reentries are reconstructed. Mapping 30 locations overlappingly around each reentry core was found to be the optimal mapping strategy. For this optimal setting, LAT, conduction direction, and core localization errors are low (6.1 [4.2-8.6] ms, 11.2 [8.6-15.5] deg and 4.1 [2.9-4.9] mm, respectively) and are weakly correlated with the degree of the meander ( ρ=0.41, ρ=0.40 and ρ=0.20, respectively). CONCLUSION: Our findings underline the feasibility of generating composite maps by stitching spatially overlapping recordings. SIGNIFICANCE: Composite maps can be instrumental in personalized ablation strategies.

High-density and high coverage composite mapping of repetitive atrial activation patterns.

BACKGROUND: Repetitive atrial activation patterns (RAAPs) during atrial fibrillation (AF) may be associated with localized mechanisms that maintain AF. Current electro-anatomical mapping systems are unsuitable for analyzing RAAPs due to the trade-off between spatial coverage and electrode density in clinical catheters. This work proposes a technique to overcome this trade-off by constructing composite maps from spatially overlapping sequential recordings. METHODS: High-density epicardial contact mapping was performed during open-chest surgery in goats (n=16, left and right atria) with 3 or 22 weeks of sustained AF (249-electrode array, electrode distance 2.4 mm). A dataset mimicking sequential recordings was generated by segmenting the grid into four spatially overlapping regions (each region 6.5 cm2, 48±10% overlap) without temporal overlap. RAAPs were detected in each region using recurrence plots of activation times. RAAPs in two different regions were joined in case of RAAP cross-recurrence between overlapping electrodes. We quantified the reconstruction success rate and quality of the composite maps. RESULTS: Of 1021 RAAPs found in the full mapping array (32±13 per recording), 328 spatiotemporally stable RAAPs were analyzed. 247 composite maps were generated (75% success) with a quality of 0.86±0.21 (Pearson correlation). Success was significantly affected by the RAAP area. Quality was weakly correlated with the number of repetitions of RAAPs (r=0.13, p<0.05) and not affected by the atrial side (left or right) or AF duration (3 or 22 weeks of AF). CONCLUSIONS: Constructing composite maps by combining spatially overlapping sequential recordings is feasible. Interpretation of these maps can play a central role in ablation planning.

State Space Embedding of Atrial Electrograms to Detect Repetitive Conduction Patterns During Atrial Fibrillation.

Repetitive atrial conduction patterns are often observed during human atrial fibrillation (AF). Repetitive patterns may be associated with AF drivers such as focal and micro-reentrant mechanisms. Therefore, tools for repetitive activity detection are of great interest as they may allow to identify the leading electrophysiological AF mechanism in an individual patient. Recurrence plots (RP) are efficient tools for repetitive activity visualization. Construction of an RP requires embedding of epicardial atrial electrograms into a phase space. In this study, we compared the conventional Takens' embedding approach and three novel approaches based on a priori AF cycle length (AFCL) information. Approaches were bench-marked based on the similarity of the RPs they produce with a previously proposed technique, the sensitivity and specificity to detect the repetitive patterns, as well as the capability to estimate overall repetitive pattern prevalence. All techniques were applied to high-density epicardial direct contact mapping recordings in AF patients with paroxysmal AF (n=12) and persistent AF (n=9). Compared to a reference method the proposed novel techniques achieved significantly higher similarity and sensitivity values (p<0.01) than conventional embedding, in both paroxysmal and persistent patients. Moreover, estimated prevalences were robust against the various degrees of AF complexity present in the recordings.Clinical relevance- This study presents three novel approaches for detection of repetitive patterns of conduction during AF in atrial direct contact recordings, which may aid in the identification of the leading AF mechanism in an individual patient.

Electrocardiographic Imaging for Atrial Fibrillation: A Perspective From Computer Models and Animal Experiments to Clinical Value.

Electrocardiographic imaging (ECGI) is a technique to reconstruct non-invasively the electrical activity on the heart surface from body-surface potential recordings and geometric information of the torso and the heart. ECGI has shown scientific and clinical value when used to characterize and treat both atrial and ventricular arrhythmias. Regarding atrial fibrillation (AF), the characterization of the electrical propagation and the underlying substrate favoring AF is inherently more challenging than for ventricular arrhythmias, due to the progressive and heterogeneous nature of the disease and its manifestation, the small volume and wall thickness of the atria, and the relatively large role of microstructural abnormalities in AF. At the same time, ECGI has the advantage over other mapping technologies of allowing a global characterization of atrial electrical activity at every atrial beat and non-invasively. However, since ECGI is time-consuming and costly and the use of electrical mapping to guide AF ablation is still not fully established, the clinical value of ECGI for AF is still under assessment. Nonetheless, AF is known to be the manifestation of a complex interaction between electrical and structural abnormalities and therefore, true electro-anatomical-structural imaging may elucidate important key factors of AF development, progression, and treatment. Therefore, it is paramount to identify which clinical questions could be successfully addressed by ECGI when it comes to AF characterization and treatment, and which questions may be beyond its technical limitations. In this manuscript we review the questions that researchers have tried to address on the use of ECGI for AF characterization and treatment guidance (for example, localization of AF triggers and sustaining mechanisms), and we discuss the technological requirements and validation. We address experimental and clinical results, limitations, and future challenges for fruitful application of ECGI for AF understanding and management. We pay attention to existing techniques and clinical application, to computer models and (animal or human) experiments, to challenges of methodological and clinical validation. The overall objective of the study is to provide a consensus on valuable directions that ECGI research may take to provide future improvements in AF characterization and treatment guidance.

A Novel Tool for the Identification and Characterization of Repetitive Patterns in High-Density Contact Mapping of Atrial Fibrillation.

INTRODUCTION: Electrical contact mapping provides a detailed view of conduction patterns in the atria during atrial fibrillation (AF). Identification of repetitive wave front propagation mechanisms potentially initiating or sustaining AF might provide more insights into temporal and spatial distribution of candidate AF mechanism and identify targets for catheter ablation. We developed a novel tool based on recurrence plots to automatically identify and characterize repetitive conduction patterns in high-density contact mapping of AF. MATERIALS AND METHODS: Recurrence plots were constructed by first transforming atrial electrograms recorded by a multi-electrode array to activation-phase signals and then quantifying the degree of similarity between snapshots of the activation-phase in the electrode array. An AF cycle length dependent distance threshold was applied to discriminate between repetitive and non-repetitive snapshots. Intervals containing repetitive conduction patterns were detected in a recurrence plot as regions with a high recurrence rate. Intervals that contained similar repetitive patterns were then grouped into clusters. To demonstrate the ability to detect and quantify the incidence, duration and size of repetitive patterns, the tool was applied to left and right atrial recordings in a goat model of different duration of persistent AF [3 weeks AF (3 wkAF, n = 8) and 22 weeks AF (22 wkAF, n = 8)], using a 249-electrode mapping array (2.4 mm inter-electrode distance). RESULTS: Recurrence plots identified frequent recurrences of activation patterns in all recordings and indicated a strong correlation between recurrence plot threshold and AF cycle length. Prolonged AF duration was associated with shorter repetitive pattern duration [mean maximum duration 3 wkAF: 74 cycles, 95% confidence interval (54-94) vs. 22 wkAF: 41 cycles (21-62), p = 0.03], and smaller recurrent regions within repetitive patterns [3 wkAF 1.7 cm2 (1.0-2.3) vs. 22 wkAF 0.5 cm2 (0.0-1.2), p = 0.02]. Both breakthrough patterns and re-entry were identified as repetitive conduction patterns. CONCLUSION: Recurrence plots provide a novel way to delineate high-density contact mapping of AF. Dominant repetitive conduction patterns were identified in a goat model of sustained AF. Application of the developed methodology using the new generation of multi-electrode catheters could identify additional targets for catheter ablation of AF.

Body Surface Mapping of Ventricular Repolarization Heterogeneity: An Ex-vivo Multiparameter Study.

BACKGROUND: Increased heterogeneity of ventricular repolarization is associated with life-threatening arrhythmia and sudden cardiac death (SCD). T-wave analysis through body surface potential mapping (BSPM) is a promising tool for risk stratification, but the clinical effectiveness of current electrocardiographic indices is still unclear, with limited experimental validation. This study aims to investigate performance of non-invasive state-of-the-art and novel T-wave markers for repolarization dispersion in an ex vivo model. METHODS: Langendorff-perfused pig hearts (N = 7) were suspended in a human-shaped 256-electrode torso tank. Tank potentials were recorded during sinus rhythm before and after introducing repolarization inhomogeneities through local perfusion with dofetilide and/or pinacidil. Drug-induced repolarization gradients were investigated from BSPMs at different experiment phases. Dispersion of electrical recovery was quantified by duration parameters, i.e., the time interval between the peak and the offset of T-wave (TPEAK-TEND) and QT interval, and variability over time and electrodes was also assessed. The degree of T-wave symmetry to the peak was quantified by the ratio between the terminal and initial portions of T-wave area (Asy). Morphological variability between left and right BSPM electrodes was measured by dynamic time warping (DTW). Finally, T-wave organization was assessed by the complexity of repolarization index (CR), i.e., the amount of energy non-preserved by the dominant eigenvector computed by principal component analysis (PCA), and the error between each multilead T-wave and its 3D PCA approximation (NMSE). Body surface indices were compared with global measures of epicardial dispersion of repolarization, and with local gradients between adjacent ventricular sites. RESULTS: After drug intervention, both regional and global repolarization heterogeneity were significantly enhanced. On the body surface, TPEAK-TEND was significantly prolonged and less stable in time in all experiments, while QT interval showed higher variability across the interventions in terms of duration and spatial dispersion. The rising slope of the repolarization profile was steeper, and T-waves were more asymmetric than at baseline. Interventricular shape dissimilarity was enhanced by repolarization gradients according to DTW. Organized T-wave patterns were associated with abnormal repolarization, and they were properly described by the first principal components. CONCLUSION: Repolarization heterogeneity significantly affects T-wave properties, and can be non-invasively captured by BSPM-based metrics.

A novel framework for noninvasive analysis of short-term atrial activity dynamics during persistent atrial fibrillation.

ECG-based representation of atrial fibrillation (AF) progression is currently limited. We propose a novel framework for a more sensitive noninvasive characterization of the AF substrate during persistent AF. An atrial activity (AA) recurrence signal is computed from body surface potential map (BSPM) recordings, and a set of characteristic indices is derived from it which captures the short- and long-term recurrent behaviour in the AA patterns. A novel measure of short- and long-term spatial variability of AA propagation is introduced, to provide an interpretation of the above indices, and to test the hypothesis that the variability in the oscillatory content of AA is due mainly to a spatially uncoordinated propagation of the AF waveforms. A simple model of atrial signal dynamics is proposed to confirm this hypothesis, and to investigate a possible influence of the AF substrate on the short-term recurrent behaviour of AA propagation. Results confirm the hypothesis, with the model also revealing the above influence. Once the characteristic indices are normalized to remove this influence, they show to be significantly associated with AF recurrence 4 to 6 weeks after electrical cardioversion. Therefore, the proposed framework improves noninvasive AF substrate characterization in patients with a very similar substrate. Graphical Abstract Schematic representation of the proposed framework for the noninvasive characterization of short-term atrial signal dynamics during persistent AF. The proposed framework shows that the faster the AA is propagating, the more stable its propagation paths are in the short-term (larger values of Speed in the bottom right plot should be interpreted as lower speed of propagation of the corresponding AA propagation patters).

Wavelet-promoted sparsity for non-invasive reconstruction of electrical activity of the heart.

We investigated a novel sparsity-based regularization method in the wavelet domain of the inverse problem of electrocardiography that aims at preserving the spatiotemporal characteristics of heart-surface potentials. In three normal, anesthetized dogs, electrodes were implanted around the epicardium and body-surface electrodes were attached to the torso. Potential recordings were obtained simultaneously on the body surface and on the epicardium. A CT scan was used to digitize a homogeneous geometry which consisted of the body-surface electrodes and the epicardial surface. A novel multitask elastic-net-based method was introduced to regularize the ill-posed inverse problem. The method simultaneously pursues a sparse wavelet representation in time-frequency and exploits correlations in space. Performance was assessed in terms of quality of reconstructed epicardial potentials, estimated activation and recovery time, and estimated locations of pacing, and compared with performance of Tikhonov zeroth-order regularization. Results in the wavelet domain obtained higher sparsity than those in the time domain. Epicardial potentials were non-invasively reconstructed with higher accuracy than with Tikhonov zeroth-order regularization (p < 0.05), and recovery times were improved (p < 0.05). No significant improvement was found in terms of activation times and localization of origin of pacing. Next to improved estimation of recovery isochrones, which is important when assessing substrate for cardiac arrhythmias, this novel technique opens potentially powerful opportunities for clinical application, by allowing to choose wavelet bases that are optimized for specific clinical questions. Graphical Abstract The inverse problem of electrocardiography is to reconstruct heart-surface potentials from recorded bodysurface electrocardiograms (ECGs) and a torso-heart geometry. However, it is ill-posed and solving it requires additional constraints for regularization. We introduce a regularization method that simultaneously pursues a sparse wavelet representation in time-frequency and exploits correlations in space. Our approach reconstructs epicardial (heart-surface) potentials with higher accuracy than common methods. It also improves the reconstruction of recovery isochrones, which is important when assessing substrate for cardiac arrhythmias. This novel technique opens potentially powerful opportunities for clinical application, by allowing to choose wavelet bases that are optimized for specific clinical questions.

In Vivo Validation of Electrocardiographic Imaging.

OBJECTIVES: The purpose of this study was to evaluate the accuracy of noninvasive reconstructions of epicardial potentials, electrograms, activation and recovery isochrones, and beat origins by simultaneously performing electrocardiographic imaging (ECGI) and invasive epicardial electrography in intact animals. BACKGROUND: Noninvasive imaging of electrical potentials at the epicardium, known as ECGI, is increasingly applied in patients to assess normal and abnormal cardiac electrical activity. METHODS: Body-surface potentials and epicardial potentials were recorded in normal anesthetized dogs. Computed tomography scanning provided a torso-heart geometry that was used to reconstruct epicardial potentials from body-surface potentials. RESULTS: Electrogram reconstructions attained a moderate accuracy compared with epicardial recordings (median correlation coefficient: 0.71), but with considerable variation (interquartile range: 0.36 to 0.86). This variation could be explained by a spatial mismatch (overall resolution was <20 mm) that was most apparent in regions with electrographic transition. More accurate derivation of activation times (Pearson R: 0.82), recovery times (R: 0.73), and the origin of paced beats (median error: 10 mm; interquartile range: 7 to 17 mm) was achieved by a spatiotemporal approach that incorporates the characteristics of the respective electrogram and neighboring electrograms. Reconstruction of beats from repeated single-site pacing showed a stable localization of origin. Cardiac motion, currently ignored in ECGI, correlates negatively with reconstruction accuracy. CONCLUSIONS: ECGI shows a decent median accuracy, but variability in electrogram reconstruction can be sizable. At present, therefore, clinical interpretations of ECGI should not be made on the basis of single electrograms only. Incorporating local spatiotemporal characteristics allows for accurate reconstruction of epicardial activation and recovery patterns, and beat origin localization to a 10-mm precision. Even more reliable interpretations are expected when the influences of cardiac motion are accounted for in ECGI.

Quantifying Neural Oscillatory Synchronization: A Comparison between Spectral Coherence and Phase-Locking Value Approaches.

Synchronization or phase-locking between oscillating neuronal groups is considered to be important for coordination of information among cortical networks. Spectral coherence is a commonly used approach to quantify phase locking between neural signals. We systematically explored the validity of spectral coherence measures for quantifying synchronization among neural oscillators. To that aim, we simulated coupled oscillatory signals that exhibited synchronization dynamics using an abstract phase-oscillator model as well as interacting gamma-generating spiking neural networks. We found that, within a large parameter range, the spectral coherence measure deviated substantially from the expected phase-locking. Moreover, spectral coherence did not converge to the expected value with increasing signal-to-noise ratio. We found that spectral coherence particularly failed when oscillators were in the partially (intermittent) synchronized state, which we expect to be the most likely state for neural synchronization. The failure was due to the fast frequency and amplitude changes induced by synchronization forces. We then investigated whether spectral coherence reflected the information flow among networks measured by transfer entropy (TE) of spike trains. We found that spectral coherence failed to robustly reflect changes in synchrony-mediated information flow between neural networks in many instances. As an alternative approach we explored a phase-locking value (PLV) method based on the reconstruction of the instantaneous phase. As one approach for reconstructing instantaneous phase, we used the Hilbert Transform (HT) preceded by Singular Spectrum Decomposition (SSD) of the signal. PLV estimates have broad applicability as they do not rely on stationarity, and, unlike spectral coherence, they enable more accurate estimations of oscillatory synchronization across a wide range of different synchronization regimes, and better tracking of synchronization-mediated information flow among networks.

Recurrence quantification analysis applied to spatiotemporal pattern analysis in high-density mapping of human atrial fibrillation.

Spatiotemporal complexity of atrial fibrillation (AF) patterns is often quantified by annotated intracardiac contact mapping. We introduce a new approach that applies recurrence plot (RP) construction followed by recurrence quantification analysis (RQA) to epicardial atrial electrograms, recorded with a high-density grid of electrodes. In 32 patients with no history of AF (aAF, n=11), paroxysmal AF (PAF, n=12) and persistent AF (persAF, n=9), RPs were constructed using a phase space electrogram embedding dimension equal to the estimated AF cycle length. Spatial information was incorporated by 1) averaging the recurrence over all electrodes, and 2) by applying principal component analysis (PCA) to the matrix of embedded electrograms and selecting the first principal component as a representation of spatial diversity. Standard RQA parameters were computed on the constructed RPs and correlated to the number of fibrillation waves per AF cycle (NW). Averaged RP RQA parameters showed no correlation with NW. Correlations improved when applying PCA, with maximum correlation achieved between RP threshold and NW (RR1%, r=0.68, p <; 0.001) and RP determinism (DET, r=-0.64, p <; 0.001). All studied RQA parameters based on the PCA RP were able to discriminate between persAF and aAF/PAF (DET persAF 0.40 ± 0.11 vs. 0.59 ± 0.14/0.62 ± 0.16, p <; 0.01). RP construction and RQA combined with PCA provide a quick and reliable tool to visualize dynamical behaviour and to assess the complexity of contact mapping patterns in AF.

Impact of hybrid procedure on P wave duration for atrial fibrillation ablation.

AIM: Hybrid procedure (HP) involves epicardial isolation of pulmonary vein and posterior wall of left atrium, and endocardial checking of lesions and touchups (if needed). We aimed at observing the effect of hybrid procedure on P wave duration (PWD), calculated automatically from surface ECG leads at start and end of HP, and also for relationship to atrial fibrillation (AF) recurrence at 9 months. METHODS: Forty-one patients (32 male; mean age, 58.4 ± 9.5 years) underwent HP, as first ever ablation. A new automated method was used for P wave segmentation and PWD estimation from recognizable P waves in ECG lead I or II before and after HP, based on fitting of each P wave by means of two Gaussian functions. RESULTS: Overall, PWD was significantly decreased after procedure (104.4 ± 25.1 ms vs. 84.7 ± 23.8 ms, p = 0.0151), especially in persistent AF patients (122.4 ± 32.2 ms vs. 85.6 ± 24.5 ms, p = 0.02). PWD preprocedure was significantly higher in persistent than in paroxysmal patients (122.4 ± 32.2 ms vs. 92.5 ± 17.9 ms, p = 0.0383). PWD was significantly decreased after procedure in prior electrical cardioverted patients (106.7 ± 30.5 ms vs. 84.7 ± 23.1 ms, p = 0.0353). After 9-month follow-up of 40 patients, HP-induced PWD decrease was significant for the 12 persistent patients without recurrence (122.4.1 ± 35.3 ms vs. 85.6 ± 22.0 ms, p = 0.0210). CONCLUSION: Preprocedure PWD was higher for persistent than paroxysmal patients. HP reduced PWD significantly. Nine-month follow-up suggests that HP is successful in restoring and maintaining sinus rhythm. To individualize AF therapy, AF type-based selection of patients may be possible before procedure. Automated analysis of PWD from surface ECG is possible.

Wavelet-sparsity based regularization over time in the inverse problem of electrocardiography.

Noninvasive, detailed assessment of electrical cardiac activity at the level of the heart surface has the potential to revolutionize diagnostics and therapy of cardiac pathologies. Due to the requirement of noninvasiveness, body-surface potentials are measured and have to be projected back to the heart surface, yielding an ill-posed inverse problem. Ill-posedness ensures that there are non-unique solutions to this problem, resulting in a problem of choice. In the current paper, it is proposed to restrict this choice by requiring that the time series of reconstructed heart-surface potentials is sparse in the wavelet domain. A local search technique is introduced that pursues a sparse solution, using an orthogonal wavelet transform. Epicardial potentials reconstructed from this method are compared to those from existing methods, and validated with actual intracardiac recordings. The new technique improves the reconstructions in terms of smoothness and recovers physiologically meaningful details. Additionally, reconstruction of activation timing seems to be improved when pursuing sparsity of the reconstructed signals in the wavelet domain.