Role In Pacemaking Research Articles

Role of Interstitial Cells of Cajal in Congenital Ureteropelvic Junction Obstruction.

Although congenital ureteropelvic junction (UPJ) obstruction is the most common cause of neonatal hydronephrosis, aetiopathogenesis is still inconclusive. Recently, the paucity of interstitial cells of Cajal (ICC) at the narrow adynamic part of UPJ has been implicated as a causative factor. This prospective study was conducted between October 2019 and March 2022 to find out the density of ICC by the immunohistochemical method using CD117 (c-kit) antibody, in resected segments of UPJ in obstruction patients and in renal tumour patients as control. ICC/high power field (hpf) was also studied from the margins of the resected segment in the obstruction group. The pre-operative and post-operative sonographic and renal scintigraphic features were compared. The median age of patients in the study group (n = 25) was 36 months and in the control group was 39 months. The mean ICC/hpf at the stenotic part of UPJ in the study group was 3.56 ± 1.26 and in the control group was 12.56 ± 1.89 (P = 0.0001). ICC density from the proximal and distal margins of the resected segment was 11.12 ± 2.12 and 11.68 ± 1.62, respectively (P < 0.001). The post-operative antero-posterior diameter of the renal pelvis and differential renal function showed significant improvement in comparison to the pre-operative value (P = 0.0045 and 0.0005, respectively). The significant decrease in the density of ICC at the stenotic part of UPJ compared to controls suggests a pacemaker role of these cells in ureteral peristalsis and the aetiopathogenesis of UPJ obstruction. Histopathological analysis of ICC should not only be limited to the stenotic part of UPJ but also should focus on the anastomosed ends of the ureter, which reflects post-pyeloplasty outcome.

Understanding the role of temporary epicardial pacemakers after heart transplantation in the cardiac intensive care unit

The International Society of Heart and Lung Transplantation (ISHLT) guidelines for the care of heart transplant recipients recommend the placement of temporary epicardial pacing wires at the time of surgery. However, there is little data regarding optimal postoperative pacing modality and its implication on ICU length of stay (LOS).We conducted a single-center retrospective cohort study of 187 patients who underwent heart transplantation from January 1, 2019 to February 28, 2023 and had postoperative epicardial pacemaker wires placed. The study's primary outcome was to observe the association between pacing modalities and prolonged ICU LOS (greater than 5 days). The secondary outcome was to observe the association between pacing modalities and prolonged hospital LOS (greater than 15 days), readmission within 30 days of discharge, days on inotropic and pressor support, death, high-grade rejection on biopsy, coronary artery vasculopathy at 1 year, primary graft dysfunction, mediastinitis, and development of a malignancy.22 patients (12%) had their pacing mode turned off at the time of arrival to the ICU, 36 patients (19%) had their pacing mode set to AAI, 101 patients (54%) had theirs set to DDD, and 28 (15%) had theirs set to VVI. No mode of epicardial pacing was associated with an increased ICU LOS, hospital LOS, increased readmission rates, increased short-term adverse effects (STAEs), increased long-term adverse effects (LTAEs), or increased duration of support with vasoactive medications.Our study demonstrated no significant association between the mode of temporary pacing and LOS or adverse effects after heart transplantation.

Biallelic variants in POPDC2 cause a novel autosomal recessive syndrome presenting with cardiac conduction defects and variable hypertrophic cardiomyopathy.

ABSTRACTPOPDC2encodes for the Popeye domain-containing protein 2 which has an important role in cardiac pacemaking and conduction, due in part to its cAMP-dependent binding and regulation of TREK-1 potassium channels. Loss ofPopdc2in mice results in sinus pauses and bradycardia and morpholino knockdown ofpopdc2 inzebrafish results in atrioventricular (AV) block. We identified bi-allelic variants inPOPDC2in 4 families that presented with a phenotypic spectrum consisting of sinus node dysfunction, AV conduction defects and hypertrophic cardiomyopathy. Using homology modelling we show that the identifiedPOPDC2variants are predicted to diminish the ability of POPDC2 to bind cAMP. Inin vitroelectrophysiological studies we demonstrated that, while co-expression of wild-type POPDC2 with TREK-1 increased TREK-1 current density, POPDC2 variants found in the patients failed to increase TREK-1 current density. While patient muscle biopsy did not show clear myopathic disease, it showed significant reduction of the expression of both POPDC1 and POPDC2, suggesting that stability and/or membrane trafficking of the POPDC1–POPDC2 complex is impaired by pathogenic variants in any of the two proteins. Single-cell RNA sequencing from human hearts demonstrated that co-expression of POPDC1 and 2 was most prevalent in AV node, AV node pacemaker and AV bundle cells. Sinoatrial node cells expressed POPDC2 abundantly, but expression of POPDC1 was sparse. Together, these results concur with predisposition to AV node disease in humans with loss-of-function variants inPOPDC1and POPDC2 and presence of sinus node disease inPOPDC2,but not inPOPDC1related disease in human. Using population-level genetic data of more than 1 million individuals we showed that none of the familial variants were associated with clinical outcomes in heterozygous state, suggesting that heterozygous family members are unlikely to develop clinical manifestations and therefore might not necessitate clinical follow-up. Our findings provide evidence forPOPDC2as the cause of a novel Mendelian autosomal recessive cardiac syndrome, consistent with previous work showing that mice and zebrafish deficient in functionalPOPDC2display sinus and AV node dysfunction.GRAPHICAL ABSTRACT

Hyper-brain hyper-frequency network topology dynamics when playing guitar in quartet.

Ensemble music performance is a highly coordinated form of social behavior requiring not only precise motor actions but also synchronization of different neural processes both within and between the brains of ensemble players. In previous analyses, which were restricted to within-frequency coupling (WFC), we showed that different frequencies participate in intra- and inter-brain coordination, exhibiting distinct network topology dynamics that underlie coordinated actions and interactions. However, many of the couplings both within and between brains are likely to operate across frequencies. Hence, to obtain a more complete picture of hyper-brain interaction when musicians play the guitar in a quartet, cross-frequency coupling (CFC) has to be considered as well. Furthermore, WFC and CFC can be used to construct hyper-brain hyper-frequency networks (HB-HFNs) integrating all the information flows between different oscillation frequencies, providing important details about ensemble interaction in terms of network topology dynamics (NTD). Here, we reanalyzed EEG (electroencephalogram) data obtained from four guitarists playing together in quartet to explore changes in HB-HFN topology dynamics and their relation to acoustic signals of the music. Our findings demonstrate that low-frequency oscillations (e.g., delta, theta, and alpha) play an integrative or pacemaker role in such complex networks and that HFN topology dynamics are specifically related to the guitar quartet playing dynamics assessed by sound properties. Simulations by link removal showed that the HB-HFN is relatively robust against loss of connections, especially when the strongest connections are preserved and when the loss of connections only affects the brain of one guitarist. We conclude that HB-HFNs capture neural mechanisms that support interpersonally coordinated action and behavioral synchrony.

Nurses’ Knowledge and Attitudes toward Pacemaker: A Cross-Sectional Study

Despite the critical role of pacemakers in managing symptomatic atrioventricular and ventricular conduction abnormalities, there remains a significant gap in the knowledge and attitudes of nurses towards these devices. This study assesses the understanding and perceptions of pacemakers among nurses in Al-Basrah Governorate hospitals, exploring associations with demographic factors such as age, gender, educational level, years of experience, and training. Employing a descriptive methodology, a non-probability sample of 200 nurses from five hospitals (Abi Al-Khasib General Hospital, Umm Qasr General Hospital, Al-Zubair General Hospital, Al-Shifaa Hospital, and Al-Mawani Teaching Hospital) was surveyed from October 15, 2022, to August 15, 2023. Content validity was ensured by engaging eleven professionals, while reliability was assessed using Cronbach's Alpha. Results indicate a concerning deficiency in pacemaker-related knowledge, with 79.5% of nurses demonstrating poor knowledge, 18% showing intermediate knowledge, and only 2.5% exhibiting high knowledge. Similarly, attitudes were predominantly negative, with 81.5% of nurses expressing low enthusiasm towards pacemakers, while 11% and 7.5% displayed intermediate and high attitudes, respectively. These findings highlight the need for targeted educational interventions aimed at enhancing nurses' competence and attitudes concerning pacemakers to improve postoperative care and management outcomes for patients with these devices. Highlights: Knowledge Gap: A significant 79.5% of nurses show insufficient knowledge of pacemakers, indicating a critical need for improved medical education. Attitudinal Barriers: Over 81% of nurses have negative attitudes towards pacemakers, which may affect patient care quality. Training Requirement: There's a clear need for specialized training programs for nurses on pacemakers to enhance their knowledge and attitudes, ultimately improving patient care. Keywords: Pacemaker Knowledge, Nursing Attitudes, Educational Interventions

Lipopolysaccharide-induced sepsis impairs M2R-GIRK signaling in the mouse sinoatrial node

Sepsis has emerged as a global health burden associated with multiple organ dysfunction and 20% mortality rate in patients. Numerous clinical studies over the past two decades have correlated the disease severity and mortality in septic patients with impaired heart rate variability (HRV), as a consequence of impaired chronotropic response of sinoatrial node (SAN) pacemaker activity to vagal/parasympathetic stimulation. However, the molecular mechanism(s) downstream to parasympathetic inputs have not been investigated yet in sepsis, particularly in the SAN. Based on electrocardiography, fluorescence Ca2+ imaging, electrophysiology, and protein assays from organ to subcellular level, we report that impaired muscarinic receptor subtype 2-G protein-activated inwardly-rectifying potassium channel (M2R-GIRK) signaling in a lipopolysaccharide-induced proxy septic mouse model plays a critical role in SAN pacemaking and HRV. The parasympathetic responses to a muscarinic agonist, namely IKACh activation in SAN cells, reduction in Ca2+ mobilization of SAN tissues, lowering of heart rate and increase in HRV, were profoundly attenuated upon lipopolysaccharide-induced sepsis. These functional alterations manifested as a direct consequence of reduced expression of key ion-channel components (GIRK1, GIRK4, and M2R) in the mouse SAN tissues and cells, which was further evident in the human right atrial appendages of septic patients and likely not mediated by the common proinflammatory cytokines elevated in sepsis.

An evolutionarily conserved pacemaker role for HCN ion channels in smooth muscle.

Although hyperpolarization-activated cation (HCN) ion channels are well established to underlie cardiac pacemaker activity, their role in smooth muscle organs remains controversial. HCN-expressing cells are localized to renal pelvic smooth muscle (RPSM) pacemaker tissues of the murine upper urinary tract and HCN channel conductance is required for peristalsis. To date, however, the Ih pacemaker current conducted by HCN channels has never been detected in these cells, raising questions on the identity of RPSM pacemakers. Indeed, the RPSM pacemaker mechanisms of the unique multicalyceal upper urinary tract exhibited by humans remains unknown. Here, we developed immunopanning purification protocols and demonstrate that 96% of isolated HCN+ cells exhibit Ih . Single-molecule STORM to whole-tissue imaging showed HCN+ cells express single HCN channels on their plasma membrane and integrate into the muscular syncytium. By contrast, PDGFR-α+ cells exhibiting the morphology of ICC gut pacemakers were shown to be vascular mural cells. Translational studies in the homologous human and porcine multicalyceal upper urinary tracts showed that contractions and pacemaker depolarizations originate in proximal calyceal RPSM. Critically, HCN+ cells were shown to integrate into calyceal RPSM pacemaker tissues, and HCN channel block abolished electrical pacemaker activity and peristalsis of the multicalyceal upper urinary tract. Cumulatively, these studies demonstrate that HCN ion channels play a broad, evolutionarily conserved pacemaker role in both cardiac and smooth muscle organs and have implications for channelopathies as putative aetiologies of smooth muscle disorders. KEY POINTS: Pacemakers trigger contractions of involuntary muscles. Hyperpolarization-activated cation (HCN) ion channels underpin cardiac pacemaker activity, but their role in smooth muscle organs remains controversial. Renal pelvic smooth muscle (RPSM) pacemakers trigger contractions that propel waste away from the kidney. HCN+ cells localize to murine RPSM pacemaker tissue and HCN channel conductance is required for peristalsis. The HCN (Ih ) current has never been detected in RPSM cells, raising doubt whether HCN+ cells are bona fide pacemakers. Moreover, the pacemaker mechanisms of the unique multicalyceal RPSM of higher order mammals remains unknown. In total, 97% of purified HCN+ RPSM cells exhibit Ih . HCN+ cells integrate into the RPSM musculature, and pacemaker tissue peristalsis is dependent on HCN channels. Translational studies in human and swine demonstrate HCN channels are conserved in the multicalyceal RPSM and that HCN channels underlie pacemaker activity that drives peristalsis. These studies provide insight into putative channelopathies that can underlie smooth muscle dysfunction.

Advantages, limitations and new perspectives on the implantation of subcutaneous cardioverter-defibrillator

Subcutaneous cardioveter-defibrillator (S-ICD) gained considerable place in sudden cardiac death (SCD) prevention. The main advantage of this device is the possiblility of implantating it outside of blood vessel. The lack of permanent pacing and antitachycardia pacing (ATP) are its key limitations. New research is focused on creating an extravessel device that could combine the role of cardioverter and pacemaker. The main difficulty is the mutual interference of sensing.

Proximal dendritic localization of NALCN channels underlies tonic and burst firing in nigral dopaminergic neurons.

In multipolar nigral dopamine (DA) neurons, the highly excitable proximal dendritic compartments (PDCs) and two Na+ -permeable leak channels, TRPC3 and NALCN, play a key role in pacemaking. However, the causal link between them is unknown. Here we report that the proximal dendritic localization of NALCN underlies pacemaking and burst firing in DA neurons. Our morphological analysis of nigral DA neurons reveals that TRPC3 is ubiquitously expressed in the whole somatodendritic compartment, but NALCN is localized within the PDCs. Blocking either TRPC3 or NALCN channels abolished pacemaking. However, only blocking NALCN, not TRPC3, degraded burst discharges. Furthermore, local glutamate uncaging readily induced burst discharges within the PDCs, compared with other parts of the neuron, and NALCN channel inhibition dissipated burst generation, indicating the importance of NALCN to the high excitability of PDCs. Therefore, we conclude that PDCs serve as a common base for tonic and burst firing in nigral DA neurons. KEY POINTS: Midbrain dopamine (DA) neurons are slow pacemakers that can generate tonic and burst firings, and the highly excitable proximal dendritic compartments (PDCs) and two Na+ -permeable leak channels, TRPC3 and NALCN, play a key role in pacemaking. We find that slow tonic firing depends on the basal activity of both the NALCN and TRPC3 channels, but that burst firing does not require TRPC3 channels but relies only on NALCN channels. We find that TRPC3 is ubiquitously expressed in the entire somatodendritic compartment, but that NALCN exists only within the PDCs in nigral DA neurons. We show that NALCN channel localization confers high excitability on PDCs and is essential for burst generation in nigral DA neurons. These results suggest that PDCs serve as a common base for tonic and burst firing in nigral DA neurons.

A novel 3D spatial model of mouse sinoatrial node cells for investigating impact of microstructure changes on pacemaker activity

Spontaneous beating of sinoatrial node (SAN) cells is mediated by a complex coupled system of both membrane- and Ca2+-clocks. Distinct from ventricular myocytes, SAN myocytes typically lack transversal tubules but instead display rich caveolae, i.e., small Ω-shaped invaginations of the plasma membrane. Disruption of caveolae has been associated with dysregulation of caveolar-associated ion channels and transporters and linked to Long QT syndrome and heart failure. However, their functional role in SAN pacemaking remains to be elucidated mechanistically.

Conduction abnormalities and role of cardiac pacing in cardiac amyloidosis: A systematic review.

Cardiac amyloidosis (CA) is an increasingly recognized cause of heart failure, characterized by extracellular deposition of insoluble protein fibrils leading to progressive myocardial dysfunction. The most common types of cardiac amyloidosis are immunoglobin light-chain (AL) and transthyretin (ATTR). Conduction abnormalities are commonly encountered among patients with cardiac amyloidosis and are an important cause of morbidity and mortality. Abnormalities range from infra-Hisian intraventricular conduction delay and bundle branch block to complete atrioventricular block. Pacemaker placement in CA patients follows established guidelines, similar to those for patients without CA, with generally good efficacy. The role and appropriate timing of pacemakers for primary prevention of brady-arrhythmias in CA remains uncertain. While biventricular (BiV) pacing has been shown to improve clinical outcomes in patients with systolic heart failure without CA, there are few data examining the utility of BiV pacing in patients with CA. With the advent of effective treatments for AL and ATTR, appropriate application of pacing is important to support patients with CA and conduction disease through therapeutic trials. This systematic review summarizes the current literature examining the utility of pacing in CA.

Central and Peripheral Clock Control of Circadian Feeding Rhythms.

Many behaviors exhibit ~24-h oscillations under control of an endogenous circadian timing system that tracks time of day via a molecular circadian clock. In the fruit fly, Drosophila melanogaster, most circadian research has focused on the generation of locomotor activity rhythms, but a fundamental question is how the circadian clock orchestrates multiple distinct behavioral outputs. Here, we have investigated the cells and circuits mediating circadian control of feeding behavior. Using an array of genetic tools, we show that, as is the case for locomotor activity rhythms, the presence of feeding rhythms requires molecular clock function in the ventrolateral clock neurons of the central brain. We further demonstrate that the speed of molecular clock oscillations in these neurons dictates the free-running period length of feeding rhythms. In contrast to the effects observed with central clock cell manipulations, we show that genetic abrogation of the molecular clock in the fat body, a peripheral metabolic tissue, is without effect on feeding behavior. Interestingly, we find that molecular clocks in the brain and fat body of control flies gradually grow out of phase with one another under free-running conditions, likely due to a long endogenous period of the fat body clock. Under these conditions, the period of feeding rhythms tracks with molecular oscillations in central brain clock cells, consistent with a primary role of the brain clock in dictating the timing of feeding behavior. Finally, despite a lack of effect of fat body selective manipulations, we find that flies with simultaneous disruption of molecular clocks in multiple peripheral tissues (but with intact central clocks) exhibit decreased feeding rhythm strength and reduced overall food intake. We conclude that both central and peripheral clocks contribute to the regulation of feeding rhythms, with a particularly dominant, pacemaker role for specific populations of central brain clock cells.

A Systematic Review of the Therapeutic Role of Gastric Pacemakers in Adults With Gastroparesis.

Gastroparesis or gastric stasis is the delayed transit of the ingested contents through the stomach in the absence of mechanical obstruction. It can have multiple etiologies, most commonly idiopathic (ID) and diabetic (DM). Gastroparesis can cause significant distress to patients as it leads to symptoms like intractable nausea and vomiting, weight loss, abdominal bloating, early satiety, etc. The pathogenesis is mainly thought to be due to the dysfunction of the gastric pacemaker cells, i.e., interstitial cells of Cajal (ICC), and their interaction with the other gastric motor function regulatory components. There are several proposed treatment options for gastroparesis. Despite that, most patients remain refractory to medical treatment and require additional interventions for symptomatic relief. One such intervention is gastric electrical stimulation or gastric pacemaker, which aids in improving gastric motility. We have searched PubMed, PubMed Central (PMC), Medline, Science Direct, and Google Scholar for articles pertaining to the use of gastric electrical stimulation in gastroparesis published in the last 10 years. The keywords used include "gastroparesis", "gastric stasis", "gastric pacemaker'', "gastric electrical stimulation", "nausea", "vomiting", "abdominal bloating", "gastric neuromodulation". We have finally included twelve studies that were the most relevant to our research question and met the quality assessment criteria. Exclusion criteria consisted of pediatric population studies, studies conducted on animals, books, and grey literature. Overall, these twelve studies helped evaluate the impact of gastric pacemakers on symptoms of gastroparesis like nausea, vomiting, weight loss, abdominal bloating, and quality of life. We found that most studies favored gastric pacemakers, improving the incidence of nausea and vomiting in patients with gastroparesis. There was a marked improvement in the BMI as well. On the other hand, most open-labeled studies showed improved quality of life and Gastroparesis Cardinal Symptom Index (GCSI) scores, while randomized controlled trials and meta-analyses did not reflect the same result. In addition, some other parameters improved with gastric pacemakers, Inflammatory markers, insulin levels (especially in diabetics), and the number of hospitalizations. In conclusion, gastric pacemaker is a potential treatment option for patients with medically refractory gastroparesis. As noted from the results of our study, nausea/vomiting, weight loss, and overall GCSI scores have shown marked improvement with gastric electrical stimulation (GES). Nevertheless, more extensive research is needed to understand better the full extent of this device’s use as a viable treatment option for patients suffering from gastroparesis.

Van der Pol equation with sine nonlinearity: dynamical behavior and real time control to a target trajectory

In this work, the dynamical behavior and real time control of a target trajectory of a modified Van der Pol model so the potential is proportional to the term is proposed. A generalization in the case of small oscillations on the function is studied. Due to function, the system presents periodical regions of stability and unstability, a very rich dynamical behavior. Analytical investigations based on the harmonic balance method came out some specific values of the excitation frequency for which the model is subjected to a phenomenon of frequency entrainment. Also, under effect of the sine function power, chaos appears for even small value of the nonlinearity coefficient, in contrast to the classical Van der Pol oscillator. An investigation as an artificial pacemaker is done based on the real frequency of the natural pacemaker. We found that the modified Van der Pol model, like the classic Van der Pol model, can play the role of an artificial pacemaker with some approximations. Due to the complexity of the analogical sine function, an experimental study was made by real implementation of an Arduino Card based on the Runge–Kutta 4th order algorithm. The results obtained show a good correlation with the numerical results.

Regulation of sinus node pacemaking and atrioventricular node conduction by HCN channels in health and disease

The funny current, If, was first recorded in the heart 40 or more years ago by Dario DiFrancesco and others. Since then, we have learnt that If plays an important role in pacemaking in the sinus node, the innate pacemaker of the heart, and more recently evidence has accumulated to show that If may play an important role in action potential conduction through the atrioventricular (AV) node. Evidence has also accumulated to show that regulation of the transcription and translation of the underlying Hcn genes plays an important role in the regulation of sinus node pacemaking and AV node conduction under normal physiological conditions - in athletes, during the circadian rhythm, in pregnancy, and during postnatal development - as well as pathological states - ageing, heart failure, pulmonary hypertension, diabetes and atrial fibrillation. There may be yet more pathological conditions involving changes in the expression of the Hcn genes. Here, we review the role of If and the underlying HCN channels in physiological and pathological changes of the sinus and AV nodes and we begin to explore the signalling pathways (microRNAs, transcription factors, GIRK4, the autonomic nervous system and inflammation) involved in this regulation. This review is dedicated to Dario DiFrancesco on his retirement.

Epilepsy as a dynamical disorder orchestrated by epileptogenic zone: a review

Epilepsy is a group of chronic neurological disorders characterized with recurrent and hypersynchronous discharge. In the epileptic brain, epileptogenic zone (EZ) with abnormal firing patterns is considered as the culprit of hyperexcitable neuronal behaviors, increasingly manifested as alterations in dynamics. Meanwhile, the brain networks of epileptic patients show greater seizure susceptibility than those from healthy controls, referred as epileptogenic networks. There is a growing recognition of an intimate, but also complex, relationship between the self-organization of epileptogenic networks and abnormal dynamics of the EZ. In this review, we discussed the short- and long-term effects of recurrent epileptiform discharge on neural circuits, involving the regulation of connection weights and network topology. In addition, progressive abnormalities associated with secondary epileptogenesis imply that the excitability of regions connected with EZ may be enhanced, leading to frequent transitions from normal to epileptic states. From the perspective of network dynamics, EZ plays a dynamical pacemaker role in the evolution of epileptogenic networks as well as the activities generated by these networks. It may provide novel insights into the mechanism of epileptogenesis and inspire new therapeutic strategies.

Dynamical Behavior of Oscillators Models with Sine Nonlinearity

This work is devoted to the dynamic behavior of two models of nonlinear oscillators with sine nonlinearity. In this work the potential energy is considered as the derivative of the sine function and given by (1/e*d)*((sin^n(x))*((sin^n(x))+e)*((sin^n(x))+d)). A study of these oscillators in their self-sustaining and forced state is made, and we observe an important frequency variation. To explain this frequency variation, with the help of mathematical developments, the limit to which sin(x) can approach was considered. This allowed us to obtain the nonlinear algebraic equations and the frequency ranks for which the models are trained in frequencies. The models present a very rich dynamic characterized by the presence of periodical regions of stability and instability. Contrary to the classic case, the sinus function brings large chaotic zones. We also observe that these models can play with some approximations the role of artificial pacemaker. Experimental realization being difficult with the presence of the analog sines, an experimental simulation by ATmega328P microcontroller was carried out. There is good agreement between digital simulation and microcontroller.

An investigation into the nonlinear coupling between CA1 layers and the dentate gyrus.

Although the activity from the dentate gyrus is known to have strong connections with other hippocampal layers, the functionality of these connections, that is, the degree to which it drives activity in the downstream regions of the hippocampus, is not well understood. This question is particularly relevant for mesoscale localfield potential (LFP) rhythms such as gamma oscillations. Following the hypothesis that fundamental features of the LFP are consistent with turbulent dynamics, we investigate the crosslayer relationship between the CA1 layers and the dentate gyrus as a function of running speed. In agreement with previous studies, same-layer spectral and bispectral analyses show that increasing input (rat speed) results in an increase of power and nonlinearity (phase coupling) between theta and gamma. The effectiveness of the connection between the 2 regions is investigated using cross-bicoherence analysis. Based on the turbulence interpretation of the evolution of spectra and bispectra as a function of the power input rate, we propose a measure for estimating the strength of the cross-frequency, cross-layer nonlinear forcing, that compares the magnitude of bicoherence (same-layer) and cross-bicoherence (cross-layer). Our results suggest that at moderate speeds gamma in CA1 is mainly driven by local theta, while the coupling of the CA1 gamma to the dentate-gyrus gamma becomes significant. Overall, these data are consistent with the hypothesis of theta-to-gamma energy cascade model for the organization of hippocampal LFP, with theta playing the role of a global pacemaker across the entire hippocampus while gamma is a local oscillation generated by through local anatomical connections. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The Intrinsic Cardiac Nervous System and Its Role in Cardiac Pacemaking and Conduction.

The cardiac autonomic nervous system (CANS) plays a key role for the regulation of cardiac activity with its dysregulation being involved in various heart diseases, such as cardiac arrhythmias. The CANS comprises the extrinsic and intrinsic innervation of the heart. The intrinsic cardiac nervous system (ICNS) includes the network of the intracardiac ganglia and interconnecting neurons. The cardiac ganglia contribute to the tight modulation of cardiac electrophysiology, working as a local hub integrating the inputs of the extrinsic innervation and the ICNS. A better understanding of the role of the ICNS for the modulation of the cardiac conduction system will be crucial for targeted therapies of various arrhythmias. We describe the embryonic development, anatomy, and physiology of the ICNS. By correlating the topography of the intracardiac neurons with what is known regarding their biophysical and neurochemical properties, we outline their physiological role in the control of pacemaker activity of the sinoatrial and atrioventricular nodes. We conclude by highlighting cardiac disorders with a putative involvement of the ICNS and outline open questions that need to be addressed in order to better understand the physiology and pathophysiology of the ICNS.

Modeling Reveals Human-Rodent Differences in H-Current Kinetics Influencing Resonance in Cortical Layer 5 Neurons.

While our understanding of human neurons is often inferred from rodent data, inter-species differences between neurons can be captured by building cellular models specifically from human data. This includes understanding differences at the level of ion channels and their implications for human brain function. Thus, we here present a full spiking, biophysically detailed multi-compartment model of a human layer 5 (L5) cortical pyramidal cell. Model development was primarily based on morphological and electrophysiological data from the same human L5 neuron, avoiding confounds of experimental variability. Focus was placed on describing the behavior of the hyperpolarization-activated cation (h-) channel, given increasing interest in this channel due to its role in pacemaking and differentiating cell types. We ensured that the model exhibited post-inhibitory rebound spiking considering its relationship with the h-current, along with other general spiking characteristics. The model was validated against data not used in its development, which highlighted distinctly slower kinetics of the human h-current relative to the rodent setting. We linked the lack of subthreshold resonance observed in human L5 neurons to these human-specific h-current kinetics. This work shows that it is possible and necessary to build human-specific biophysical neuron models in order to understand human brain dynamics.