Spike Amplitude Research Articles

Value of Quantitative Intraoperative Electrocorticography During Anterior Temporal Lobectomy in Temporal Lobe Epilepsy Patients

Introduction: There is debate on the predictive usefulness of electrocorticography (ECoG) during anterior temporal lobectomy (ATL) in temporal lobe epilepsy (TLE) patients. The purpose of this study was to determine the usefulness of quantitative intraoperative ECoG monitoring for postoperative seizure outcomes after ATL in TLE patients. Methods: The study enrolled thirteen TLE patients who underwent ECoG-assisted ATL. Pre- and post-resection ECoG spike frequency (/min) and spike amplitude (μv/mm) were analyzed with histopathological and preoperative video-electroencephalography (EEG) data. After one year of follow-up, patients were classified as seizure-free (Engel Class I) or with residual seizure outcomes using the Engel Seizure Outcome Classification Scheme. Results: The pre-resection and post-resection ECoG showed significant differences in spike frequency (/min) and amplitude (μv/mm) (P-value < 0.001). Patients with residual seizures (15.4%) showed significantly greater pre- and post-resection ECoG spike frequency and amplitude, as well as significantly higher seizure frequency before surgery, compared to patients with postoperative seizure freedom (84.6%). The pre-resection ECoG spike frequency was significantly greater in TLE patients with histopathology focal cortical dysplasia (FCD) than in those with non-FCD. The post-resection ECoG revealed a sensitivity of 100%, a specificity of 50%, a negative predictive value of 100%, and a positive predictive value of 91.67%. Conclusions: Pre-resection ECoG spike frequency and amplitude can be used as a predictive tool for postoperative seizure outcomes, particularly when video-EEG can't identify the epileptogenic zone (EZ) in TLE patients undergoing ATL.

Simulation-based effective comparative analysis of neuron circuits for neuromorphic computation systems

The spiking neural networks (SNN) which are inspired by the human brain offers wider scope for application in the growth of neuromorphic computing systems due to their brain level computational capabilities, reduced power consumption, minimal data movement cost, and among other advantages. Spike-based neurons and synapses are the essential building blocks of SNN, and their efficient implementation is vital to its performance enhancement. In this regard, the design and implementation of spiking neurons have been the major focus among the researchers. In this paper, functioning of different leaky integrate fire (LIF)-based spiking neuron circuits like frequency adaptable CMOS-based LIF, resistor-capacitor-based (RC) LIF, and volatile memristor-based LIF are subjected to comparison. The work mainly focuses on revealing analysis of spike duration and amplitude, number of spikes produced during excitation period, threshold operation, field of application, and various other significant parameters of aforementioned neuron circuits. Extensive simulations of these circuits are carried out utilizing the Cadence Virtuoso simulation environment in order to validate their behavior. Further, a brief comparative analysis is executed considering into account the attributes like circuit complexity, supply voltage, firing rate, membrane capacitance, nature of input/output, refractory mechanism, and energy consumption per spike. This work seeks to assist researchers in selecting an appropriate LIF model to efficiently construct memristors and/or non-memristors based SNN for certain application.

Programmable Optical Synaptic Linking of Neuromorphic Photonic-Electronic RTD Spiking Circuits.

Interconnectivity between functional building blocks (such as neurons and synapses) represents a fundamental functionality for realizing neuromorphic systems. However, in the domain of neuromorphic photonics, synaptic interlinking and cascadability of spiking optical artificial neurons remains challenging and mostly unexplored in experiments. In this work, we report an optical synaptic link between optoelectronic spiking artificial neurons based upon resonant tunneling diodes (RTDs) that allows for cascadable spike propagation. First, deterministic spiking is triggered using multimodal (electrical and optical) inputs in RTD-based spiking artificial neurons, which are optoelectronic (OE) circuits incorporating either micron-scale RTDs or photosensitive nanopillar-based RTDs. Second, feedforward linking with dynamical weighting of optical spiking signals between pre- and postsynaptic RTD artificial neurons is demonstrated, including cascaded spike activation. By dynamically weighting the amplitude of optical spikes, it is shown how the cascaded spike activation probability in the postsynaptic RTD node directly follows the amplitude of the weighted optical spikes. This work therefore provides the first experimental demonstration of programmable synaptic optical link and spike cascading between multiple fast and efficient RTD OE spiking artificial neurons, therefore providing a key functionality for photonic-electronic spiking neural networks and light-enabled neuromorphic hardware.

Investigation of recessed‐source/drain SOI feedback FET‐based integrate and fire neuron circuit with compact model of threshold switching devices

AbstractIn this article, the investigation of recessed‐source/drain (Re‐S/D) SOI feedback FET (FBFET)‐based integrate and fire (IF) neuron circuit parameters is presented using a threshold switching device compact model. FBFETs offer high ION and low SS with minimal power consumption, operating efficiently at lower voltages and currents than conventional MOSFETs. Utilizing ION/IOFF ratio and threshold voltage limits (Vt2/Vt1) of the device, a model is developed to mimic hysteresis characteristics, which is then used to implement an IF neuron circuit. Our findings show that altering the Re‐S/D thickness between 0 and 50 nm enhances the ION of the device under study while decreasing hysteresis width. We detected a significant increase in output spike frequency of 46.8% and 65.14% for input current pulse amplitudes of 5 and 20 nA, respectively. Furthermore, increasing the Re‐S/D thickness from 0 to 50 nm led to a significant 29.97% enhancement in spike amplitude. In addition, when using input current pulse amplitudes of 5 and 20 nA, we saw energy savings per spike of 3.36% and 12.7%, respectively. At the same time, there was an increase in power of 8.69% and 9.54%. These enhancements in performance metrics establish our proposed integrate and fire neuron circuit as a promising candidate for efficient neuromorphic system implementation.

Roles of metabotropic glutamate receptor 5 in low [Mg2+]o-induced interictal epileptiform activity in rat hippocampal slices.

Group I metabotropic glutamate receptors (mGluRs) modulate postsynaptic neuronal excitability and epileptogenesis. We investigated roles of group I mGluRs on low extracellular Mg2+ concentration ([Mg2+]o)-induced epileptiform activity and neuronal cell death in the CA1 regions of isolated rat hippocampal slices without the entorhinal cortex using extracellular recording and propidium iodide staining. Exposure to Mg2+-free artificial cerebrospinal fluid can induce interictal epileptiform activity in the CA1 regions of rat hippocampal slices. MPEP, a mGluR 5 antagonist, significantly inhibited the spike firing of the low [Mg2+]o-induced epileptiform activity, whereas LY367385, a mGluR1 antagonist, did not. DHPG, a group 1 mGluR agonist, significantly increased the spike firing of the epileptiform activity. U73122, a PLC inhibitor, inhibited the spike firing. Thapsigargin, an ER Ca2+-ATPase antagonist, significantly inhibited the spike firing and amplitude of the epileptiform activity. Both the IP3 receptor antagonist 2-APB and the ryanodine receptor antagonist dantrolene significantly inhibited the spike firing. The PKC inhibitors such as chelerythrine and GF109203X, significantly increased the spike firing. Flufenamic acid, a relatively specific TRPC 1, 4, 5 channel antagonist, significantly inhibited the spike firing, whereas SKF96365, a relatively non-specific TRPC channel antagonist, did not. MPEP significantly decreased low [Mg2+]o DMEM-induced neuronal cell death in the CA1 regions, but LY367385 did not. We suggest that mGluR 5 is involved in low [Mg2+]oinduced interictal epileptiform activity in the CA1 regions of rat hippocampal slices through PLC, release of Ca2+ from intracellular stores and PKC and TRPC channels, which could be involved in neuronal cell death.

Continuous exercise training rescues hippocampal long-term potentiation in the VPA rat model of Autism: Uncovering sex-specific effects

Long‐term potentiation (LTP) impairment has been reported in many studies of autistic models. The aim of the present study was to investigate the effects of interval training (IT) and continuous training (CT) exercises on LTP in the hippocampal dentate gyrus (DG) neurons of valproic acid (VPA) rat model of autism. To induce an autism-like model, pregnant rats were injected 500 mg/kg NaVPA (intraperitoneal) on the embryonic day 12.5. IT and CT aerobic exercises started on postnatal day 56 in the offspring. Four weeks after IT and/or CT exercises, the offspring were urethane-anesthetized and placed into a stereotaxic apparatus for surgery, electrode implantation, and field potential recording. In the DG region, excitatory post synaptic potentials (EPSP) slope and population spike (PS) amplitude were measured. Sex differences in LTP were evident for control rats but not for VPA-exposed offspring. LTP was significantly smaller in VPA-exposed male offspring compared with control male rats. In contrast to males, there was no difference between VPA-exposed female offspring and control female rats. Interestingly, we observed a sex difference in the response to exercise between VPA-exposed male and female offspring. CT exercise training (but not IT) increased LTP in VPA-exposed male offspring. Both IT and CT exercise trainings had no effect on intact LTP in VPA-exposed female offspring. Our work suggests that there may be differences in the benefits of exercise interventions based on sex, and CT exercise training could be more beneficial for LTP improvements.

Automatic Detection of the EEG Spike-Wave Patterns in Epilepsy: Evaluation of the Effects of Transcranial Current Stimulation Therapy.

This study aims to develop a detection method based on morphological features of spike-wave (SW) patterns in the EEG of epilepsy patients and evaluate the effect of cathodal transcranial direct current stimulation (ctDCS) treatment. The proposed method is based on several simple features describing the shape of SW patterns and their synchronous occurrence on at least two EEG channels. High sensitivity, specificity and selectivity values were achieved for each patient and condition. ctDCS resulted in a significant reduction in the number of detected patterns, a decrease in spike duration and amplitude, and an increased spike mobility. The proposed method allows efficient identification of SW patterns regardless of brain condition, although the recruitment of patterns may be modified by ctDCS. This method can be useful in the clinical evaluation of ctDCS effects.

A case of recurrent convulsions caused by acute sulfuryl fluoride gas poisoning

Sulfuryl fluoride is a kind of pesticide with strong permeability, convenient use at low temperature, non-corrosive and other characteristics, which can kill food pests and has strong lethality to termites. In acute sulfuryl fluoride poisoning, patients can see recurrent convulsions, epileptic electroencephalogram abnormalities such as matrix spikes or high amplitude spikes. In this paper, a patient with sulfuryl fluoride poisoning with convulsion-based mental system symptoms was reported, and after clinical treatment with dexamethasone and phenobarbital sodium, the patient was cured and discharged.

Changes recorded in cardiac graphoelements of bees (Apis mellifera) during contact with fipronil

A mortality of bees (Apis mellifera) caused by fipronil intoxication, due to its indiscriminate use in crops, has long been attracting the scientific community’s attention, either due to its acute or residual effects. In this study, we assessed the cardiac activity as a biomarker of fipronil intoxication through electrophysiological recordings of bees. Eighteen foragers, from the apiary of EMBRAPA—Eastern Amazon (Belém-Pará), bees were previously anesthetized at low temperature (− 10 °C) for 5 min and properly restrained and fixed on a stereotaxic base, where electrodes were implanted. All these procedures were carried out within a Faraday cage. Eighteen bees were used in the study. Worker bees engaged in foraging activities were selected. The bees were divided into a control group and a group treated with fipronil at 0.025 mg/bee (n = 9). The recordings lasted for 4 min and were evaluated at 1-s intervals represented by the following letters: A = (2–3 s), B = (59–60 s), C = (119–120 s), D = (179–180 s), and E = (239–240 s). The results showed that fipronil reduced the frequency and intensity of cardiac activity, exhibiting rapidly evolving effects, and promoting a disruption of homeostasis in bee hemodynamics. Through the obtained data, it was observed variation in spike amplitude, with a loss of cardiac strength and magnitude of the electrical impulse in the bee’s heart during exposure to fipronil.

Memristor based on carbon nanotube gelatin composite film as artificial optoelectronic synapse for image processing

Photoelectric artificial synapses based on memristors is an effective method to realize neuromorphic computation. This study presents an optoelectronic responsive artificial synapse made of a composite material consisting of gelatin and carbon nanotubes. The memristor demonstrates characteristics of analog resistive switching, the ability to store multiple memory states, and impressive retention properties. It has the capability to induce an excitatory post-synaptic current by means of electrical pulses or pulsed light exposure. The excitatory post-synaptic current can be modulated by the number, amplitude and interval of electrical pulses, as well as the action time, interval and light intensity of optical pulses. The artificial synapse showcases the emulation of fundamental Hebbian learning protocols, including spike timing dependent plasticity and spike amplitude dependent plasticity. In addition, the charge transfer in the carbon nanotube gelatin composite optoelectronic memristor is investigated through first-principles calculations, shedding light on its operational mechanism. Experimental results show that these devices have the potential to be utilized for processing image information, resulting in a significant reduction of input data and training expenses when recognizing handwritten numbers. Overall, the optoelectronic synapse exhibits promising image processing prospects in the field of neuromorphic computing.

Deconvoluting and derisking QRS complex widening to improve cardiac safety profile of novel plasmepsin X antimalarials.

Quinoline-related antimalarial drugs have been associated with cardiotoxicity risk, in particular QT prolongation and QRS complex widening. In collaboration with Medicines for Malaria Venture, we discovered novel plasmepsin X (PMX) inhibitors for malaria treatment. The first lead compounds tested in anesthetized guinea pigs (GPs) induced profound QRS widening, although exhibiting weak inhibition of NaV1.5-mediated currents in standard patch clamp assays. To understand the mechanism(s) underlying QRS widening to identify further compounds devoid of such liability, we established a set of in vitro models including CaV1.2, NaV1.5 rate-dependence, and NaV1.8 patch clamp assays, human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), and Langendorff-perfused isolated GP hearts. Six compounds were tested in all models including anesthetized GP, and 8 additional compounds were tested in vitro only. All compounds tested in anesthetized GP and isolated hearts showed a similar cardiovascular profile, consisting of QRS widening, bradycardia, negative inotropy, hypotension, and for some, QT prolongation. However, a left shift of the concentration-response curves was noted from in vitro to in vivo GP data. When comparing in vitro models, there was a good consistency between decrease in sodium spike amplitude in hiPSC-CM and QRS widening in isolated hearts. Patch clamp assay results showed that the QRS widening observed with PMX inhibitors is likely multifactorial, primarily due to NaV1.8 and NaV1.5 rate-dependent sodium blockade and/or calcium channel-mediated mechanisms. In conclusion, early de-risking of QRS widening using a set of different in vitro assays allowed to identify novel PMX inhibitors with improved cardiac safety profile.

Electromechanical Coupling and Anatomy of the In-Vivo Gastroduodenal Junction.

Few biomarkers support diagnosis and treatment of disorders of gut-brain interaction (DGBI), although gastroduodenal junction (GDJ) electromechanical coupling is a target for novel interventions. Rhythmic 'slow waves', generated by interstitial cells of Cajal (ICC), and myogenic 'spikes' are bioelectrical mechanisms underpinning motility. In this study, simultaneous in-vivo high-resolution electrophysiological and impedance planimetry measurements were paired with immunohistochemistry to elucidate GDJ electromechanical coupling. Following ethical approval, the GDJ of anaesthetized pigs (N=12) was exposed. Anatomically-specific, high-resolution electrode arrays (256 electrodes) were applied to the serosa. EndoFLIP catheters (16 electrodes; Medtronic, MN, USA) were positioned luminally to estimate diameter. Post-mortem tissue samples were stained with Masson's trichrome and Ano1 to quantify musculature and ICC. Electrical mapping captured slow-waves (N=512) and spikes (N=1071). Contractions paralleled electrical patterns. Localized slow waves and spikes preceded rhythmic contractions of the antrum, and non-rhythmic contractions of the duodenum. Slow-wave and spike amplitudes were correlated in the antrum (r=0.74, p<0.001) and duodenum (r=0.42, p<0.001). Slow-wave and contractile amplitudes were correlated in the antrum (r=0.48, p<0.001) and duodenum (r=0.35, p<0.001). Distinct longitudinal and circular muscle layers of the antrum and duodenum had a total thickness of (2.8 ± 0.9) mm and (0.4 ± 0.1) mm, respectively. At the pylorus, muscle layers merged and thickened to (3.5 ± 1.6) mm. Pyloric myenteric ICC covered less area (1.5 ± 1.1 %) compared to the antrum (4.2 ± 3.0 %) and duodenum (5.3 ± 2.8 %). Further characterization of electromechanical coupling and ICC biopsies may generate DGBI biomarkers.

Polymer-based laminar probes with an ultra-long flexible spiral-shaped cable for in vivo neural recordings

Compared to conventional rigid silicon probes, flexible penetrating neural implants exhibit improved mechanical compliance with brain tissue, enabling high-quality neural recordings over extended periods of time. However, the length of the implantable shank and extension cable of most flexible devices falls short of clinical electrodes used in diagnostics and treatment of neurological disorders. In this study, we demonstrate the design, fabrication, and in vivo validation of polyimide-based neural probes with a thin spiral-shaped cable that reaches a length of 27 centimeters, comparable to that of clinical electrodes. The spiral probe comprises a 3.9-mm-long, 75–280-µm-wide and 10-µm-thick implantable shank with 24 linearly placed gold microelectrodes (diameter: 20 µm; electrode pitch: 150 µm) placed either close to the shank edge or centered on the shank. The electrical impedance of the microelectrodes was ∼266 kΩ at 1 kHz measured in vitro. In acute rodent experiments, we recorded high-quality local field potentials (e.g., cortical slow waves and hippocampal gamma activity), single and multiunit activities. In addition, the probes could simultaneously detect the activity of about 10 well-isolated single units, with an average spike amplitude of 65 µV. Furthermore, devices chronically implanted in rats successfully recorded spiking activity over several consecutive days. As demonstrated here, the developed spiral probes can be applied to various tasks, such as the laminar analysis of brain oscillations or the study of the sleep-wake cycle in naturally sleeping animals. In conclusion, our flexible probe design may stimulate the development of novel implantable devices for application in large animal models or clinical settings.

Promotion of maturation of human pluripotent stem cell-derived cardiomyocytes via treatment with the peroxisome proliferator-activated receptor alpha agonist Fenofibrate.

As research on in vitro cardiotoxicity assessment and cardiac disease modeling becomes more important, the demand for human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is increasing. However, it has been reported that differentiated hPSC-CMs are in a physiologically immature state compared to in vivo adult CMs. Since immaturity of hPSC-CMs can lead to poor drug response and loss of acquired heart disease modeling, various approaches have been attempted to promote maturation of CMs. Here, we confirm that peroxisome proliferator-activated receptor alpha (PPARα), one of the representative mechanisms of CM metabolism and cardioprotective effect also affects maturation of CMs. To upregulate PPARα expression, we treated hPSC-CMs with fenofibrate (Feno), a PPARα agonist used in clinical hyperlipidemia treatment, and demonstrated that the structure, mitochondria-mediated metabolism, and electrophysiology-based functions of hPSC-CMs were all mature. Furthermore, as a result of multi electrode array (MEA)-based cardiotoxicity evaluation between control and Feno groups according to treatment with arrhythmia-inducing drugs, drug response was similar in a dose-dependent manner. However, main parameters such as field potential duration, beat period, and spike amplitude were different between the 2 groups. Overall, these results emphasize that applying matured hPSC-CMs to the field of preclinical cardiotoxicity evaluation, which has become an essential procedure for new drug development, is necessary.

Primary somatosensory cortex CB1 and 5‑HT1A receptors interaction in the penicillin model of epilepsy.

Cannabinoid and serotonin systems regulate many biological processes. The aim of the present study was to investigate the functional interaction between the cannabinoid and serotonergic systems of the primary somatosensory region (S1) of the brain in epileptiform activity caused by penicillin. The ACEA (an agonist of CB1 receptor), AM‑251 (an antagonist of CB1 receptor), 8‑OH‑DPAT (an agonist of 5‑HT1A receptor) and WAY‑100635 (an antagonist of 5‑HT1A receptor) were administered into the S1 after the same site administration of penicillin in urethane‑anesthetized rats. Electrocorticographic recording was done for a 90‑min period. The spike waves number and amplitude were recorded in 15‑min intervals. Areas under the curve (AUC) of the above‑mentioned spike alterations was calculated in 90 min. Spike waves with frequency of 30/min and amplitude of 1.3 mV were appeared after penicillin microinjection. The ACEA (50 ng), 8‑OH‑DPAT (500 ng) and ACEA (10 ng) plus 8‑OH‑DPAT (100 ng) reduced epileptiform activity. The AM‑251 (50 ng) and WAY‑100365 (500 ng) prevented the reducing effects of ACEA (50 ng) and 8‑OH‑DPAT (500 ng). The AM‑251 alone increased spike waves frequency. The AUC results supported the effects of the above‑mentioned treatments. The results showed that activating CB1 and 5‑HT1A receptors in the S1 may reduce the epileptiform activity caused by penicillin. Therefore, alone and together activation of central CB1 and 5‑HT1A receptors might be considered in the management of epilepsy treatment.

Effects of hand dominance on myoelectric signal of non‑fatigued lumbar multifidus muscle during single arm lifts.

Some evidence indicates that lower back muscles located at the non‑dominant side of the body are more fatigue resistant than their opposite counterparts presumably due to preferential use of the dominant hand. The aim of the study was to determine if any distinction exists in the surface electromyographic activity of corresponding contralateral non‑fatigued lumbar multifidus (LM) muscles as a function of hand dominance. The relative to maximum root mean square, the median frequency (MdF) and spike shape parameters were computed from the surface myoelectric signals of ipsilateral and contralateral lumbar multifidus muscle of 46 adult healthy subjects (27 right‑handed, 19 left‑handed) during voluntary contractions evoked by the single arm lifts in prone position. Activation of LM as a contralateral muscle to lifted arm was greater than as ipsilateral muscle, independently of handedness. Regardless if LM performed ipsi‑ or contralateral action to the lifted arm, the mean spike amplitude, slope, number of peaks per spike and spike duration were greater and mean spike frequency as well as MdF were smaller in the muscle of dominant than non‑dominant side. Combined changes of spike shape measures indicate increased recruitment, lower firing rates and higher synchronization of motor units in the LM of dominant side as compared to its counterpart.

Optical spike amplitude weighting and neuromimetic rate coding using a joint VCSEL-MRR neuromorphic photonic system

Spiking neurons and neural networks constitute a fundamental building block for brain-inspired computing, which is poised to benefit significantly from photonic hardware implementations. In this work, we experimentally investigate an interconnected optical neuromorphic system based on an ultrafast spiking vertical cavity surface emitting laser (VCSEL) neuron and a silicon photonics (SiPh) integrated micro-ring resonator (MRR). We experimentally demonstrate two different functional arrangements of these devices: first, we show that MRR weight banks can be used in conjunction with the spiking VCSEL-neurons to perform amplitude weighting of sub-ns optical spiking signals. Second, we show that a continuously firing VCSEL-neuron can be directly modulated using a locking signal propagated through a single weighting MRR, and we utilise this functionality to perform optical spike firing rate-coding via thermal tuning of the MRR. Given the significant track record of both integrated weight banks and photonic VCSEL-neurons, we believe these results demonstrate the viability of combining these two classes of devices for use in functional neuromorphic photonic systems.

Antiseizure properties of fenamate NSAIDs determined in mature human stem-cell derived neuroglial circuits.

Repeated and uncontrolled seizures in epilepsy result in brain cell loss and neural inflammation. Current anticonvulsants primarily target ion channels and receptors implicated in seizure activity. Identification of neurotherapeutics that can inhibit epileptiform activity and reduce inflammation in the brain may offer significant benefits in the long-term management of epilepsy. Fenamates are unique because they are both non-steroidal anti-inflammatory drugs (NSAIDs) and highly subunit selective modulators of GABAA receptors. In the current study we have investigated the hypothesis that fenamates have antiseizure properties using mature human stem cell-derived neuro-glia cell cultures, maintained in long-term culture, and previously shown to be sensitive to first, second and third generation antiepileptics. Mefenamic acid, flufenamic acid, meclofenamic acid, niflumic acid, and tolfenamic acid (each tested at 10-100μM) attenuated 4-aminopyridine (4-AP, 100μM) evoked epileptiform activity in a dose-dependent fashion. These actions were as effective diazepam (3-30μM) and up to 200 times more potent than phenobarbital (300-1,000μM). The low (micromolar) concentrations of fenamates that inhibited 4-AP evoked epileptiform activity correspond to those reported to potentiate GABAA receptor function. In contrast, the fenamates had no effect on neural spike amplitudes, indicating that their antiseizure actions did not result from inhibition of sodium-channels. The antiseizure actions of fenamates were also not replicated by either of the two non-fenamate NSAIDs, ibuprofen (10-100μM) or indomethacin (10-100μM), indicating that inhibition of cyclooxygenases is not the mechanism through which fenamates have anticonvulsant properties. This study therefore shows for the first time, using functionally mature human stem cell-derived neuroglial circuits, that fenamate NSAIDs have powerful antiseizure actions independent of, and in addition to their well-established anti-inflammatory properties, suggesting these drugs may provide a novel insight and new approach to the treatment of epilepsy in the future.

HiPSC-CM electrophysiology: impact of temporal changes and study parameters on experimental reproducibility.

Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are frequently used for preclinical cardiotoxicity testing and remain an important tool for confirming model-based predictions of drug effects in accordance with the comprehensive in vitro proarrhythmia assay (CiPA). Despite the considerable benefits hiPSC-CMs provide, concerns surrounding experimental reproducibility have emerged. We investigated the effects of temporal changes and experimental parameters on hiPSC-CM electrophysiology. iCell cardiomyocytes2 were cultured and biosignals were acquired using a microelectrode array (MEA) system (2-14 days). Continuous recordings revealed a 22.6% increase in the beating rate and 7.7% decrease in the field potential duration (FPD) during a 20-min equilibration period. Location-specific differences across a multiwell plate were also observed, with iCell cardiomyocytes2 in the outer rows beating 8.8 beats/min faster than the inner rows. Cardiac endpoints were also impacted by cell culture duration; from 2 to 14 days, the beating rate decreased (-12.7 beats/min), FPD lengthened (+257 ms), and spike amplitude increased (+3.3 mV). Cell culture duration (4-10 days) also impacted cardiomyocyte drug responsiveness (E-4031, nifedipine, isoproterenol). qRT-PCR results suggest that daily variations in cardiac metrics may be linked to the continued maturation of hiPSC-CMs in culture (2-30 days). Daily experiments were also repeated using a second cell line (Cor.4U). Collectively, our study highlights multiple sources of variability to consider and address when performing hiPSC-CM MEA studies. To improve reproducibility and data interpretation, MEA-based studies should establish a standardized protocol and report key experimental conditions (e.g., cell line, culture time, equilibration time, electrical stimulation settings, and raw data values).NEW & NOTEWORTHY We demonstrate that iCell cardiomyocytes2 electrophysiology measurements are impacted by deviations in experimental techniques including electrical stimulation protocols, equilibration time, well-to-well variability, and length of hiPSC-CM culture. Furthermore, our results indicate that hiPSC-CM drug responsiveness changes within the first 2 wk following defrost.

Cacao consumption improves passive avoidance memory impairment in a rat model of Alzheimer's disease: the role of hippocampal synaptic plasticity and oxidative stress.

Introduction: Alzheimer's disease (AD) causes progressive loss of cognitive function and synaptic plasticity, which is the most common form of dementia. The present study was designed to scrutinize the effects of cacao on passive avoidance memory function and to identify the roles of hippocampal synaptic plasticity and oxidative stress in an AD rat model induced by unilateral intracerebroventricular (UICV) injection of amyloid-beta (Aβ). Methods: Oral administration of cacao (500 mg/kg/ day) was given for 2 consecutive months. A memory retention test was conducted 24 h after passive avoidance training was completed. Subsequently, the amplitude of population spike (PS) and slope of field excitatory postsynaptic potentials (fEPSPs) were assessed at hippocampal long-term potentiation (LTP) in perforant pathway-dentate gyrus (PP-DG) synapses. Moreover, total thiol group (TTG) and malondialdehyde (MDA) concentrations were evaluated in the plasma. Furthermore, compact Aβ plaques were detected in the hippocampal DG by performing Congo red staining. Results: As a result of AD induction, passive avoidance memory was impaired; also, reduced fEPSP slopes, PS amplitudes, and content of TTG, and increase in MDA levels in the rats were observed. In contrast, cacao treatment ameliorated passive avoidance memory impairment, improved hippocampal LTP impairment, modulated oxidative-antioxidative status, and delayed Aβ plaques production in AD rats. Disscussion: Conclusively, cacao alleviates Aβ-induced cognitive deficit, probably by the amelioration of hippocampal LTP impairment, modulation of oxidative-antioxidative status, and inhibition of Aβ plaque accumulation.