Triggered Firing Research Articles

512-Channel and 13-Region Simultaneous Recordings Coupled with Optogenetic Manipulation in Freely Behaving Mice.

The development of technologies capable of recording both single-unit activity and local field potentials (LFPs) over a wide range of brain circuits in freely behaving animals is the key to constructing brain activity maps. Although mice are the most popular mammalian genetic model, in vivo neural recording has been traditionally limited to smaller channel count and fewer brain structures because of the mouse’s small size and thin skull. Here, we describe a 512-channel tetrode system that allows us to record simultaneously over a dozen cortical and subcortical structures in behaving mice. This new technique offers two major advantages – namely, the ultra-low cost and the do-it-yourself flexibility for targeting any combination of many brain areas. We show the successful recordings of both single units and LFPs from 13 distinct neural circuits of the mouse brain, including subregions of the anterior cingulate cortices, retrosplenial cortices, somatosensory cortices, secondary auditory cortex, hippocampal CA1, dentate gyrus, subiculum, lateral entorhinal cortex, perirhinal cortex, and prelimbic cortex. This 512-channel system can also be combined with Cre-lox neurogenetics and optogenetics to further examine interactions between genes, cell types, and circuit dynamics across a wide range of brain structures. Finally, we demonstrate that complex stimuli – such as an earthquake and fear-inducing foot-shock – trigger firing changes in all of the 13 brain regions recorded, supporting the notion that neural code is highly distributed. In addition, we show that localized optogenetic manipulation in any given brain region could disrupt network oscillations and caused changes in single-unit firing patterns in a brain-wide manner, thereby raising the cautionary note of the interpretation of optogenetically manipulated behaviors.

An Analytical Evaluation of the Factor $k^{2}$ for Protective Conductors

At the occurrence of phase-to-ground faults, abnormal levels of thermal energy I2t, due to the Joule effect, will be developed during the clearing time that protective devices take to operate. The I2t, also referred to as specific energy or Joule Integral, is accumulated within the elements forming the fault loop, such as the protective conductors (also referred to as equipment grounding conductors), responsible to return ground-fault currents to the source. As a consequence, the temperature of these conductors elevates and may exceed, in the case of an incorrect design, the maximum value that their insulation can withstand. This dangerous situation can cause the failure of the conductor insulation and/or trigger fires in neighboring materials. The maximum I2t that protective conductors can endure is, therefore, crucial in order to guarantee the electrical safety. The parameters on which the maximum I2t depends are described by the factor k2, which will be herein discussed and analytically evaluated. The intention of the authors is to provide a theoretical support to the Power Systems Grounding Working Group of the Technical Books Coordinating Committee IEEE P3003.2 “Recommended Practice for Equipment Grounding and Bonding in Industrial and Commercial Power Systems”; the working group is currently elaborating a dot standard based on IEEE Standard 142-2007, also referred to as the Green Book. To this purpose, a comparison with existing formulas, currently present in codes, standards of the International Electrotechnical Commission and of the IEEE, as well in the literature, will be also presented.

Triggered Firing and Atrial Fibrillation in Transgenic Mice With Selective Atrial Fibrosis Induced by Overexpression of TGF-β1

Calcium transient triggered firing (CTTF) is induced by large intracellular calcium (Ca(i)) transient and short action potential duration (APD). We hypothesized that CTTF underlies the mechanisms of early afterdepolarization (EAD) and spontaneous recurrent atrial fibrillation (AF) in transgenic (Tx) mice with overexpression of transforming growth factor β1 (TGF-β1). MHC-TGFcys(33)ser Tx mice develop atrial fibrosis because of elevated levels of TGF-β1. We studied membrane potential and Ca(i)transients of isolated superfused atria from Tx and wild-type (Wt) littermates. Short APD and persistently elevated Ca(i) transients promoted spontaneous repetitive EADs, triggered activity and spontaneous AF after cessation of burst pacing in Tx but not Wt atria (39% vs. 0%, P=0.008). We were able to map optically 4 episodes of spontaneous AF re-initiation. All first and second beats of spontaneous AF originated from the right atrium (4/4, 100%), which is more severely fibrotic than the left atrium. Ryanodine and thapsigargin inhibited spontaneous re-initiation of AF in all 7 Tx atria tested. Western blotting showed no significant changes of calsequestrin or sarco/endoplasmic reticulum Ca(2+)-ATPase 2a. Spontaneous AF may occur in the Tx atrium because of CTTF, characterized by APD shortening, prolonged Ca(i) transient, EAD and triggered activity. Inhibition of Ca(2+) release from the sarcoplasmic reticulum suppressed spontaneous AF. Our results indicate that CTTF is an important arrhythmogenic mechanism in TGF-β1 Tx atria.

Triggers and Monitoring in Intelligent Personal Health Record

Although Web-based personal health records (PHRs) have been widely deployed, the existing ones have limited intelligence. Previously, we introduced expert system technology and Web search technology into the PHR domain and proposed the concept of an intelligent PHR (iPHR). iPHR provides personalized healthcare information to facilitate users' daily activities of living. The current iPHR is passive and follows the pull model of information distribution. This paper introduces triggers and monitoring into iPHR to make iPHR become active. Our idea is to let medical professionals pre-compile triggers and store them in iPHR's knowledge base. Each trigger corresponds to an abnormal event that may have potential medical impact. iPHR keeps collecting, processing, and analyzing the user's medical data from various sources such as wearable sensors. Whenever an abnormal event is detected from the user's medical data, the corresponding trigger fires and the related personalized healthcare information is pushed to the user using natural language generation technology, expert system technology, and Web search technology.

Architecture of a level 1 track trigger for the CMS experiment

The luminosity goal for the Super-LHC is 1035/cm2/s. At this luminosity the number of proton-proton interactions in each beam crossing will be in the hundreds. This will stress many components of the CMS detector. One system that has to be upgraded is the trigger system. To keep the rate at which the level 1 trigger fires manageable, information from the tracker has to be integrated into the level 1 trigger. Current design proposals foresee tracking detectors that perform on-detector filtering to reject hits from low-momentum particles. In order to build a trigger system, the filtered hit data from different layers and sectors of the tracker will have to be transmitted off the detector and brought together in a logic processor that generates trigger tracks within the time window allowed by the level 1 trigger latency. This paper describes a possible architecture for the off-detector logic that accomplishes this goal.

Predictive Value of Alert Triggers for Identification of Developing Adverse Drug Events

Adverse drug events (ADEs) are the most common type of iatrogenic injury in hospitalized patients. However; the ability of electronic triggers to identify patients at high risk for inpatient ADEs before they occur has not been well studied. The objective of this study was to assess the positive predictive value of event triggers to detect developing ADEs. We conducted a prospective observational study in patients at a university-based teaching hospital during a 5-month period. Patients were monitored using electronic triggers designed to detect patients at increased risk for 4 types of ADEs: hypoglycemia, hypokalemia, hyperkalemia, and thrombocytopenia. Each patient for whom a trigger fired was followed to determine whether a drug-induced markedly abnormal laboratory result occurred between 1 and 72 hours after the initial trigger firing. Overall, the triggers fired 611 times on 456 patients. Of the 456 patients, 101 experienced 1 or more related ADEs between 1 and 72 hours after the initial trigger firing. The positive predictive value of the triggers and median time from trigger firing to ADE was 31% and 11.6 hours for hypoglycemia, 4.0% and 17 hours for hypokalemia, 31% and 25.4 hours for hyperkalemia, and 21% and 48.4 hours for thrombocytopenia. Computerized triggers have sufficient predictive value to detect developing ADEs and can help clinicians avert ADEs. More research is required to determine whether real-time, primary-prevention alerts may reduce the incidence of ADEs.

Pathophysiologic basis of autonomic ganglionated plexus ablation in patients with atrial fibrillation

The intrinsic cardiac autonomic nervous system (ganglionated plexuses [GP]) plays a significant role in the initiation and maintenance of atrial fibrillation (AF) in both experimental models and AF patients. Left atrial GP, located in epicardial fat pads and the ligament of Marshall, contain afferent neurons from the atrial myocardium and the central autonomic nervous system, efferent neurons (cholinergic and adrenergic neurons), and interconnecting neurons, which allow communication between GP. Stimulation of the GP produces both parasympathetic stimulation (markedly shortens action potential duration) and sympathetic stimulation (increases calcium transient) in the pulmonary vein (PV) myocardium and atrial myocardium. In a canine model, GP stimulation resulted in early afterdepolarizations, and calcium transient triggered firing in the adjacent PV and initiated AF. Fractionated atrial potentials (FAP) were consistently located in the left atrium close to the stimulated GP. Ablation of the stimulated GP eliminated the FAP surrounding the GP. In patients with paroxysmal AF, epicardial and endocardial high-frequency stimulation produced a positive vagal response (transient AV block during AF and hypotension), allowing the identification and localization of five major left atrial GP (superior left GP, inferior left GP, Marshall tract GP, anterior right GP, inferior right GP). High-density electroanatomic maps of the left atrium and PVs obtained during AF showed the FAP are located in four main left atrial areas (left atrial appendage ridge FAP area, superior-left FAP area, inferoposterior FAP area, anterior-right FAP area). All five GP are located within one of the four FAP areas. In 63 patients with paroxysmal AF, GP ablation alone (before PV antrum isolation) significantly decreased the occurrence of PV firing (47/63 patients before ablation vs 9/63 patients after ablation, P <.01). GP ablation also decreased the inducibility of sustained AF (43/63 patients vs 23/63 patients, P <.01) and markedly reduced or eliminated the left atrial FAP areas.

Activating Autoantibodies to the Beta-1 Adrenergic and M2 Muscarinic Receptors Facilitate Atrial Fibrillation in Patients With Graves' Hyperthyroidism

We studied activating autoantibodies to beta-1 adrenergic receptors (AAbeta1AR) and activating autoantibodies to M2 muscarinic receptors (AAM2R) in the genesis of atrial fibrillation (AF) in Graves' hyperthyroidism. Atrial fibrillation frequently complicates hyperthyroidism. Both AAbeta1AR and AAM2R have been described in some patients with dilated cardiomyopathy and AF. We hypothesized that their copresence would facilitate AF in autoimmune Graves' hyperthyroidism. Immunoglobulin G purified from 38 patients with Graves' hyperthyroidism with AF (n=17) or sinus rhythm (n=21) and 10 healthy control subjects was tested for its effects on isolated canine Purkinje fiber contractility with and without atropine and nadolol. Immunoglobulin G electrophysiologic effects were studied using intracellular recordings from isolated canine pulmonary veins. Potential cross-reactivity of AAbeta1AR and AAM2R with stimulating thyrotropin receptor (TSHR) antibodies was evaluated before and after adsorption to Chinese hamster ovary cells expressing human TSHRs using flow cytometry and enzyme-linked immunosorbent assays. The frequency of AAbeta1AR and/or AAM2R differed significantly between patients with AF and sinus rhythm (AAbeta1AR=94% vs. 38%, p<0.001; AAM2R=88% vs. 19%, p<0.001; and AAbeta1AR+AAM2R=82% vs. 10%, p<0.001). The copresence of AAbeta1AR and AAM2R was the strongest predictor of AF (odds ratio: 33.61, 95% confidence interval: 1.17 to 964.11, p=0.04). Immunoglobulin G from autoantibody-positive patients induced hyperpolarization, decreased action potential duration, enhanced early afterdepolarization formation, and facilitated triggered firing in pulmonary veins by local autonomic nerve stimulation. Immunoadsorption studies showed that AAbeta1AR and AAM2R were immunologically distinct from TSHR antibodies. When present in patients with Graves' hyperthyroidism, AAbeta1AR and AAM2R facilitate development of AF.

Performance and Strategies of theb-Jet Selection for the ATLAS High-Level Trigger

The ATLAS detector will operate in a highly challenging environment that requires a sophisticated trigger strategy. The online <i xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">b</i> -jet selection is an important part of the trigger which greatly improves its flexibility and extends the ATLAS physics programme. More specifically, <i xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">b</i> -jet acceptance is increased and background reduced by lowering jet transverse energy thresholds at the first trigger level and then applying <i xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">b</i> -tagging at subsequent levels. Several physics channels, especially those with topologies containing more than one <i xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">b</i> -jet, benefit from requesting this kind of trigger firing. We present an overview of the <i xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">b</i> -jet trigger algorithms and menu at the experiment start-up.

Spontaneous Pulmonary Vein Firing in Man: Relationship to Tachycardia‐Pause Early Afterdepolarizations and Triggered Arrhythmia in Canine Pulmonary Veins In Vitro

Rapid firing originating within pulmonary veins (PVs) initiates atrial fibrillation (AF). The following studies were performed to evaluate spontaneous PV firing in patients with AF to distinguish focal versus reentrant mechanisms. Intracardiac recordings were obtained in 18 patients demonstrating paroxysmal AF. Microelectrode (ME) recordings were obtained from superfused canine PV sleeves (N = 48). Spontaneous PV firing (566 +/- 16 bpm; 127 +/- 6 ms cycle length) giving rise to AF (52 episodes) was observed. Tachycardia-pause initiation was present in 132 of 200 episodes of rapid PV firing and 34 of 52 AF episodes. The pause cycle length preceding PV firing was 1,039 +/- 86 ms following tachycardia (420 +/- 40 ms cycle length). The remaining episodes were initiated following a 702 +/- 32 ms pause during sinus rhythm (588 +/- 63 ms). Spontaneous firing recorded with a multipolar mapping catheter did not detect electrical activity bridging the diastolic interval between the initial ectopic and preceding post-pause sinus beat. Tachycardia-pause initiated PV firing (138 +/- 7 ms coupling interval) in patients correlated with tachycardia-pause enhanced isometric force, early afterdepolarization (EAD) amplitude, and triggered firing within canine PVs. Rapid firing (1,172 +/- 134 bpm; 51 +/- 8 ms cycle length) following an abbreviated coupling interval (69 +/- 12 ms) was initiated in 13 of 18 canine PVs following tachycardia-pause pacing during norepinephrine + acetylcholine superfusion. Stimulation selectively activating local autonomic nerve terminals facilitated tachycardia-pause triggered firing in canine PVs (5 of 15 vs 0 of 15; P < 0.05). The studies demonstrate (1) tachycardia-pause initiation of rapid, short-coupled PV firing in AF patients and (2) tachycardia-pause facilitation of isometric force, EAD formation, and autonomic-dependent triggered firing within canine PVs, suggestive of a common arrhythmia mechanism.

Suppression of autonomic-mediated triggered firing in pulmonary veins, 24 hrs post coronary artery occlusion

Suppression of autonomic-mediated triggered firing in pulmonary veins, 24 hrs post coronary artery occlusion

Potential role of body surface ECG mapping for localization of atrial fibrillation trigger sites

Catheter ablation has revolutionized the clinical management of atrial fibrillation (AF) by offering a curative treatment option for this highly prevalent arrhythmia. Ablation therapy is aimed at electrical isolation of the pulmonary veins (PVs) as a means to prevent rapidly firing focal activation within the PVs from penetrating into the left atrium (LA) and initiate reentrant wavelet propagation. However, non-PV AF trigger sites may be present and lead to unsuccessful ablation or post-ablation AF recurrences. Infrequent trigger firing and the difficulty or inability to induce focal trigger activity in the electrophysiology laboratory limits invasive catheter-based mapping of non-PV trigger sites. Identification of AF trigger sites using the surface electrocardiogram (ECG) P wave morphology is feasible but conventional 12-lead scalar recordings do not offer the resolving power to provide discrete regional localization to potentially target catheter ablation. The present paper includes a review of preliminary clinical data on the use of a 65-lead ECG mapping system (Resolution Medical, Inc) for the non-invasive localization of AF trigger sites. This method utilizes a unique previously developed reference database of 34 mean paced P wave integral map patterns which are each specific to activation arising from a discrete segment in the LA and right atrium (RA). Trigger site localization is obtained by matching the P wave integral map morphology of a premature atrial contraction (PAC) with the reference database of 34 mean paced P wave integral map patterns.

Nonparametric inference for Markovian interval processes

Consider a p-variate counting process N = ( N ( i) ) with jump times { τ ( i) 1, τ ( i) 2, …}. Suppose that the intensity of jumps λ ( i) of N ( i) at time t depends on the time since its last jump as well as on the times since the last jumps of the other components, i.e. λ ( i) ( t) = α ( i) ( t − τ (1) N (1)( t −) , … t − τ ( p) N ( p) ( t −) ), where the α ( i) s are unknown, nonrandom functions. From observing one single trajectory of the process N over an increasing interval of time we estimate nonparametrically the functions α ( i) . The estimators are shown to be uniformly consistent over compact subsets. We derive a nonparametric asymptotic test for the hypothesis that α (1)( x 1, …, x p ) does not depend on x 2, …, x p , i.e. that N (1) is a renewal process. The results obtained are applied in the analysis of simultaneously recorded neuronal spike train series. In the example given, inhibition of one neuron (target) through another neuron (trigger) is characterized and identified as a geometric feature in the graphical representation of the estimate of α ( i) as a surface. Estimating the intensity of the target as a function of time of only the most recent trigger firing the estimate is displayed as a planar curve with a sharp minimum. This leads to a new method of assessing neural connectivity which is proposed as an alternative to existing cross-correlation-based methods.

Generation of arrhythmias in myocardial ischemia and infarction

In recent years an enhanced interest among researchers combined with the availability of new technologies has increased our knowledge of the mechanisms that generate arrhythmias in patients with ischemic heart disease. Convincing evidence has been obtained to support the occurrence of reentry in ischemic myocardium. This has been especially apparent in canine studies in the surviving layers overlying infarctions several days after coronary occlusion. In this planar model, the reentry circuit forms a figure-8 configuration around an arc of functional block due to refractoriness; the center of the arc is the site of unidirectional block and reentry. The reentry circuit is sustained by wavefronts of activation encircling segments in which the tissue on either side is alternately receptive and refractory, a variant of the leading circle model of reentry. The relatively prolonged refractoriness in ischemic tissue is due to time-dependent refractoriness, i.e., postrepolarization refractoriness, which is most prominent in more severely depolarized cells. Slow conduction is related in part to primary depression of the fast channels. There is a great variation in refractory periods in ischemic tissue because of variation in action potential duration and in the duration of time-dependent refractoriness. The depolarized resting potentials of cells in acute ischemia are due in part to extracellular accumulation of potassium and intracellular accumulation of calcium. In the latter stages of ischemia it is likely that abnormalities of ion distribution across the sarcolemma play a role. It has also been demonstrated that ischemic Purkinje fibers show abnormal automaticity, i.e., enhanced phase 4 depolarization at depolarized diastolic potentials, and afterdepolarizations with triggered firing. The relative importance of these 2 phenomena in arrhythmias in vivo is controversial. There is evidence that reflection may be a mechanism for the generation of ectopic beats in the first few minutes of acute ischemia.

An afterhyperpolarization model for vestibular afferents

A stochastic afterhyperpolarization model, modified from Kernell (Brain Res. 11, 685–687 (1968)], simulates many features of the steady‐state discharge of vestibular afferents, and may be relevant for spike initiation mechanisms in auditory afferents. Major assumptions are: (a) a single trigger site and firing occurs when the transmembrane voltage reaches a fixed critical level; (b) postsynaptic voltage fluctuations are responsible for interspike‐interval variability and are due to random times of occurrence of quantal synaptic inputs; (c) postpike recovery is due to a time‐dependent decrease in the potassium conductance (gk), i.e., an afterhyperpolarization; (d) cumulative after hyperpolarization is responsible for the lengthening of the mean interval following an interposed spike; and (e) regular and irregular afferents differ only in the magnitudes of their afterhyperpolarization. The model predicts a stronger dependence of galvanic sensitivity on normalized coefficient of variation of interspike inter...