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Dual chamber leadless pacemakers are multi-unit, battery-driven implants utilized for treating patients with bradyarrhythmias and sino-atrial dysfunctions. Establishing synchronization between the units provides coordination between the atrium and ventricular contraction, and this mechanism depletes battery energy. Due to implant size constraints, reducing the synchronization energy consumed to enhance the lifetime of the implant is crucial. In this paper, a set of strategies are proposed and evaluated to indicate the best strategy to enhance the lifetime of atrial unit based on the patient's heart condition. Beat selective pulse transmission is employed instead of pulse tr 4?0ansmission on every beat to reduce energy consumption. The characteristics of interbeat contraction timing of the atrium and ventricle from the patient data is modeled as time series. The designed model is extended to model synchronization strategies with sufficient synchronization accuracy and reduction in energy consumption. It is found that the implant lifetime is dependent on the natural atrial contraction probability, which is patient specific. A relation between the transmission duty-cycle and natural atrial contraction probability is derived for all the strategies, and this analysis is used in a case study to quantify the longevity. The proposed strategies show improved lifetime in comparison to the reference strategy. In the case study, for natural atrial contraction probability of 0.1, longevity is increased by two orders in relation to the reference strategy with the longevity of 4 years. However, there is no one best strategy; instead, the most energy-efficient strategy is determined from patient's natural atrial contraction probability and tolerance to suboptimal coordination.

International audience; In this work we present a coupled electromechanical model of the heart for patient-specific simulations, and in particular cardiac resynchronisation therapy. To this end, we propose a fast fully autonomous and flexible pipeline to generate and optimise the data required to run the mechanical simulation. After the meshing of the biventricular segmentation image and the construction of the associated fibres arrangement, we compute the electrical potential propagation in the myocardial tissue from selected onset points on the endocardium. We generate a 12-lead electrocardiogram corresponding to the latter activation map by extrapolating the electrical potential on a virtual torso. This electrical activation is coupled to a mechanical model, featuring a small set of interpretable parameters. We also propose an efficient algorithm to optimise the model parameters, based on patient data. The whole pipeline including a cardiac cycle is computed in 30 minutes, enabling to use this digital twin for diagnosis and therapy planning.

International audience; Background:Frequency and distribution of left ventricular (LV) venous collaterals were studied in vivo to evaluate the ease and feasibility of implanting a new ultra-thin LV quadripolar microlead for cardiac resynchronization therapy (CRT).Methods and Results:Evaluable venograms were analyzed to define the prevalence of venous collaterals (>0.5 mm diameter) between: (1) different LV segments; and (2) different major LV veins in: unselected patients who underwent CRT from 2008 to 2012 at Rouen Hospital, France (retrospective); and CRT patients from the Axone Acute pilot study in 2018 (prospective). In prospective patients with evaluable venograms, LV microlead implantation was attempted. Thirty-six (21/65 retrospective, 15/20 prospective) patients had evaluable venograms with ≥1 visible venous collaterals. Collaterals were found between LV veins in all CRT patients with evaluable venograms. Regionally, prevalence was highest between: the apical inferior and apical lateral (42%); and mid inferior and mid inferolateral (42%) segments. Collateral connections were most prevalent between: the inferior interventricular vein (IIV) and lateral vein (64% [23/36]); and IIV and infero-lateral vein (36% [13/36]). Cross-vein microlead implantation was possible in 18 patients (90%), and single-vein implantation was conducted in the other 2 patients (10%).Conclusions:Venous collaterals were found in vivo between LV veins in all CRT patients with evaluable venograms, making this network an option for accessing multiple LV sites using a single LV microlead.

As the next generation of implanted medical devices for cardiac rhythm management moves towards multi-nodal leadless systems that do without the limitations of transvenous leads, new security threats arise from the wireless communication between the systems' nodes. Key management and the key distribution problem used in traditional cryptographic methods are considered to be too computationally expensive for small implanted medical devices. Instead, inherent human biometrics could provide a reliable alternative. In this work, we tested the key generation process across different nodes of a mimicked dual-chamber leadless cardiac pacemaker system and a subcutaneous implantable relay (S-relay). The proposed key generation process utilizes the randomness available from inter beat intervals (IBIs). A pre-clinical in-vivo experiment was performed in one dog in order to validate the concept by implanting conventional bipolar cardiac pacemaker leads in the right atrium, the right ventricle and the subcutaneous space. Based on the available randomness and entropy of recorded IBIs, 3-bits were extracted per IBI by approximating a sequence of intervals with a normal distribution. This allowed for the generation of a 128-bit key string across the nodes with an average bit mismatch rate of about 3%. Parity check methods were used to reconciliate the keys across the multiple nodes of a multi-nodal leadless pacemaker and subcutaneous device system. The findings are encouraging and demonstrate that IBIs can be used to generate secure keys for data encryption across different nodes of a leadless pacemaker system and S-relay.

A modern understanding of how cerebral cortical lesions develop after acute brain injury is based on Aristides Leão’s historic discoveries of spreading depression and asphyxial/anoxic depolarization. Treated as separate entities for decades, we now appreciate that these events define a continuum of spreading mass depolarizations, a concept that is central to understanding their pathologic effects. Within minutes of acute severe ischemia, the onset of persistent depolarization triggers the breakdown of ion homeostasis and development of cytotoxic edema. These persistent changes are diagnosed as diffusion restriction in magnetic resonance imaging and define the ischemic core. In delayed lesion growth, transient spreading depolarizations arise spontaneously in the ischemic penumbra and induce further persistent depolarization and excitotoxic damage, progressively expanding the ischemic core. The causal role of these waves in lesion development has been proven by real-time monitoring of electrophysiology, blood flow, and cytotoxic edema. The spreading depolarization continuum further applies to other models of acute cortical lesions, suggesting that it is a universal principle of cortical lesion development. These pathophysiologic concepts establish a working hypothesis for translation to human disease, where complex patterns of depolarizations are observed in acute brain injury and appear to mediate and signal ongoing secondary damage.

Multi-axial accelerometers are invaluable for the analysis of anisotropic cardiac vibrations during the first-heart-sound (S1). However, most studies simply consider the multi-axial accelerometer components independently along the different anatomical axes and rarely properly account for this anisotropy. The objective of this study was to evaluate a simple method, intended for chronically implanted medical devices, to identify a physiological reference frame maximizing S1 vibrations in the transverse plane. We attached a tri-axial accelerometer on the tip of a cardiac pacing lead to the chest of 10 human volunteers and implanted it subcutaneously in one pig. The volunteers and pig underwent separate experimental protocols capturing a wide range of conditions. The acceleration components of the tri-axial accelerometer were projected along the identified reference frame and a frame perpendicular to this. These were denoted the cardiac systolic mechanical axis and perpendicular axis, respectively. Results showed that projection along the mechanical axis tended to maximize signal-to-noise ratio and minimize cycle-to-cycle morphological variability. Significant differences were also observed between the mechanical and perpendicular axes projections, demonstrating sensibility to orientation. Along the mechanical axis, signal-to-noise-ratio was up to 21.72 dB greater, and cycle-to-cycle variability was up to 7.47 dB smaller, than along the perpendicular axis. The transverse plane angle defining the reference frame was relatively similar throughout the volunteers (28.5–44.0° from the medial-lateral axis), demonstrating inter-subject homogeneity. Also, it varied little across the different conditions (15.6° mean standard deviation across the volunteers), demonstrating stability. In conclusion, the proposed algorithm optimized signal quality at low computational cost.

Measuring cardiac hemodynamics subcutaneously offers a novel and minimally-invasive means of monitoring mechanical heart performance. Four accelerometer-based hemodynamic sensors were implanted at various subcutaneous sites of the thorax in one dog. Three of the sensors were on the tips of cardiac pacing leads, one was embedded inside an inactive pacemaker device can. The first heart sound could be well identified and its amplitude quantified in all subcutaneous sensors on a beat-to-beat basis. Its magnitude was comparable to that of the external signal, and about half that of the intracardiac signal. It also correlated well to cardiac contractility during transient pharmacologically induced hemodynamic challenges. This is the first evidence that heart sounds can be measured in the subcutaneous space to monitor heart function.

We analyzed the metabolic response to cortical spreading depression that drastically increases local energy demand to restore ion homeostasis. During single and multiple cortical spreading depressions in the rat cortex, we simultaneously monitored extracellular levels of glucose and lactate using rapid sampling microdialysis and glucose influx using 18 F-fluorodeoxyglucose positron emission tomography while tracking cortical spreading depression using laser speckle imaging. Combining the acquired data with steady-state requirements we developed a mass-conserving compartment model including neurons and glia that was consistent with the observed data. In summary, our findings are: (1) Early breakdown of glial glycogen provides a major source of energy during increased energy demand and leaves 80% of blood-borne glucose to neurons. (2) Lactate is used solely by neurons and only if extracellular lactate levels are >80% above normal. (3) Although the ratio of oxygen and glucose consumption transiently reaches levels 90%) of the overall energy supply is from oxidative metabolism. (4) During cortical spreading depression, brain release of lactate exceeds its consumption suggesting that lactate is only a circumstantial energy substrate. Our findings provide a general scenario for the metabolic response to increased cerebral energy demand.

Regional cerebral blood flow ( rCBF) is spatially and temporally adjusted to local energy needs. This coupling involves dilation of vessels both at the site of metabolite exchange and upstream of the activated region. Deficits in upstream blood supply limit the ‘capacity to raise rCBF’ in response to functional activation and therefore compromise brain function. We here demonstrate in rats that the ‘capacity to raise rCBF’ can be determined from real-time measurements of rCBF using laser speckle imaging during an energy challenge induced by cortical spreading depolarizations (CSDs). Cortical spreading depolarizations (CSDs) occur with high incidence in stroke and various other brain injuries and cause large metabolic changes. Various conditions of cerebral perfusion were induced, either by modifying microvascular tone, or by altering upstream blood supply independently. The increase in rCBF per unit of time in response to CSD was linearly correlated to the upstream blood supply. In an experimental model of stroke, we found that this marker of the capacity to raise rCBF which, in pathologic tissue may be additionally limited by impaired vasoactive signaling, was a better indicator of the functional status of cerebral tissue than local rCBF levels.

Microfluidic glucose biosensors and potassium ion selective electrodes were used in an in vivo study to measure the neurochemical effects of spreading depolarizations (SD), which have been shown to be detrimental to the injured human brain. A microdialysis probe implanted in the cortex of rats was connected to a microfluidic PDMS chip containing the sensors. The dialysate was also analyzed using our gold standard, rapid sampling microdialysis (rsMD). The glucose biosensor performance was validated against rsMD with excellent results. The glucose biosensors successfully monitored concentration changes, in response to SD wave induction, in the range of 10–400 μM with a second time-resolution. The data show that during a SD wave, there is a time delay of 62 ± 24.8 s (n = 4) between the onset of the increase in potassium and the decrease in glucose. This delay can be for the first time demonstrated, thanks to the high-temporal resolution of the microfluidic sensors sampling from a single tissue site (the microdialysis probe), and it indicates that the decrease in glucose is due to the high demand of energy required for repolarization.

International audience; Sleep apnea syndrome (SAS) is a common disease characterized by recurrent episodes of breathing pauses or important reductions in respiratory amplitude during patient's sleep. These episodes provoke significant cardiorespiratory modifications that may have long-term cardiovascular consequences. This paper proposes a novel approach for the treatment of SAS, based on a closed-loop kinesthetic stimulation, adapted as a function of the patient's physiological response. The closed-loop control system is based on concurrent, coupled proportional-derivative (PD) controllers that modulate the stimulation amplitude delivered to the patient. The controller was tested on a first phase of a clinical protocol including 12 patients with previously diagnosed SAS. Results from one patient are presented in this paper, showing how the proposed controller is capable to adapt stimulation parameters, converging to a minimum patient-specific amplitude. These results are encouraging regarding the feasibility of the integration of the proposed controller into the therapy for the adaptive optimization of the kinesthetic stimulation amplitude and warrant a second phase of the clinical study of this system.

International audience; Sleep apnea syndromes are characterized by repeated episodes of breathing pauses (apnea) or significant reductions in respiratory amplitude (hypopnea) during the patient's sleep. These episodes significantly alter the sleep structure of the patient and provoke acute cardiorespiratory responses that may be deleterious in the long term. Continuous positive airway pressure (CPAP) therapy is the gold-standard treatment for SAS, but patient compliance to this therapy is low. This paper presents a new system for real-time detection, monitoring and treatment of SAS, based on triggered kinesthetic stimulation. The system is composed of 3 components: i) a cardio-respiratory recorder, ii) a kinesthetic stimulator and iii) a real-time processing application, integrating an " on-off " control method to trigger the kinesthetic stimulation as a function respiratory event detections. A preliminary evaluation of the system , performed on 46 patients suffering from severe SAS is also presented. This evaluation is focused on i) the performance characterization of the real-time respiratory event detector and ii) a qualitative description of the effect of the therapy. A satisfactory real-time respiratory event detection performance (sensitivity= 89.2%, positive predictive value = 59%) was obtained with the proposed detector, when evaluated retrospectively using the acquired data. Three case reports, describing the cardiorespiratory response to the therapy of a responder, a partially-responder and a non-responder patients are

Spreading depolarizations (SD) are waves of abrupt, near-complete breakdown of neuronal transmembrane ion gradients, are the largest possible pathophysiologic disruption of viable cerebral gray matter, and are a crucial mechanism of lesion development. Spreading depolarizations are increasingly recorded during multimodal neuromonitoring in neurocritical care as a causal biomarker providing a diagnostic summary measure of metabolic failure and excitotoxic injury. Focal ischemia causes spreading depolarization within minutes. Further spreading depolarizations arise for hours to days due to energy supply-demand mismatch in viable tissue. Spreading depolarizations exacerbate neuronal injury through prolonged ionic breakdown and spreading depolarization-related hypoperfusion (spreading ischemia). Local duration of the depolarization indicates local tissue energy status and risk of injury. Regional electrocorticographic monitoring affords even remote detection of injury because spreading depolarizations propagate widely from ischemic or metabolically stressed zones; characteristic patterns, including temporal clusters of spreading depolarizations and persistent depression of spontaneous cortical activity, can be recognized and quantified. Here, we describe the experimental basis for interpreting these patterns and illustrate their translation to human disease. We further provide consensus recommendations for electrocorticographic methods to record, classify, and score spreading depolarizations and associated spreading depressions. These methods offer distinct advantages over other neuromonitoring modalities and allow for future refinement through less invasive and more automated approaches.

International audience; Diagnosis of sleep-related breathing disorders (SBD) usually relies on manual retrospective analysis of the signals recorded during a whole night. We evaluated a novel detector, implemented in a cardio-respiratory Holter device, and capable of automatic event-based detection of SBDs in real time. Events (hypopneas and apneas) detected in real time were compared to those scored on the simultaneously recorded gold standard polysomnography (PSG). 4240 events were recorded by the PSG in 30 severe obstructive SBD patients. The sensitivity and positive predictive value of the detector were 86.2% (CI. 85.2-87.2%) and 60. 7% (C.l. 59.5-61.9%) respectively. The performance of this novel detector suggests that it could be used to trigger and/or adjust an event-based SBD treatment. © 2015 CCAL.

Brain function critically relies on the supply with energy substrates (oxygen and glucose) via blood flow. Alterations in energy demand as during neuronal activation induce dynamic changes in substrate fluxes and blood flow. To study the complex system that regulates cerebral metabolism requires the combination of methods for the simultaneous assessment of multiple parameters. We developed a multimodal imaging device to combine positron emission tomography (PET) with laser speckle imaging (LSI) and RGB reflectometry (RGBR). Depending on the radiotracer, PET provides 3-dimensional quantitative information of specific molecular processes, while LSI and RGBR measure cerebral blood flow (CBF) and hemoglobin oxygenation at high temporal and spatial resolution. We first tested the functional capability of each modality within our system and showed that interference between the modalities is negligible. We then cross-calibrated the system by simultaneously measuring absolute CBF using (15)O-H2O PET (CBF(PET)) and the inverse correlation time (ICT), the LSI surrogate for CBF. ICT and CBF(PET) correlated in multiple measurements in individuals as well as across different animals (R(2)=0.87, n=44 measurements) indicating that ICT can be used for absolute quantitative assessment of CBF. To demonstrate the potential of the combined system, we applied it to cortical spreading depression (CSD), a wave of transient cellular depolarization that served here as a model system for neurovascular and neurometabolic coupling. We analyzed time courses of hemoglobin oxygenation and CBF alterations coupled to CSD, and simultaneously measured regional uptake of (18)F-2-fluoro-2-deoxy-D-glucose ((18)F-FDG) used as a radiotracer for regional glucose metabolism, in response to a single CSD and to a cluster of CSD waves. With this unique combination, we characterized the changes in cerebral metabolic rate of oxygen (CMRO2) in real-time and showed a correlation between (18)F-FDG uptake and the number of CSD waves that passed the local tissue. Finally, we examined CSD spontaneously occurring during focal ischemia also referred to as peri-infarct depolarization (PID). In the vicinity of the ischemic territory, we observed PIDs that were characterized by reduced CMRO2 and increased oxygen extraction fraction (OEF), indicating a limitation of oxygen supply. Simultaneously measured PET showed an increased (18)F-FDG uptake in these regions. Our combined system proved to be a novel tool for the simultaneous study of dynamic spatiotemporal alterations of cortical blood flow, oxygen metabolism and glucose consumption under normal and pathologic conditions.

Sedatives in the neurointensive care unit can strongly influence patients' risks of developing secondary brain damage. In particular, isoflurane, a volatile anesthetic, has been recently re-introduced to the neurointensive care unit, and first clinical studies suggest beneficial effects due to elevation of cerebral blood flow and reduction of metabolism. In contrast, propofol is a commonly used intravenous sedative that reduces cerebral blood flow and intra-cranial pressure. We have here studied the influence of these two sedatives on the occurrence of cortical spreading depolarizations (CSDs), which have emerged over the last decade as a major mechanism of delayed brain injury in stroke and brain trauma, constituting a substantial vascular and metabolic threat to peri-infarct tissue and being associated with poor patient outcome. Two experimental models were tested in Wistar rats anesthetized either with isoflurane or with propofol: KCl-evoked CSDs (n=10) and spontaneous CSDs after occlusion of the middle cerebral artery (n=14). Spatiotemporal patterns of CSD waves were observed by real-time laser speckle imaging of regional cerebral blood flow changes associated with the CSDs. During 30 min of cortical KCl application, 5.2±0.7 CSDs were induced under isoflurane compared to 10.2±1.8 CSDs under propofol (p

Complex biological systems often require measurements of multiple parameters with high temporal and spatial resolution. Multimodal approaches and the combination of methods are therefore a powerful tool to address such scientific questions. Laser speckle imaging (LSI) is an optical method that monitors dynamic changes in cortical blood flow (CBF) with high temporal resolution. Positron emission tomography (PET) allows for quantitative imaging of physiological processes and is a gold standard method to determine absolute cerebral blood flow. We developed a setup that allows simultaneous measurement with both modalities. Here, we simultaneously measured CBF with PET and LSI in rats and analyzed how the correlation of PET and LSI is modified when (1) different methods are used for the calculation of speckle inverse correlation time (ICT), (2) speckle data is acquired through thinned or craniectomized skull, (3) influence of surface vessels is removed from the speckle data. For the latter, a method for automated vessel segmentation from LSI data was developed. We obtained the best correlation (R2 = 0.890, p

Spreading depolarizations (SDs) occur spontaneously with high incidence in patients with acute brain injury. They can be detected by subdural electrocorticographic recordings. We here characterize the dynamic metabolic response to these events. A microdialysis catheter was inserted into perilesional cortical tissue adjacent to a strip for electrocorticography following craniotomy in 10 patients. The microdialysis catheter was connected to an online microdialysis assay measuring glucose and lactate concentrations every 30 to 60 secs. Spontaneously occurring SDs systematically caused a reduction in dialysate glucose by −32.0 μmol/L (range: −92.3 to −18.4 μmol/L, n=90) and increase in lactate by +23.1 μmol/L (range: +5.5 to +93.6 μmol/L, n=49). The changes were sustained at 20 mins after the SD events and highly significant using an area under the curve analysis ( P

A new approach to signal processing of analytical time-domain data is presented. It consists in identifying the types of noise, characterizing them, and subsequently subtracting them from the otherwise unprocessed data set. The algorithms have been successfully applied to three classes of noise commonly found in analytical signals: spikes, ripples, and baseline drift. Traditional filters have been used as an intermediary step to detect and remove spikes in the signal with 96.8% success. Adaptive ensemble average subtraction has been developed to remove nonstationary ripples that have similar time scales as the signal of interest. This method increased the signal-to-noise ratio by up to 250% and led to minimal distortion of the signal, unlike conventional Fourier filters. Finally the removal of baseline drift has been achieved by subtraction of a mathematical model for the baseline. These three methods are generic, computationally fast, and applicable to a wide range of analytical techniques. Full Matlab codes and examples are included as Supporting Information.