Mammalian octopus cells are direction selective to frequency sweeps by synaptic sequence detection

Octopus cells are remarkable projection neurons of the mammalian cochlear nucleus, with extremely fast membranes and wide frequency tuning. They are considered prime examples of coincidence detectors but are poorly characterized in vivo. We discover that octopus cells are selective to frequency sweep direction, a feature that is absent in their auditory nerve inputs. In vivo intracellular recordings reveal that direction selectivity does not derive from cross-channel coincidence detection but hinges on the amplitudes and activation sequence of auditory nerve inputs tuned to clusters of hotspot frequencies. A simple biophysical model of octopus cells excited with real nerve spike trains recreates direction selectivity through interaction of intrinsic membrane conductances with activation sequence of clustered inputs. We conclude that octopus cells are sequence detectors, sensitive to temporal patterns across cochlear frequency channels. The detection of sequences rather than coincidences is a much simpler but powerful operation to extract temporal information.

Importance of the Activation Sequence of the His or Right Bundle for Diagnosis of Complex Tachycardia Circuits

In this review, we emphasize the unique value of recording the activation sequence of the His bundle or right bundle branch (RB) for diagnoses of various supraventricular and fascicular tachycardias. A close analysis of the His to RB (H-RB) activation sequence can help differentiate various forms of supraventricular tachycardias, namely atrioventricular nodal reentry tachycardia from concealed nodofascicular tachycardia, a common clinical dilemma. Furthermore, bundle branch reentry tachycardia and fascicular tachycardias often are included in the differential diagnosis of supraventricular tachycardia with aberrancy, and the use of this technique can help the operator make the distinction between supraventricular tachycardias and these other forms of ventricular tachycardias using the His-Purkinje system. We show that this technique is enhanced by the use of multipolar catheters placed to span the proximal His to RB position to record the activation sequence between proximal His potential to the distal RB potential. This allows the operator to fully analyze the activation sequence in sinus rhythm as compared to that during tachycardia and may help target ablation of these arrhythmias. We argue that 3 patterns of H-RB activation are commonly identified—the anterograde H-RB pattern, the retrograde H-RB (right bundle to His bundle) pattern, and the chevron H-RB pattern (simultaneous proximal His and proximal RB activation)—and specific arrhythmias tend to be associated with specific H-RB activation sequences. We show that being able to record and categorize this H-RB relationship can be instrumental to the operator, along with standard pacing maneuvers, to make an arrhythmia diagnosis in complex tachycardia circuits. We highlight the importance of H-RB activation patterns in these complex tachycardias by means of case illustrations from our groups as well as from prior reports.

Linear increase in the number of non-pulmonary vein triggers from paroxysmal to persistent and long-standing persistent AF in patients undergoing repeat procedure after successful isolation of pulmona

Introduction This study evaluated the prevalent triggers responsible for recurrence following successful PVI in different types of atrial fibrillation (AF). Methods Consecutive AF patients undergoing repeat catheter ablation with permanently isolated PV were included in the analysis. High-dose isoproterenol challenge (20- 30μg/min for 15–20min) was used to confirm PV reconnection and identify non-PV triggers. Circular mapping catheter (CMC) was used to map the site of origin of significant ectopic activity by comparing the activation sequence of the sinus beat with that of the ectopic beat. For the coronary sinus (CS), ablation catheter was positioned at the level of the mitral valve annulus, parallel to the one positioned in the CS. Left atrial appendage (LAA) firing was detected by placing the CMC in the left superior PV and thus recording far-field potentials from the LAA. Results This prospective study included 1850 AF patients undergoing repeat AF ablation (Table 1), of which 573 (31%) had received one and the remaining 1277 patients had received 2 earlier ablations. Permanent PVI was confirmed with isoproterenol challenge. Table 1 shows the distribution of non-PV triggers. A linear increase in the number of non-PV triggers was observed from PAF to PerAF to LSPAF. Significantly higher number of LSPAF patients had detectable non-PV triggers compared to PerAF and PAF cases. Conclusion We observed a linear increase in the number of non-PV triggers in PAF to PerAF and LSPAF patients experiencing recurrence with successful isolation of PVs. As non-PV triggers are often not targeted by operators, this could be the underlying mechanism for more frequent recurrences in non-paroxysmal AF. FUNDunding Acknowledgement Type of funding sources: None. Table 1

Machine Learning Identification of Pro-arrhythmic Structures in Cardiac Fibrosis

Cardiac fibrosis and other scarring of the heart, arising from conditions ranging from myocardial infarction to ageing, promotes dangerous arrhythmias by blocking the healthy propagation of cardiac excitation. Owing to the complexity of the dynamics of electrical signalling in the heart, however, the connection between different arrangements of blockage and various arrhythmic consequences remains poorly understood. Where a mechanism defies traditional understanding, machine learning can be invaluable for enabling accurate prediction of quantities of interest (measures of arrhythmic risk) in terms of predictor variables (such as the arrangement or pattern of obstructive scarring). In this study, we simulate the propagation of the action potential (AP) in tissue affected by fibrotic changes and hence detect sites that initiate re-entrant activation patterns. By separately considering multiple different stimulus regimes, we directly observe and quantify the sensitivity of re-entry formation to activation sequence in the fibrotic region. Then, by extracting the fibrotic structures around locations that both do and do not initiate re-entries, we use neural networks to determine to what extent re-entry initiation is predictable, and over what spatial scale conduction heterogeneities appear to act to produce this effect. We find that structural information within about 0.5 mm of a given point is sufficient to predict structures that initiate re-entry with more than 90% accuracy.

Cyclic Derivatives of the Chemerin C-Terminus as Metabolically Stable Agonists at the Chemokine-Like Receptor 1 for Cancer Treatment

Chemerin is a small chemotactic protein and a modulator of the innate immune system. Its activity is mainly mediated by the chemokine-like receptor 1 (CMKLR1), a receptor expressed by natural killer cells, dendritic cells, and macrophages. Downregulation of chemerin is part of the immune evasion strategy exploited by several cancer types, including melanoma, breast cancer, and hepatocellular carcinoma. Administration of chemerin can potentially counteract these effects, but synthetically accessible, metabolically stable analogs are required. Other tumors display overexpression of CMKLR1, offering a potential entry point for targeted delivery of chemotherapeutics. Here, we present cyclic derivatives of the chemerin C-terminus (chemerin-9), the minimal activation sequence of chemerin. Chemerin-9 derivatives that were cyclized through positions four and nine retained activity while displaying full stability in blood plasma for more than 24 h. Therefore, these peptides could be used as a drug shuttle system to target cancer cells as demonstrated here by methotrexate conjugates.