QTc intervals at rest and during exercise assessed by group correction formulas in survivors of childhood acute lymphoblastic leukemia.

INTRODUCTION: Early signs of subclinical cardiac damage must be identified before they turn into clinical manifestations. Tailoring a formula is relevant for precise QTc evaluation in childhood acute lymphoblastic leukemia (ALL) survivors considering they are at risk of long-term cardiac problems. Therefore, we aim to develop group heart rate correction formulas for QT intervals in childhood ALL survivors at rest and during exercise, and to assess the applicability of these methods across a variety of risk groups exposed to diverse chemotherapy dosages. METHODS: Two hundred and fifty childhood ALL survivors in the PETALE study were classified into 3 groups depending on their prognostic risk group. ECG measurements (QT and RR intervals) were made at rest and during a cardiopulmonary exercise test. QT correction for heart rate was applied using 5 different formulas, which included 2 previously published formulas and 3 group-specific formulas for each sex. RESULTS: The QT/RR relation showed 2 different curves between rest and during exercise, which was worse for females. Group-specific QTc formulas allowed adequate heart rate-corrected QT interval, independently of the cumulative dose of doxorubicin received during treatment. Group-specific formulas showed significantly shorter QTc intervals than QTc from Bazett's formula. QTc (Bazett's formula) values surpassed the established clinical norm in 22 males (11%) and 22 females (11%), with a majority occurring during exercise, affecting 15 males (7.5%) and 10 females (5%). CONCLUSION: This study shows the applicability of personalized group correction of QT/RR data in childhood ALL survivors. Our comprehensive assessments (spanning rest, exercise, and recovery) is an effective approach for risk stratification of cardiac complications in childhood ALL survivors.

In Silico Human Cardiomyocyte Action Potential Modeling: Exploring Ion Channel Input Combinations.

In silico modeling offers an opportunity to supplement and accelerate cardiac safety testing. With in silico modeling, computational simulation methods are used to predict electrophysiological interactions and pharmacological effects of novel drugs on critical physiological processes. The O'Hara-Rudy's model was developed to predict the response to different ion channel inhibition levels on cardiac action potential duration (APD) which is known to directly correlate with the QT interval. APD data at 30% 60% and 90% inhibition were derived from the model to delineate possible ventricular arrhythmia scenarios and the marginal contribution of each ion channel to the model. Action potential values were calculated for epicardial, myocardial, and endocardial cells, with action potential curve modeling. This study assessed cardiac ion channel inhibition data combinations to consider when undertaking in silico modeling of proarrhythmic effects as stipulated in the Comprehensive in Vitro Proarrhythmia Assay (CiPA). As expected, our data highlight the importance of the delayed rectifier potassium channel (IKr) as the most impactful channel for APD prolongation. The impact of the transient outward potassium channel (Ito) inhibition on APD was minimal while the inward rectifier (IK1) and slow component of the delayed rectifier potassium channel (IKs) also had limited APD effects. In contrast, the contribution of fast sodium channel (INa) and/or L-type calcium channel (ICa) inhibition resulted in substantial APD alterations supporting the pharmacological relevance of in silico modeling using input from a limited number of cardiac ion channels including IKr, INa, and ICa, at least at an early stage of drug development.

Increased vulnerability of nigral dopamine neurons after expansion of their axonal arborization size through D2 dopamine receptor conditional knockout.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). Rare genetic mutations in genes such as Parkin, Pink1, DJ-1, α-synuclein, LRRK2 and GBA are found to be responsible for the disease in about 15% of the cases. A key unanswered question in PD pathophysiology is why would these mutations, impacting basic cellular processes such as mitochondrial function and neurotransmission, lead to selective degeneration of SNc DA neurons? We previously showed in vitro that SNc DA neurons have an extremely high rate of mitochondrial oxidative phosphorylation and ATP production, characteristics that appear to be the result of their highly complex axonal arborization. To test the hypothesis in vivo that axon arborization size is a key determinant of vulnerability, we selectively labeled SNc or VTA DA neurons using floxed YFP viral injections in DAT-cre mice and showed that SNc DA neurons have a much more arborized axon than those of the VTA. To further enhance this difference, which may represent a limiting factor in the basal vulnerability of these neurons, we selectively deleted in mice the DA D2 receptor (D2-cKO), a key negative regulator of the axonal arbour of DA neurons. In these mice, SNc DA neurons have a 2-fold larger axonal arborization, release less DA and are more vulnerable to a 6-OHDA lesion, but not to α-synuclein overexpression when compared to control SNc DA neurons. This work adds to the accumulating evidence that the axonal arborization size of SNc DA neurons plays a key role in their vulnerability in the context of PD.

Simulation of atrial fibrillation in a non-ohmic propagation model with dynamic gap junctions.

Gap junctions exhibit nonlinear electrical properties that have been hypothesized to be relevant to arrhythmogenicity in a structurally remodeled tissue. Large-scale implementation of gap junction dynamics in 3D propagation models remains challenging. We aim to quantify the impact of nonlinear diffusion during episodes of arrhythmias simulated in a left atrial model. Homogenization of conduction properties in the presence of nonlinear gap junctions was performed by generalizing a previously developed mathematical framework. A monodomain model was solved in which conductivities were time-varying and depended on transjunctional potentials. Gap junction conductances were derived from a simplified Vogel-Weingart model with first-order gating and adjustable time constant. A bilayer interconnected cable model of the left atrium with 100 µm resolution was used. The diffusion matrix was recomputed at each time step according to the state of the gap junctions. Sinus rhythm and atrial fibrillation episodes were simulated in remodeled tissue substrates. Slow conduction was induced by reduced coupling and by diffuse or stringy fibrosis. Simulations starting from the same initial conditions were repeated with linear and nonlinear gap junctions. The discrepancy in activation times between the linear and nonlinear diffusion models was quantified. The results largely validated the linear approximation for conduction velocities >20 cm/s. In very slow conduction substrates, the discrepancy accumulated over time during atrial fibrillation, eventually leading to qualitative differences in propagation patterns, while keeping the descriptive statistics, such as cycle lengths, unchanged. The discrepancy growth rate was increased by impaired conduction, fibrosis, conduction heterogeneity, lateral uncoupling, fast gap junction time constant, and steeper action potential duration restitution.

Simulation of diffuse and stringy fibrosis in a bilayer interconnected cable model of the left atrium.

AIMS: The aim of this study is to design a computer model of the left atrium for investigating fibre-orientation-dependent microstructure such as stringy fibrosis. METHODS AND RESULTS: We developed an approach for automatic construction of bilayer interconnected cable models from left atrial geometry and epi- and endocardial fibre orientation. The model consisted of two layers (epi- and endocardium) of longitudinal and transverse cables intertwined-like fabric threads, with a spatial discretization of 100 µm. Model validation was performed by comparison with cubic volumetric models in normal conditions. Then, diffuse (n = 2904), stringy (n = 3600), and mixed fibrosis patterns (n = 6840) were randomly generated by uncoupling longitudinal and transverse connections in the interconnected cable model. Fibrosis density was varied from 0% to 40% and mean stringy obstacle length from 0.1 to 2 mm. Total activation time, apparent anisotropy ratio, and local activation time jitter were computed during normal rhythm in each pattern. Non-linear regression formulas were identified for expressing measured propagation parameters as a function of fibrosis density and obstacle length (stringy and mixed patterns). Longer obstacles (even below tissue space constant) were independently associated with prolonged activation times, increased anisotropy, and local fluctuations in activation times. This effect was increased by endo-epicardial dissociation and mitigated when fibrosis was limited to the epicardium. CONCLUSION: Interconnected cable models enable the study of microstructure in organ-size models despite limitations in the description of transmural structures.

Observations on changes in ventricular repolarization following four weeks of exercise training in chronic heart failure patients.

OBJECTIVE: The aim of this study was to investigate the effects of exercise training on ventricular repolarization dynamicity and heart rate variability in chronic heart failure patients. DESIGN: A total of 22 chronic heart failure patients with reduced ejection fraction in sinus rhythm were included in the study. The patients were in NYHA classes II-III with an ejection fraction of 29.7 ± 7.7%. Before and after 4 weeks of aerobic exercise training, all patients performed a cardiopulmonary exercise test, a standard twelve-lead electrocardiogram and a 24 h Holter recording from which heart rate variability and ventricular repolarization dynamicity were assessed. RESULTS: We observed a significant decrease of QTpeak (p < .001) and QTend (p < .001) at RR intervals ranging from 600 to 1000 ms on 24 h QT/RR regressions after 4 weeks of exercise training. Our analyses revealed that short-term exercise training induced significant changes in the frequency and time domain HRV parameters on an overall time-period of 24 h. CONCLUSION: Four weeks of exercise training induced significant changes in ventricular repolarization dynamicity in chronic heart failure patients. In addition, short-term exercise training was enough to improve patients' heart rate variability.

Time resolution for wavefront and phase singularity tracking using activation maps in cardiac propagation models.

The dynamics of cardiac fibrillation can be described by the number, the trajectory, the stability, and the lifespan of phase singularities (PSs). Accurate PS tracking is straightforward in simple uniform tissues but becomes more challenging as fibrosis, structural heterogeneity, and strong anisotropy are combined. In this paper, we derive a mathematical formulation for PS tracking in two-dimensional reaction-diffusion models. The method simultaneously tracks wavefronts and PS based on activation maps at full spatiotemporal resolution. PS tracking is formulated as a linear assignment problem solved by the Hungarian algorithm. The cost matrix incorporates information about distances between PS, chirality, and wavefronts. A graph of PS trajectories is generated to represent the creations and annihilations of PS pairs. Structure-preserving graph transformations are applied to provide a simplified description at longer observation time scales. The approach is validated in 180 simulations of fibrillation in four different types of substrates featuring, respectively, wavebreaks, ionic heterogeneities, fibrosis, and breakthrough patterns. The time step of PS tracking is studied in the range from 0.1 to 10 ms. The results show the benefits of improving time resolution from 1 to 0.1 ms. The tracking error rate decreases by an order of magnitude because the occurrence of simultaneous events becomes less likely. As observed on PS survival curves, the graph-based analysis facilitates the identification of macroscopically stable rotors despite wavefront fragmentation by fibrosis.

In silico study of multicellular automaticity of heterogeneous cardiac cell monolayers: Effects of automaticity strength and structural linear anisotropy.

The biological pacemaker approach is an alternative to cardiac electronic pacemakers. Its main objective is to create pacemaking activity from added or modified distribution of spontaneous cells in the myocardium. This paper aims to assess how automaticity strength of pacemaker cells (i.e. their ability to maintain robust spontaneous activity with fast rate and to drive neighboring quiescent cells) and structural linear anisotropy, combined with density and spatial distribution of pacemaker cells, may affect the macroscopic behavior of the biological pacemaker. A stochastic algorithm was used to randomly distribute pacemaker cells, with various densities and spatial distributions, in a semi-continuous mathematical model. Simulations of the model showed that stronger automaticity allows onset of spontaneous activity for lower densities and more homogeneous spatial distributions, displayed more central foci, less variability in cycle lengths and synchronization of electrical activation for similar spatial patterns, but more variability in those same variables for dissimilar spatial patterns. Compared to their isotropic counterparts, in silico anisotropic monolayers had less central foci and displayed more variability in cycle lengths and synchronization of electrical activation for both similar and dissimilar spatial patterns. The present study established a link between microscopic structure and macroscopic behavior of the biological pacemaker, and may provide crucial information for optimized biological pacemaker therapies.

Simulated P wave morphology in the presence of endo-epicardial activation delay.

AIMS: Evidences of asynchrony between epicardial and endocardial activation in the atrial wall have been reported. We used a computer model of the atria and torso to investigate the consequences of such activation delay on P wave morphology, while controlling for P wave duration. METHODS AND RESULTS: We created 390 models of the atria based on the same geometry. These models differed by atrial wall thickness (from 2 to 3 mm), transmural coupling, and tissue conductivity in the endocardial and epicardial layers. Among them, 18 were in baseline, 186 had slower conduction in the epicardium layer and 186 in the endocardial layer. Conduction properties were adjusted in such a way that total activation time was the same in all models. P waves on a 16-lead system were simulated during sinus rhythm. Activation maps were similar in all cases. Endo-epicardial delay varied between -5.5 and 5.5 ms vs. 0 ± 0.5 ms in baseline. All P waves had the same duration but variability in their morphology was observed. With slower epicardial conduction, P wave amplitude was reduced by an average of 20% on leads V3-V5 and P wave area decreased by 50% on leads V1-V2 and by 40% on lead V3. Reversed, lower magnitude effects were observed with slower endocardial conduction. CONCLUSION: An endo-epicardial delay of a few milliseconds is sufficient to significantly alter P wave morphology, even if the activation map remains the same.

Clinical applications of QT/RR hysteresis assessment: A systematic review.

BACKGROUND: QT/RR hysteresis (QT-hys) is an index of the time accommodation of ventricular repolarization to heart rate changes. This report comprehensively reviews studies addressing QT-hys as a biomarker of medical conditions. METHODS: This is a secondary analysis of data from a recent systematic review pertaining to methods of assessment of QT-hys. Articles included in the former review were filtered in order to select original articles investigating the association of QT-hys with medical conditions in humans. RESULTS: Nineteen articles fulfilled our inclusion criteria. Given the heterogeneity of the methods and investigated conditions, no pooled analysis of data could be implemented. QT-hys was mostly studied as a risk marker of severe arrhythmias, as a predictor of the long QT syndrome (LQTS) phenotypes and genotypes and as a marker of exercise-induced ischemia. An increased QT-hys appears to be implicated in arrhythmogenesis, although the evidence in this regard relies on few human studies. An augmented QT-hys was reported in the LQTS, predominantly in the LQT2 genotype, but conflicting results were obtained between studies using different methods of assessment. In addition, QT-hys appears to be a useful marker of stress-induced myocardial ischemia in patients suspected of coronary artery disease. CONCLUSIONS: QT-hys evaluation has potential clinical utility in at least some clinical conditions. Further studies of the clinical validity of QT-hys assessment are warranted, particularly condition specific studies based on QT-hys evaluation methods that provide separate estimates of QT-hys and QT/RR dependency.

Categorization and theoretical comparison of quantitative methods for assessing QT/RR hysteresis.

BACKGROUND: In the human electrocardiogram, there is a lag of adaptation of the QT interval to heart rate changes, usually termed QT/RR hysteresis (QT-hys). Subject-specific quantifiers of QT-hys have been proposed as potential biomarkers, but there is no consensus on the choice of the quantifier. METHODS: A comprehensive literature search was conducted to identify original articles reporting quantifiers of repolarization hysteresis from the surface ECG in humans. RESULTS: Sixty articles fulfilled our inclusion criteria. Reported biomarkers were grouped under four categories. A simple mathematical model of QT/RR loop was used to illustrate differences between the methods. Category I quantifiers use direct measurement of QT time course of adaptation. They are limited to conditions where RR intervals are under strict control. Category IIa and IIb quantifiers compare QT responses during consecutive heart rate acceleration and deceleration. They are relevant when a QT/RR loop is observed, typically during exercise and recovery, but are not robust to protocol variations. Category III quantifiers evaluate the optimum RR memory in dynamic QT/RR relationship modeling. They estimate an intrinsic memory parameter independent from the nature of RR changes, but their reliability remains to be confirmed when multiple memory parameters are estimated. Promising approaches include the differentiation of short-term and long-term memory and adaptive estimation of memory parameters. CONCLUSION: Model-based approaches to QT-hys assessment appear to be the most versatile, as they allow separate quantification of QT/RR dependency and QT-hys, and can be applied to a wide range of experimental settings.

A statistical model of false negative and false positive detection of phase singularities.

The complexity of cardiac fibrillation dynamics can be assessed by analyzing the distribution of phase singularities (PSs) observed using mapping systems. Interelectrode distance, however, limits the accuracy of PS detection. To investigate in a theoretical framework the PS false negative and false positive rates in relation to the characteristics of the mapping system and fibrillation dynamics, we propose a statistical model of phase maps with controllable number and locations of PSs. In this model, phase maps are generated from randomly distributed PSs with physiologically-plausible directions of rotation. Noise and distortion of the phase are added. PSs are detected using topological charge contour integrals on regular grids of varying resolutions. Over 100 × 106 realizations of the random field process are used to estimate average false negative and false positive rates using a Monte-Carlo approach. The false detection rates are shown to depend on the average distance between neighboring PSs expressed in units of interelectrode distance, following approximately a power law with exponents in the range of 1.14 to 2 for false negatives and around 2.8 for false positives. In the presence of noise or distortion of phase, false detection rates at high resolution tend to a non-zero noise-dependent lower bound. This model provides an easy-to-implement tool for benchmarking PS detection algorithms over a broad range of configurations with multiple PSs.

Lessons from computer simulations of ablation of atrial fibrillation.

This paper reviews the simulations of catheter ablation in computer models of the atria, from the first attempts to the most recent anatomical models. It describes how postulated substrates of atrial fibrillation can be incorporated into mathematical models, how modelling studies can be designed to test ablation strategies, what their current trade-offs and limitations are, and what clinically relevant lessons can be learnt from these simulations. Drawing a parallel between clinical and modelling studies, six ablation targets are considered: pulmonary vein isolation, linear ablation, ectopic foci, complex fractionated atrial electrogram, rotors and ganglionated plexi. The examples presented for each ablation target illustrate a major advantage of computer models, the ability to identify why a therapy is successful or not in a given atrial fibrillation substrate. The integration of pathophysiological data to create detailed models of arrhythmogenic substrates is expected to solidify the understanding of ablation mechanisms and to provide theoretical arguments supporting substrate-specific ablation strategies.

Vagal stimulation targets select populations of intrinsic cardiac neurons to control neurally induced atrial fibrillation.

Mediastinal nerve stimulation (MNS) reproducibly evokes atrial fibrillation (AF) by excessive and heterogeneous activation of intrinsic cardiac (IC) neurons. This study evaluated whether preemptive vagus nerve stimulation (VNS) impacts MNS-induced evoked changes in IC neural network activity to thereby alter susceptibility to AF. IC neuronal activity in the right atrial ganglionated plexus was directly recorded in anesthetized canines (n = 8) using a linear microelectrode array concomitant with right atrial electrical activity in response to: 1) epicardial touch or great vessel occlusion vs. 2) stellate or vagal stimulation. From these stressors, post hoc analysis (based on the Skellam distribution) defined IC neurons so recorded as afferent, efferent, or convergent (afferent and efferent inputs) local circuit neurons (LCN). The capacity of right-sided MNS to modify IC activity in the induction of AF was determined before and after preemptive right (RCV)- vs. left (LCV)-sided VNS (15 Hz, 500 µs; 1.2× bradycardia threshold). Neuronal (n = 89) activity at baseline (0.11 ± 0.29 Hz) increased during MNS-induced AF (0.51 ± 1.30 Hz; P < 0.001). Convergent LCNs were preferentially activated by MNS. Preemptive RCV reduced MNS-induced changes in LCN activity (by 70%) while mitigating MNS-induced AF (by 75%). Preemptive LCV reduced LCN activity by 60% while mitigating AF potential by 40%. IC neuronal synchrony increased during neurally induced AF, a local neural network response mitigated by preemptive VNS. These antiarrhythmic effects persisted post-VNS for, on average, 26 min. In conclusion, VNS preferentially targets convergent LCNs and their interactive coherence to mitigate the potential for neurally induced AF. The antiarrhythmic properties imposed by VNS exhibit memory.

Changes in P-wave morphology after pulmonary vein isolation: insights from computer simulations.

AIMS: Apparently conflicting clinical measurements of P-wave duration (PWD) pre- vs. post-ablation have been reported. To assist the interpretation of these clinical data, we used a computer model of the atria and torso to simulate P waves before and after pulmonary vein (PV) isolation. METHODS AND RESULTS: Twenty ablation patterns were designed (segmental or ipsilateral ablation; five distances to PV sleeves; addition of a roof line or not). Possible PV reconnections were introduced as gaps in the ablation lines. PWD and area were measured during sinus rhythm in vectorcardiogram (VCG) magnitude signals and on the 16-lead ECG before and after ablation, and after PV reconnection. After PV isolation, biatrial activation time was prolonged by 0-5 ms without and by 48±5 ms with roof line. Yet PWD was shortened in lead V3 and V4 by up to 15 ms. The effect of ablation on P-wave morphology was stronger when larger PV areas were isolated. Segmental and ipsilateral PV isolation led to concordant results. P-wave area increased in V1 and decreased in V6. Changes in PWD and area on the VCG were sensitive to the threshold used for detecting the end of the P wave. The occurrence of PV reconnection was best identified on leads V3, V4, and V9. CONCLUSION: PV isolation and reconnection induced measurable changes on the 16-lead ECG that might be used to improve patient follow-up after ablation.

Dynamics of atrial arrhythmias modulated by time-dependent acetylcholine concentration: a simulation study.

AIM: The autonomic nervous system modulates atrial activity, notably through acetylcholine (ACh) release. This time-dependent action may alter the dynamics of atrial arrhythmia. Our aim is to investigate in a computer model the changes induced by ACh release and degradation on the dynamical regime of a reentry. METHODS AND RESULTS: A functional reentry was simulated in a 10 × 5 cm(2) two-dimensional tissue with canine atrial membrane kinetics including an ACh-dependent K(+) current. The local ACh concentration was altered over time in a circular region following a predefined spatiotemporal profile (ACh release and degradation) characterized by its maximum ACh level, time constant of release/degradation, and diameter of the region. Phase singularities were tracked to monitor the complexity of the dynamics. Four scenarios were identified: (i) the original reentry remained stable; (ii) repolarization gradients induced by ACh release caused wavebreaks, resulting in a transient complex dynamics that spontaneously converted to a single stable reentry; (iii) the reentry self-terminated through wavebreaks and wavefront interactions; (4) wavebreaks led to a complex dynamics that converted to two or three reentries that remained stable after ACh degradation. Higher ACh level, short ACh release time constant, larger heterogeneous region, and short distance between the heterogeneous region and the spiral tip were associated with higher occurrence of ACh-induced wavebreaks. CONCLUSION: Variation of ACh concentration over time may modulate the complexity of atrial arrhythmias.

Influence of atrial substrate on local capture induced by rapid pacing of atrial fibrillation.

AIMS: Preliminary studies showed that the septum area was the only location allowing local capture of both the atria during rapid pacing of atrial fibrillation (AF) from a single site. The present model-based study investigated the influence of atrial substrate on the ability to capture AF when pacing the septum. METHODS AND RESULTS: Three biophysical models of AF with an identical anatomy from human atria but with different AF substrates were used: (i) AF based on multiple wavelets, (ii) AF based on heterogeneities in vagal activation, (iii) AF based on heterogeneities in repolarization. A fourth anatomical model without Bachmann's bundle (BB) was also implemented. Rapid pacing was applied from the septum at pacing cycle lengths in the range of 50-100% of AF cycle length. Local capture was automatically assessed with 24 pairs of electrodes evenly distributed on the atrial surface. The results were averaged over 16 AF simulations. In the homogeneous substrate, AF capture could reach 80% of the atrial surface. Heterogeneities degraded the ability to capture during AF. In the vagal substrate, the capture tended to be more regular and the degradation of the capture was not directly related to the spatial extent of the heterogeneities. In the third substrate, heterogeneities induced wave anchorings and wavebreaks even in areas close to the pacing site, with a more dramatic effect on AF capture. Finally, BB did not significantly affect the ability to capture. CONCLUSION: Atrial fibrillation substrate had a significant effect on rapid pacing outcomes. The response to therapeutic pacing may therefore be specific to each patient.

Geometrical measurement of cardiac wavelength in reaction-diffusion models.

The dynamics of reentrant arrhythmias often consists in multiple wavelets propagating throughout an excitable medium. An arrhythmia can be sustained only if these reentrant waves have a sufficiently short wavelength defined as the distance traveled by the excitation wave during its refractory period. In a uniform medium, wavelength may be estimated as the product of propagation velocity and refractory period (electrophysiological wavelength). In order to accurately measure wavelength in more general substrates relevant to atrial arrhythmias (heterogeneous and anisotropic), we developed a mathematical framework to define geometrical wavelength at each time instant based on the length of streamlines following the propagation velocity field within refractory regions. Two computational methods were implemented: a Lagrangian approach in which a set of streamlines were integrated, and an Eulerian approach in which wavelength was the solution of a partial differential equation. These methods were compared in 1D/2D tissues and in a model of the left atrium. An advantage of geometrical definition of wavelength is that the wavelength of a wavelet can be tracked over time with high temporal resolution and smaller temporal variability in an anisotropic and heterogeneous medium. The results showed that the average electrophysiological wavelength was consistent with geometrical measurements of wavelength. Wavelets were however often shorter than the electrophysiological wavelength due to interactions with boundaries and other wavelets. These tools may help to assess more accurately the relation between substrate properties and wavelet dynamics in computer models.

Improved algorithm for generating evenly-spaced streamlines from an orientation field on a triangulated surface.

BACKGROUND: Vector fields such as cardiac fiber orientation can be visualized on a surface using streamlines. The application of evenly-spaced streamline generation to the construction of interconnected cable structure for cardiac propagation models has more stringent requirements imperfectly fulfilled by current algorithms. METHOD: We developed an open-source C++/python package for the placement of evenly-spaced streamlines on a triangulated surface. The new algorithm improves upon previous works by more accurately handling streamline extremities, U-turns and limit cycles, by providing stronger geometrical guarantees on inter-streamline minimal distance, particularly when a high density of streamlines (up to 10µm spacing) is desired, and by making a more efficient parallel implementation available. The approach requires finding intersections between geometrical capsules and triangles to update an occupancy mask defined on the triangles. This enables fast streamline integration from thousands of seed points to identify optimal streamline placement. RESULTS: The algorithm was assessed qualitatively on different left atrial models of fiber orientation with varying mesh resolutions (up to 375k triangles) and quantitatively by measuring streamline lengths and distribution of inter-streamline minimal distance. The complexity and the computational performance of the algorithm were studied as a function of streamline spacing in relation to triangular mesh resolution. CONCLUSION: More accurate geometrical computations, attention to details and fine-tuning led to an algorithm more amenable to applications that require precise positioning of streamlines.

Intermittent nicotine access is as effective as continuous access in promoting nicotine seeking and taking in rats.

RATIONALE: Nicotine is a principal psychoactive agent in tobacco, contributing to tobacco's addictive potential. Preclinical studies on the effects of voluntary nicotine intake typically use self-administration procedures that provide continuous nicotine access during each self-administration session. However, many smokers consume cigarettes intermittently rather than continuously throughout each day. For drugs including cocaine and opioids, research in laboratory rats shows that intermittent intake can be more effective than continuous intake in producing patterns of drug use relevant to addiction. OBJECTIVE: We determined how intermittent versus continuous nicotine self-administration influences nicotine seeking and taking behaviours. METHODS: Female and male rats had continuous (i.e., Long Access; LgA, 6 h/day) or intermittent (IntA; 12 min ON, 60 min OFF, for 6 h/day) access to intravenous nicotine (15 µg/kg/infusion), for 12 daily sessions. We then assessed intake, responding for nicotine under a progressive ratio schedule of drug reinforcement and cue- and nicotine-induced reinstatement of drug seeking. We also estimated nicotine pharmacokinetic parameters during LgA and IntA self-administration. RESULTS: Overall, LgA rats took twice more nicotine than did IntA rats, yielding more sustained increases in estimated brain concentrations of the drug. However, the two groups showed similar motivation to seek and take nicotine, as measured using reinstatement and progressive ratio procedures, respectively. CONCLUSIONS: Intermittent nicotine use is just as effective as continuous use in producing addiction-relevant behaviours, despite significantly less nicotine exposure. This has implications for modeling nicotine self-administration patterns in human smokers and resulting effects on brain and behaviour.