Persistent Current Research Articles

Probe for bound states of SU(3) fermions and colour deconfinement

Fermionic artificial matter realized with cold atoms grants access to an unprecedented degree of control on sophisticated many-body effects with an enhanced flexibility of the operating conditions. Here, we consider three-component fermions with attractive interactions to study the formation of complex bound states, whose nature goes beyond the standard fermion pairing occurring in quantum materials. Such systems display clear analogies with quark matter. We address the nature of the bound states of a three-component fermionic system in a ring-shaped trap through the persistent current. In this way, we demonstrate that we can distinguish between color superfluid and trionic bound states. By analyzing finite temperature effects, we show how finite temperature can lead to the deconfinement of bound states. For weak interactions, the deconfinement occurs because of scattering states. In this regime, the deconfinement depends on the trade-off between interactions and thermal fluctuations. For strong interactions the features of the persistent current result from the properties of a suitable gas of bound states.

Development of electrophysiological properties of fusiform neurons from the dorsal cochlear nucleus of mice before and after hearing onset.

The dorsal cochlear nucleus (DCN) in the auditory brainstem integrates auditory and somatosensory information. Mature DCN fusiform neurons fall into two qualitatively distinct types: quiet, with no spontaneous regular action potential firing, or active, with regular spontaneous action potential firing. However, how these firing states and other electrophysiological properties of fusiform neurons develop during early postnatal days to adulthood is not known. Thus, we recorded fusiform neurons from mice from P4 to P21 and analyzed their electrophysiological properties. In the prehearing phase (P4-P13), we found that most fusiform neurons are quiet, with active neurons emerging after hearing onset at P14. Subthreshold properties underwent significant changes before hearing onset, whereas changes to the action potential waveform occurred mainly after P14, with the depolarization and repolarization phases becoming markedly faster and half-width significantly decreased. The activity threshold in posthearing neurons was more negative than in prehearing cells. Persistent sodium current (INaP) was increased after P14, coinciding with the emergence of spontaneous firing. Thus, we suggest that posthearing expression of INaP leads to hyperpolarization of the activity threshold and the active state of the fusiform neuron. At the same time, other changes refine the passive membrane properties and increase the speed of action potential firing of fusiform neurons.NEW & NOTEWORTHY Auditory brainstem neurons express unique electrophysiological properties adapted for their complex physiological functions that develop before hearing onset. Fusiform neurons of the DCN present two firing states, quiet and active, but the origin of these states is not known. Here, we showed that the quiet and active states develop after hearing onset at P14, along with changes in action potentials, suggesting an influence of auditory input on the refining of fusiform neuron's excitability.

Upwelling processes driven by contributions from wind and current in the Southwest East Sea (Japan Sea)

The occurrence of coastal upwelling is influenced by the intensity and duration of sea surface wind stress and geophysical components such as vertical stratification, bottom topography, and the entrainment of water masses. In addition, strong alongshore currents can drive upwelling. Accordingly, this study analyzes how wind stress and ocean currents contribute to changing coastal upwelling along the southwest coast of the East Sea (Japan Sea), which has not yet been reported quantitatively. This study aims to estimate each geophysical factor affecting upwelling processes using the Upwelling Age index. The index assesses the major contributors to the upwelling process using the relationship between physical forcing and upwelling water fraction estimated from shipboard hydrographic data from January 1993 to October 2018. These findings reveal that wind-driven upwelling was dominant off the northern coast. In contrast, current-driven upwelling prevailed off the southern coast. These results suggest that persistent alongshore currents through the Korea Strait make the southern region a prolific upwelling area. Accordingly, it can shed light on the mechanisms of coastal upwelling in the study area, which is crucial for understanding the influence of physical forces on ocean ecosystems.

Persistent currents, revival time and effects of rotation on an attractive inverse-square-type potential in a magnetic quadrupole moment system

We study the appearance of an Aharonov–Bohm-type effect around a cylindrical cavity in a magnetic quadrupole moment system in a rotating reference frame. The analogue of the Aharonov–Bohm-type effect of bound states arises from the interaction of the magnetic quadrupole moment of a neutral particle with an induced electric field when the neutral particle is subject to an attractive inverse-square-type potential, which in turn stems from the interaction of the magnetic quadrupole moment of a neutral particle with a magnetic field. We also discuss how the effects of rotation modify the degeneracy of the energy levels in contrast to the case of absence of rotation. Besides this, we calculate the revival time and the persistent currents.

Interaction of the mechanosensitive microswimmer Paramecium with obstacles.

In this work, we report investigations of the swimming behaviour of Paramecium tetraurelia, a unicellular microorganism, in micro-engineered pools that are decorated with thousands of cylindrical pillars. Two types of contact interactions are measured, either passive scattering of Paramecium along the obstacle or avoiding reactions (ARs), characterized by an initial backward swimming upon contact, followed by a reorientation before resuming forward motion. We find that ARs are only mechanically triggered approximately 10% of the time. In addition, we observe that only a third of all ARs triggered by contact are instantaneous while two-thirds are delayed by approximately 150 ms. These measurements are consistent with a simple electrophysiological model of mechanotransduction composed of a strong transient current followed by a persistent one upon prolonged contact. This is in apparent contrast with previous electrophysiological measurements where immobilized cells were stimulated with thin probes, which showed instantaneous behavioural responses and no persistent current. Our findings highlight the importance of ecologically relevant approaches to unravel the motility of mechanosensitive microorganisms in complex environments.

Estimates of persistent inward currents in lower limb motoneurons are larger in females than in males.

Noninvasive recordings of motor unit (MU) spike trains help us understand how the nervous system controls movement and how it adapts to various physiological conditions. The majority of participants in human and nonhuman animal physiology studies are male, and it is assumed that mechanisms uncovered in these studies are shared between males and females. However, sex differences in neurological impairment and physical performance warrant the study of sex as a biological variable in human physiology and performance. To begin addressing this gap in the study of biophysical properties of human motoneurons, we quantified MU discharge rates and estimates of persistent inward current (PIC) magnitude in both sexes. We decomposed MU spike trains from the tibialis anterior (TA), medial gastrocnemius (MG), and soleus (SOL) using high-density surface electromyography and blind source separation algorithms. Ten participants of each sex performed slow triangular (10 s up and down) isometric contractions to a peak of 30% of their maximum voluntary contraction. We then used linear mixed-effects models to determine if peak discharge rate and estimates of PICs were predicted by the fixed effects of sex, muscle, and their interaction. Despite a lack of sex-differences in peak discharge rates across all muscles, estimates of PICs were larger [χ2(1) = 6.26, P = 0.012] in females [4.73 ± 0.242 pulses per second (pps)] than in males (3.81 ± 0.240 pps). These findings suggest that neuromodulatory drive, inhibitory input, and/or biophysical properties of motoneurons differ between the sexes and may contribute to differences in MU discharge patterns.NEW & NOTEWORTHY Sex-related differences in motoneuron analyses have emerged with greater inclusion of female participants, however, mechanisms for these differences remain unclear. Estimates of persistent inward currents (i.e., ΔF) in motoneurons of the lower limb muscles were larger in females than in males. This suggests neuromodulatory drive, monoaminergic signaling, intrinsic motoneuron properties, and/or descending motor commands may differ between the sexes, which provides a potential mechanism underlying previously reported sex-related differences in motoneuron discharge patterns.

PRAX-628 is a Novel, Well-Tolerated, Activity Dependent Sodium Channel Blocker with Potent Anticonvulsant Activity (P4-9.012)

<h3>Objective:</h3> We sought to define the <i>in vivo</i> efficacy and tolerability profile of PRAX-628, a novel activity dependent sodium channel blocker. <h3>Background:</h3> Gain-of-function (GoF) pathogenic variants in voltage-gated sodium channel (Na_V) genes can increase persistent sodium current (I_Na) leading to neuronal hyperexcitability and severe developmental and epileptic encephalopathies (DEE). We show in Kahlig et al., (this meeting) that PRAX-628 inhibits I_Na with greater activity dependence compared to standard of care carbamazepine (CBZ) and lamotrigine (LTG). Here we further define its <i>in vivo</i> efficacy and tolerability profile in mice. <h3>Design/Methods:</h3> The anticonvulsant activity of PRAX-628 (0.3–10 mg/kg) was assessed using the maximal electroshock seizure (MES) assay in outbred CD-1 mice. Effects of PRAX-628 (3–20 mg/kg) on spontaneous locomotor activity (sLMA) were measured to assess tolerability. The protective index (PI) of PRAX-628 was determined as the ratio of plasma concentrations in sLMA (TC₅₀) to MES (EC₅₀). The effects of CBZ and LTG were also assessed using MES (3–30 mg/kg and 1–10 mg/kg, respectively) and sLMA (30–96 mg/kg and 20–63.4 mg/kg, respectively), and their corresponding PIs computed. The concentration of PRAX-628 in terminal plasma and brain samples was measured using mass spectrometry. <h3>Results:</h3> PRAX-628 (10 mg/kg) completely blocked evoked seizures (MES ED₅₀ 0.67 mg/kg, brain EC₅₀ 67.2 ng/g) without affecting sLMA (TD₅₀ 10.27 mg/kg, plasma TC₅₀ 1123 ng/g; PI 16.7). In contrast, CBZ and LTG had PIs of 5–6x; full anticonvulsant efficacy with CBZ or LTG was not achieved without reducing sLMA. <h3>Conclusions:</h3> PRAX-628 exhibited markedly improved preclinical tolerability compared to standard of care Na_V blockers, potentially due to its improved activity dependent inhibition of peak I_Na. The profile of PRAX-628 may translate into well-tolerated efficacy in epilepsy as well as other indications caused by neuronal hyperexcitability. <b>Disclosure:</b> Dr. Eckert has received personal compensation for serving as an employee of Praxis Precision Medicines. Dr. Eckert has received personal compensation for serving as an employee of Janssen Research &amp; Development, LLC. Dr. Eckert has received personal compensation for serving as an employee of Inspire Pharmaceuticals, Inc.. Dr. Eckert has stock in Praxis Precision Medicines. Dr. Eckert has stock in Janssen Research and Development. Dr. Eckert has received intellectual property interests from a discovery or technology relating to health care. Dr. Kahlig has received personal compensation for serving as an employee of Praxis Precisoin Medicines. Dr. Kahlig has stock in Praxis Precision Medicines. Dr. Anderson has received personal compensation for serving as an employee of Praxis Precision Medicines. Steven Petrou has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Praxis Precision Medicines. Steven Petrou has stock in Praxis Precision Medicines. The institution of Steven Petrou has received research support from Praxis Precision Medicines. The institution of Steven Petrou has received research support from Medical Research Future Fund. Steven Petrou has received intellectual property interests from a discovery or technology relating to health care. Steven Petrou has received intellectual property interests from a discovery or technology relating to health care.

PRAX-562 is a Well-Tolerated, Novel Persistent Sodium Channel Blocker with Broad Anticonvulsant Activity in Multiple DEE Mouse Models (S34.007)

PRAX-562 is a Well-Tolerated, Novel Persistent Sodium Channel Blocker with Broad Anticonvulsant Activity in Multiple DEE Mouse Models (S34.007)

Persistent currents and electronic properties of Mandelbrot quantum rings

In this study, we investigate the persistent current, and electronic energy levels of Mandelbrot quantum rings. For this purpose, three types of Mandelbrot quantum rings are proposed. Furthermore, Mandelbrot equation is generalized by introducing parameter m, which makes Mandelbrot’s shape more symmetric by adding new branches to it, on the other hand, the iteration parameter M, controls geometrical deficiencies. We explain the procedure needed to form these structures, including a padding scheme, then we solve the resulting two-dimensional Schrodinger equation using the central finite difference method with uniform distribution of the mesh points. Thereafter, we obtain the persistent current in different situations including different Mandelbrot orders and quantum ring shapes. We show that the persistent current can have different shapes and intensities by changing the described geometrical parameters of Mandelbrot quantum rings. We explain this phenomenon by considering symmetries in the potential, and consequently the wavefunction.

Astrocytes mediate cell non-autonomous correction of aberrant firing in human FXS neurons

Pre-clinical studies of fragile X syndrome (FXS) have focused on neurons, with the role of glia remaining largely underexplored. We examined the astrocytic regulation of aberrant firing of FXS neurons derived from human pluripotent stem cells. Human FXS cortical neurons, co-cultured with human FXS astrocytes, fired frequent short-duration spontaneous bursts of action potentials compared with less frequent, longer-duration bursts of control neurons co-cultured with control astrocytes. Intriguingly, bursts fired by FXS neurons co-cultured with control astrocytes are indistinguishable from control neurons. Conversely, control neurons exhibit aberrant firing in the presence of FXS astrocytes. Thus, the astrocyte genotype determines the neuronal firing phenotype. Strikingly, astrocytic-conditioned medium, and not the physical presence of astrocytes, is capable of determining the firing phenotype. The mechanistic basis of this effect indicates that the astroglial-derived protein, S100β, restores normal firing by reversing the suppression of a persistent sodium current in FXS neurons.

Spin current and internal Zeeman field in spin-orbit coupled rings

We investigate the one-dimensional quantum ring constructed by the spin-orbit coupled material, in which the quantum spin-Hall Bernevig-Zhang (BZ) Hamiltonian and Rashba-Dirac (RD) type spin-orbit coupling are taken into account (called RD-BZ Hamiltonian in this paper). It is known that the curvature of the ring generates an out-of-plane effective magnetic field, acting as an internal Zeeman field. We find that only the BZ coupling can change the strength of the internal Zeeman field, which enables us to detect the effect of the internal Zeeman field. Furthermore, we find that the total angular momentum is conserved in the RD-BZ Hamiltonian, and the energy eigenvalue and wave function must be modified to fit the conserved quantity, which are ignored in the previous studies. The conductance without leads is discussed. Different from the previous results, we find that the conductance behaves like a beat phenomenon resulting from the interplay between the magnetic flux and Aharonov-Casher (AC) phase, and thus, it can oscillate without passing through the insulating state in some regimes of magnetic flux or AC phase. Importantly, we find that the conductance with integer and half-integer magnetic flux provides us a method to measure the AC phase. The cancellation of the internal Zeeman field due to the BZ coupling can be detected by using specific fractional magnetic flux. In the ring with nonvanishing RD and BZ couplings, the conductance can exhibit a quasiplateau near the small RD coupling. The increase in the strength of BZ coupling would result in wider quasiplateau in conductance, which implies that the ring could remain insulating state (or conducting state) regardless of the small change in RD coupling. The thermal average of spin and charge currents are calculated at low temperatures without impurities. Importantly, we find that the persistent spin and charge currents as a function of the magnetic flux exhibit nodelike lines, which amazingly are perpendicular to each other. As a consequence, the persistent spin current could be nonzero even when the charge current vanishes at nonzero magnetic flux. The result suggests a pure spin current in quantum rings, and its direction can be reversed by changing the magnetic flux. The increase in the BZ coupling would exhibit the plateaulike pure spin current.

Can local vibration alter the contribution of persistent inward currents to human motoneuron firing?

The response of spinal motoneurons to synaptic input greatly depends on the activation of persistent inward currents (PICs), which in turn are enhanced by the neuromodulators serotonin and noradrenaline. Local vibration (LV) induces excitatory Ia input onto motoneurons and may alter neuromodulatory inputs. Therefore, we investigated whether LV influences the contribution of PICs to motoneuron firing. This was assessed in voluntary contractions with concurrent, ongoing LV, as well as after a bout of prolonged LV. High-density surface electromyograms (HD-EMG) of the tibialis anterior were recorded with a 64-electrode matrix. Twenty males performed isometric, triangular, dorsiflexion contractions to 20% and 50% of maximal torque at baseline, during LV of the tibialis anterior muscle, and after 30-min of LV. HD-EMG signals were decomposed, and motor units tracked across time points to estimate PICs through a paired motor unit analysis, which quantifies motor unit recruitment-derecruitment hysteresis (ΔF). During ongoing LV, ΔF was lower for both 20% and 50% ramps. Although significant changes in ΔF were not observed after prolonged LV, a differential effect across the motoneuron pool was observed. This study demonstrates that PICs can be non-pharmacologically modulated by LV. Given that LV leads to reflexive motor unit activation, it is postulated that lower PIC contribution to motoneuron firing during ongoing LV results from decreased neuromodulatory inputs associated with lower descending corticospinal drive. A differential effect in motoneurons of different recruitment thresholds after prolonged LV is provocative, challenging the interpretation of previous observations and motivating future investigations. KEY POINTS: Neuromodulatory inputs from the brainstem influence motoneuron intrinsic excitability through activation of persistent inward currents (PICs). PICs make motoneurons more responsive to excitatory input. We demonstrate that vibration applied on the muscle modulates the contribution of PICs to motoneuron firing, as observed through analysis of the firing of single motor units. The effects of PICs on motoneuron firing were lower when vibration was concurrently applied during voluntary ramp contractions, likely due to lower levels of neuromodulation. Additionally, prolonged exposure to vibration led to differential effects of lower- vs. higher-threshold motor units on PICs, with lower-threshold motor units tending to present an increased and higher-threshold motor units a decreased contribution of PICs to motoneuron firing. These results demonstrate that muscle vibration has the potential to influence the effects of neuromodulation on motoneuron firing. The potential of using vibration as a non-pharmacological neuromodulatory intervention should be further investigated.

Steady state oscillations of circular currents in concentric polariton condensates

Concentric ring exciton polariton condensates emerging under non-resonant laser pump in an annular trapping potential support persistent circular currents of polaritons. The trapping potential is formed by a cylindrical micropillar etched in a semiconductor microcavity with embedded quantum wells and a repulsive cloud of optically excited excitons under the pump spot. The symmetry of the potential is subject to external control via manipulation by its pump-induced component. In the manuscript, we demonstrate excitation of concentric ring polariton current states with predetermined vorticity which we trace using interferometry measurements with a spherical reference wave. We also observe the polariton condensate dynamically changing its vorticity during observation, which results in pairs of fork-like dislocations on the time-averaged interferogram coexisting with azimuthally homogeneous photoluminescence distribution in the micropillar.

The fascinating phenotypic spectrum of SCN1A gain-of-function epilepsies.

The fascinating phenotypic spectrum of SCN1A gain-of-function epilepsies.

Interplay between hopping dimerization and quasi-periodicity on flux-driven circular current in an incommensurate Su–Schrieffer–Heeger ring

We report for the first time the phenomenon of flux-driven circular current in an isolated Su–Schrieffer–Heeger (SSH) quantum ring in presence of cosine modulation in the form of the Aubry–André–Harper (AAH) model. The quantum ring is described within a tight-binding framework, where the effect of magnetic flux is incorporated through Peierls substitution. Depending on the arrangements of AAH site potentials we have two different kinds of ring systems that are referred to as staggered and non-staggered AAH SSH rings. The interplay between the hopping dimerization and quasiperiodic modulation leads to several new features in the energy band spectrum and persistent current which we investigate critically. An atypical enhancement of current with increasing AAH modulation strength is obtained that gives a clear signature of transition from a low conducting phase to a high conducting one. The specific roles of AAH phase, magnetic flux, electron filling, intra- and inter-cell hopping integrals, and ring size are discussed thoroughly. We also study the effect of random disorder on persistent current with hopping dimerization to compare the results with the uncorrelated ones. Our analysis can be extended further in studying magnetic responses of similar kinds of other hybrid systems in presence of magnetic flux.

Thermodynamic Properties and Persistent Currents of Harmonic Oscillator Under AB-Flux Field in a Point-Like Defect with Inverse Square Potential

In this analysis, we study the eigenvalue solution of the non-relativistic particles confined by the Aharonov-Bohm (AB) flux field in the presence of potential the superposition of a harmonic oscillator plus inverse square potential with constant term in the background of a point-like global monopole. Afterwards, we study the thermodynamic properties of the quantum system at finite temperatures $$T\ne 0$$ and calculate the vibrational free energy, mean energy, specific heat capacity, and the entropy by using the partition function $$Z(\beta )$$ . These quantities are then analyzed and show the influences of the topological defect with flux field and potential. We also see that the energy eigenvalue depends on the geometric quantum phase, and thus an electromagnetic analogue of the Aharonov-Bohm effect is observed. This dependence of the eigenvalue gives rise to a persistent current and we analyze the effects of the topological defect with potential on it.

Do long-lasting effects of epidural polarization of afferent fibres depend on persistent sodium current?

Few attempts have so far been made to define the mechanisms underlying the hour-long effects of trans-spinal stimulation combined with epidural polarization. In the present study, we investigated the potential involvement of non-inactivating sodium channels in afferent fibres. To this end, riluzole, a blocker of these channels, was administered locally to the dorsal columns close to the site of the excitation of afferent nerve fibres by epidural stimulation in deeply anaesthetized rats in vivo. Riluzole did not prevent the induction of the polarization-evoked sustained increase in the excitability of dorsal column fibres but tended to weaken it. It likewise weakened but did not abolish the sustained polarization-evoked shortening of the refractory period of these fibres. These results lead to the conclusion that the persistent sodium current may contribute to the sustained post-polarization-evoked effects but is only partly involved in both the induction and the expression of these effects.

Blockade of 5-HT2 receptors suppresses motor unit firing and estimates of persistent inward currents during voluntary muscle contraction in humans.

Serotonergic neuromodulation contributes to enhanced voluntary muscle activation. However, it is not known how the likely motoneurone receptor candidate (5-HT2 ) influences the firing rate and activation threshold of motor units (MUs) in humans. The purpose of this study was to determine whether 5-HT2 receptor activity contributes to human MU behaviour during voluntary ramped contractions of differing intensity. High-density surface EMG (HDsEMG) of the tibialis anterior was assessed during ramped isometric dorsiflexions at 10, 30, 50 and 70% of maximal voluntary contraction (MVC). MU characteristics were successfullyextracted from HDsEMG of 11 young adults (four female) pre- and post-ingestion of 8mg cyproheptadine or a placebo. Antagonism of 5-HT2 receptorscaused a reduction in MU discharge rate during steady-state muscle activation that was independent of the level of contraction intensity [P<0.001; estimated mean difference (∆)=1.06pulses/s], in addition to an increase in MU derecruitment threshold (P<0.013, ∆=1.23% MVC), without a change in force during MVC (P=0.652). A reduction in estimates of persistent inward current amplitude was observed at 10% MVC (P<0.001, ∆=0.99 Hz) and 30% MVC (P=0.003, ∆=0.75 Hz) that aligned with 5-HT changes in MU firing behaviour attributable to 5-HT2 antagonism. Overall, these findings indicate that 5-HT2 receptor activity has a role in regulating the discharge rate in populations of spinal motoneurones when performing voluntary contractions. This study provides evidence of a direct link between MU discharge properties, persistent inward current activity and 5-HT2 receptor activity in humans. KEY POINTS: Activation of 5-HT receptors on the soma and dendrites of motoneurones regulates their excitability. Previous work using chlorpromazine and cyproheptadine has demonstrated that the 5-HT2 receptor regulates motoneurone activity in humans with chronic spinal cord injury and non-injured control subjects. It is not known how the 5-HT2 receptor directly influences motor unit (MU) discharge and MU recruitment in larger populations of human motoneurones during voluntary contractions of differing intensity. Despite the absence of change in force during maximal voluntary dorsiflexions, 5-HT2 receptor antagonism caused a reduction in MU discharge rate during submaximal steady-state muscle contraction, in addition to an increase in MU derecruitment threshold, irrespective of the submaximal contraction intensity. Reductions in estimates of persistent inward currents after 5-HT2 receptor antagonism support the viewpoint that the 5-HT2 receptor plays a crucial role in regulating motor activity, whereby a persistent inward current-based mechanism is involved in regulating the excitability of human motoneurones.

A terminal Messinian flooding of the Mediterranean evidenced by contouritic deposits on Sicily

ABSTRACTThe evolution of marine gateways and sea straits exerts major control on bottom current depositional systems. A well‐known interval in geological history characterized by frequent changes in marine connectivity is the Messinian Salinity Crisis (5.97 to 5.33 Ma) when the Mediterranean allegedly experienced major (&gt;1 km) sea‐level drawdown followed by a catastrophic marine replenishment at the base of the Zanclean. Controversy exists around the timing and mode of this event as unambiguous flood deposits have so far never been drilled or recognized in outcrops. In the Sicilian Caltanissetta Basin (Italy), the Messinian/Zanclean boundary is directly underlain by the Arenazzolo Formation. This 5 to 7 m thick sandy sedimentary interval may reveal a genetic link with the abrupt refilling of the Mediterranean, but at present a detailed study to understand its origin is lacking. In this work, the Arenazzolo Formation at Eraclea Minoa has been studied by a multi‐method approach, employing detailed facies description, grain‐size analyses, petrographic analyses and palaeocurrent analyses. Palaeogeographical reconstructions and facies associations show that the Arenazzolo Formation sands were deposited on the northern flank of the Gela thrust front by persistent bottom currents, flowing parallel to the regional slope physiography, during a transgression. It is hypothesized that these currents are associated with the active circulation of surface and intermediate water masses coeval with a terminal Messinian flood, when basin margins overtopped and a reconnection between western and eastern Mediterranean was created. The Arenazzolo Formation is a unique example of a contouritic deposit formed by bottom currents that establish during the reconnection of major isolated water bodies.

Cenobamate in Generalized Epilepsy and Combined Generalized and Focal Epilepsy.

Cenobamate (CNB) is a United States Food and Drug Administration-approved antiseizure medication (ASM) for focal-onset seizures; however, its potential clinical effectiveness as a broad-spectrum ASM is not established. CNB has a proposed dual mechanism of action with preferential blockade of persistent sodium currents and positive allosteric modulation of the γ-aminobutyric acid-A (GABA-A) receptor. We evaluated the efficacy of CNB in drug refractory patients with genetic generalized epilepsies (GGE) or combined generalized and focal epilepsies (CGFE), including developmental and epileptic encephalopathies. We performed a retrospective review and identified the following: cohort 1 (n = 4) with GGE, of which 2 patients had idiopathic generalized epilepsy, and cohort 2 with CGFE (n = 9), of which 4 patients had Lennox-Gastaut syndrome and 1 had Dravet syndrome. In cohort 1, all 3 patients with frequent generalized tonic-clonic seizures (GTCs) had a greater than 50% reduction in GTCs. In cohort 2, reduction in both generalized and focal-onset seizures was noted. In these groups together, the mean reduction of all seizure types was 58%, and ≥50% responder rate was 70% (SD = ±34.16, median = 50%). No worsening of generalized-onset seizures occurred in either cohort. Seventy-seven percent of patients experienced side effects, warranting a modification of treatment managed by slower titration, dose reduction of CNB, or discontinuing other ASMs. In our retrospective case series, CNB seems to be an effective ASM for patients with drug-resistant GGE and CGFE. The ongoing CNB trial assessing effectiveness for primary GTCs will provide more data on generalized-onset seizures. This study provides Class IV evidence that CNB in generalized epilepsy and combined generalized and focal epilepsy reduces seizure frequency.