Possible mechanism of schizophrenia origin by excess GABA and synaptic pruning.

Schizophrenia is a psychotic disorder that affects approximately 1% of the global population. However, the etiology of this illness remains a subject of debate. One of the proposed mechanisms underlying schizophrenia is the synaptic pruning mediated by microglia in the brains of individuals with schizophrenia, although the precise mechanisms of this process remain elusive. In this regard, we propose that the potential development of the disease stems from both a genetic predisposition leading to an excessive production of GABAergic neurons and an exaggerated effort to maintain the E/I (excitation/inhibition) balance in the brain.

A possible new cardiac heterogeneity as an arrhythmogenic driver.

Atrial fibrillation (AF) is the commonest cardiac arrhythmia, affecting 3 million people in the USA and 8 million in the EU (according to the European Society of Cardiology). So, why is it that even with the best medical care, around a third of the patients are treatment resistant. Extensive research of its etiology showed that AF and its mechanisms are still debatable. Some of the AF origins are ascribed to functional and ionic heterogeneities of the heart tissue and possibly to additional triggering agents. But, have all AF origins been detected? Are all accepted origins, in fact, arrhythmogenic? In order to study these questions and specifically to check our new idea of intermittency as an arrhythmogenesis agent, we chose to employ a mathematical model which was as simple as possible, but which could still be used to observe the basic network processes of AF development. At this point we were not interested in the detailed ionic propagations nor in the actual shapes of the induced action potentials (APs) during the AF outbreaks. The model was checked by its ability to exactly recapture the basic AF developmental stages known from experimental cardiac observations and from more elaborate mathematical models. We use a simple cellular automata 2D mathematical model of N × N matrices to elucidate the field processes leading to AF in a tissue riddled with randomly distributed heterogeneities of different types, under sinus node operation, simulated by an initial line of briefly stimulated cells inducing a propagating wave, and with or without an additional active ectopic action potential pulse, in turn simulated by a transitory operation of a specific cell. Arrhythmogenic contributions, of three different types of local heterogeneities in myocytes and their collaborations, in inducing AF are examined. These are: a heterogeneity created by diffuse fibrosis, a heterogeneity created by myocytes having different refractory periods, and a new heterogeneity type, created by intermittent operation of some myocytes. The developmental stages (target waves and spirals) and the different probabilities of AF occurring under each condition, are shown. This model was established as being capable of reproducing the known AF origins and their basic development stages, and in addition has shown: (1) That diffuse fibrosis on its own is not arrhythmogenic but in combination with other arrhythmogenic agents it can either enhance or limit AF. (2) In general, combinations of heterogeneities can act synergistically, and, most importantly, (3) The new type of intermittency heterogeneity proves to be extremely arrhythmogenic. Both the intermittency risk and the fibrosis role in AF generation were established. Knowledge of the character of these arrhythmogenesis agents can be of real importance in AF treatment.

Sudden cardiac death prevention in the era of novel heart failure medications.

Sudden cardiac death (SCD) occurs unexpectedly and is usually a result of ventricular arrhythmia in patients with structural heart disease. The implantable cardioverter-defibrillator (ICD), with or without biventricular pacing, has been proven to be protective for heart failure patients with reduced ejection fraction of <35 % (HFrEF). This device therapy prevents SCD, with additional optimal medications, namely angiotensin-converting enzyme-inhibitors, angiotensin-II receptor-blockers, beta-blockers and mineralocorticoid receptor-antagonists. HFrEF patients present the majority of SCD incidents, as they are characterized by cardiac fibrosis, the main arrhythmogenic element. The introduction of angiotensin-receptor-neprilysin inhibitors, sodium-glucose co-transporter-2 inhibitors and guanylate-cyclase stimulators was associated with reduction of SCD. Additionally, clinical trials have evaluated the improved outcome of these new medications on left ventricular ejection fraction, arrhythmias and HFrEF. These beneficial effects could possibly lead to important changes in decision-making on ICD implantation for primary prevention in patients with HFrEF and reduce the need for device therapy. In this review, we highlight the pathophysiological mechanisms of the new drug agents, and evaluate the possible effect they could have on the role of device therapy as a primary prevention of SCD.

Percolation and tortuosity in heart-like cells.

In the last several years, quite a few papers on the joint question of transport, tortuosity and percolation have appeared in the literature, dealing with passage of miscellaneous liquids or electrical currents in different media. However, these methods have not been applied to the passage of action potential in heart fibrosis (HF), which is crucial for problems of heart arrhythmia, especially of atrial tachycardia and fibrillation. In this work we address the HF problem from these aspects. A cellular automaton model is used to analyze percolation and transport of a distributed-fibrosis inflicted heart-like tissue. Although based on a rather simple mathematical model, it leads to several important outcomes: (1) It is shown that, for a single wave front (as the one emanated by the heart's sinus node), the percolation of heart-like matrices is exactly similar to the forest fire case. (2) It is shown that, on the average, the shape of the transport (a question not dealt with in relation to forest fire, and deals with the delay of action potential when passing a fibrotic tissue) behaves like a Gaussian. (3) Moreover, it is shown that close to the percolation threshold the parameters of this Gaussian behave in a critical way. From the physical point of view, these three results are an important contribution to the general percolation investigation. The relevance of our results to cardiological issues, specifically to the question of reentry initiation, are discussed and it is shown that: (A) Without an ectopic source and under a mere sinus node operation, no arrhythmia is generated, and (B) A sufficiently high refractory period could prevent some reentry mechanisms, even in partially fibrotic heart tissue.

Origin of post-ictal and post-anesthesia adverse effects and possibly of SUDEP.

The origin of post-ictal malfunctions is debatable. We want to propose a novel idea of a cause of these adverse results occurring following epileptic seizures and anesthesia. Previously we have put forward the idea that epileptic seizures termination is caused by the function of the glymphatic system in the brain. A new measurement shows that this system can be much faster than what was estimated before. Moreover, the method enabling this speeding was actually measured in brains of epilepsy subjects. So, the main objection to our model is relegated. As a possible consequence of the glymphatic process, there can be an excess cleaning of the brain's interstitial fluid. We discuss possible adverse results of this process. This over-cleaning (that can, to a lower extent, occur also during anesthesia) which results post-ictally from the previous overexpression of fluid materials by the neurons during their seizure operation, can reduce ingredients essential for regular neuronal functioning, thereby leading to function reduction and EEG suppression which last until those materials are replenished. We argue that this ingredients' scarcity is the cause of post-ictal generalized EEG suppression (PGES), of post-ictal immobility (PI) and possibly of Sudden Unexpected Death in Epilepsy Patients (SUDEP). Similarly, such cleaning can lead to morbidity and even mortality problems following anesthesia. If our assumption is correct, this understanding of the process of the problems' origin can lead to a method to remedy them by judicial supplement of the lost materials.

Explaining recent postictal epilepsy EEG results by the G-lymphatic clearance hypothesis.

Two recent postictal EEG measurements demonstrate somewhat conflicting results of epileptic behavior clearance in different brain parts. Both measurements observed two modes of seizure cessation, an abrupt and a gradual one, with slightly different statistics. No explanations were given for the appearance of these modes. Both measurements differ also in assessing the postictal brain activity or lack thereof, specifically the gamma activity. Using our G-Lymphatic clearance hypothesis, these results can be explained theoretically. The presence of two modes can be related to the order of ISF-CSF cleaning of brain parts. The reduced activity can be ascribed to neuronal ingredients deficiency brought about by the seizure related excess brain activity and by an over cleaning by the G-Lymphatic system.

Reentry as an Origin for Rotors.

The aim of the study is to understand in depth the meaning of "reentry", and to decipher if and how it can lead to malfunctions of the heart and possibly of the brain. A simple model is used to reveal the mechanism by which a single pulse of action potential rotating around a ring of excitable medium, the latter simulating a reentry circuit, can generate spirals (single and/or double) when the pulse can emerge from and develop outside the ring. Two mechanisms of spiral generation are demonstrated: (1) a mechanism in which a source of single spirals is created at the contact with the core soon after the pulse freeing action, their chirality being due to the sense of the preceding pulse rotation. Interestingly, these spirals, adhering to the core, become "double-spiral patterns" while leaving behind the seeds of the new single spirals. (2) A second possible mechanism, similar to the known "arms encountering methods", in which a double spiral (a figure of eight) is repeatedly created on the other side of the core. Similar procedures are assumed to occur in the heart, leading to tachycardia and fibrillation and possibly in the brain leading to epilepsy. The exact processes of the hitherto assumed spiral generations by reentry were established. The novel deep understanding of the mechanisms involved in these processes can lead to new methods of treating heart fibrillation (e.g., by judicial ablation).

Singular Value Decomposition of Optically-Mapped Cardiac Rotors and Fibrillatory Activity.

Our progress of understanding how cellular and structural factors contribute to the arrhythmia is hampered in part because of controversies whether a fibrillating heart is driven by a single, several, or multiple number of sources, and whether they are focal or reentrant, and how to localize them. Here we demonstrate how a novel usage of the neutral singular value decomposition (SVD) method enables the extraction of the governing spatial and temporal modes of excitation from a rotor and fibrillatory waves. Those modes highlight patterns and regions of organization in the midst of the otherwise seemingly-randomly propagating excitation waves. We apply the method to experimental models of cardiac fibrillation in rabbit hearts. We show that the SVD analysis is able to enhance the classification of the heart electrical patterns into regions harboring drivers in the form of fast reentrant activity and other regions of by-standing activity. This enhancement is accomplished without any prior assumptions regarding the spatial, temporal or spectral properties of those drivers. The analysis corroborates that the dominant mode has the highest activation rate and further reveals a new feature: A transfer of modes from the driving to the passive regions resulting in a partial reaction of the passive region to the driving region.

The Baroreflex Mechanism Revisited.

We state that the autonomic part of the brain controls the blood pressure (BP) and the heart rate (HR) via the baroreflex mechanism in all situations of human activity (at sleep, at rest, during exercise, fright etc.), in a way which is not, as was hitherto assumed, a mere homeostatic tool or even a resetting device, designed to bring these variables on the road to preset values. The baroreflex is rather a continuous feedback mechanism commanded by the autonomic part of the brain, leading to values appropriate to the situation at hand. Feasibility of this assertion is demonstrated here by using the Seidel-Herzel feedback system outside of its regular practice. Results show indeed that the brain can, and we claim that it does, control the HR and BP throughout life. New responses are demonstrated, e.g., to a sudden fear or apnea. In this event, large BP and HR overshoots are expected before the variables can relax to a new level. Response to abrupt downward change in the controlling parameter shows an undershoot in HR and just a gradual resetting in the BP. The relaxation from sudden external changes to various expected states are calculated and discussed and properties of the Rheos test are explained. Experimental findings for orthostatic tests and for babies under translations and rotations reveal complete qualitative agreement with our model and show no need to invoke the operation of additional body systems. Our method should be the preferred one by the Occam Razor approach. The outcomes may lead to beneficial clinical implication.

Time-periodic lattice of spiral pairs in excitable media.

The feasibility of a spiral-type solution, periodic both in time and in space, of a reaction-diffusion equation (specifically the FitzHugh-Nagumo system) in an excitable medium is numerically demonstrated. The solution consists of arrays of interacting spiral pairs, which repeatedly create by partial annihilation a system of residual portions (RPs). The latter behaves as a source to the next generation of the spiral-pair array. If basic (highest) translational symmetry is not conserved, pointwise perturbations, above a certain threshold, are shown to be able to destroy the pattern after a certain transient time by changing its symmetry. If the basic translational symmetry is preserved, such perturbations do not cause destruction unless occurring at the nearest vicinity of the RP site. Singular value decomposition methods are used to analyze the structure of the pattern, revealing the importance of the spiral pairs and the RPs.

Theory of the mechanical response of focal adhesions to shear flow.

The response of cells to shear flow is primarily determined by the asymmetry of the external forces and moments that are sensed by each member of a focal adhesion pair connected by a contractile stress fiber. In the theory presented here, we suggest a physical model in which each member of such a pair of focal adhesions is treated as an elastic body subject to both a myosin-activated contractile force and the shear stress induced by the external flow. The elastic response of a focal adhesion complex is much faster than the active cellular processes that determine the size of the associated focal adhesions and the direction of the complex relative to the imposed flow. Therefore, the complex attains its mechanical equilibrium configuration which may change because of the cellular activity. Our theory is based on the experimental observation that focal adhesions modulate their cross-sectional area in order to attain an optimal shear. Using this assumption, our elastic model shows that such a complex can passively change its orientation to align parallel to the direction of the flow.

The cellular response to curvature-induced stress.

We present a theoretical model to explain recent observations of the orientational response of cells to unidirectional curvature. Experiments show that some cell types when plated on a rigid cylindrical surface tend to reorient their shape and stress fibers along the axis of the cylinder, while others align their stress fibers perpendicular to that axis. Our model focuses on the competition of the shear stress--that results from cell adhesion and active contractility--and the anisotropic bending stiffness of the stress fibers. We predict the cell orientation angle that results from the balance of these two forces in a mechanical equilibrium. The conditions under which the different experimental observations can be obtained are discussed in terms of the theory.

Dynamics of a spiral pair source and its interaction with plane waves.

Spiral pair creation and dynamics is a widely occurring phenomenon in nature. It can appear in the heart tissue, causing severe arrhythmia, known as a figure-eight reentry. We consider the appearance of a spiral pair source, its minimal strength for survival, and the possible results of its interaction with a plane wave. In particular, its ability to outlast such an encounter is of interest. We also consider the question of exposing the source to a train of pulses, in terms of the frequency and angle of encounter. Results show different regimes of behavior, e.g. source annihilation, motion of the source away from, or towards the origin of the plane waves, its breaking and multiplication. Relevance of these results to heart arrhythmia and their possible cancellation by external pacing are briefly discussed.

Dynamics of spiral pairs induced by unidirectional propagating pulses.

The dynamics of unidirectionally propagating pulses in a two-dimensional uniform excitable reaction-diffusion medium is investigated. It is shown that under weak diffusion coupling between medium points such a pulse can evolve into a pair of counter-rotating spirals (spiral pair). We analyze the drift of such a pair and examine the collisions between several drifting pairs. It is demonstrated that collisions can result in a special type of reflection or, alternatively, in new types of complex stationary spiral structures. A possible application of these findings for the diagnosis of cardiac arrhythmias is suggested.