Spike Amplitude Research Articles

A Novel Algorithmic Approach to the Analysis of Multi-Electrode Array Signals of hiPSC-Derived Cardiomyocytes.

In order to perform in vitro cardiotoxicity screening of pharmacological substances, multi-electrode array systems are increasingly used to measure the extracellular field potentials of cell layers of human induced pluripotent stem cell cardiomyocytes. The analysis of the field potentials is usually performed using complex analysis software provided by the hardware manufacturers. In the case of the Cardiac Analysis Tool software from Axion Biosystems, inconsistencies were found in the results, which can significantly influence the cardiotoxicity screening results. In order to obtain more reliable results, a new algorithm was developed and implemented in an easy-to-use software tool, the INCardio Data Analysis Tool, which, due to its high degree of automation, can also be used by inexperienced users. The validation reveals differences in the results of the two tools both in depolarization spike amplitudes and in the time course of the field potential durations. The manual analysis of all signals affected by deviations shows that the results of the newly developed Data Analysis Tool are correct in all cases and can therefore be classified as more accurate and reliable than the reference analysis software.

Stitching Flexible Electronics into the Brain.

Understanding complex neuronal networks requires monitoring long-term neuronal activity in various regions of the brain. Significant progress has been made in multisite implantations of well-designed probes, such as multisite implantation of Si-based and polymer-based probes. However, these multiprobe strategies are limited by the sizes and weights of interfaces to the multiple probes and the inability to track the activity of the same neurons and changes in neuronal activity over longer time periods. Here, a long single flexible probe that can be implanted by stitching into multiple regions of the mouse brain and subsequently transmit chronically stable neuronal signals from the multiple sites via a single low-mass interface is reported. The probe at four different sites is implemented using a glass capillary needle or two sites using an ultrathin metal needle. In vitro tests in brain-mimicking hydrogel show that multisite probe implantations achieve a high connection yield of >86%. In vivo histological images at each site of probes, implanted by stitching using either glass capillary or ultrathin metal insertion needles exhibit seamless tissue-probe interfaces with negligible chronic immune response. In addition, electrophysiology studies demonstrate the ability to track single neuron activities at every injection site with chronic stability over at least one month. Notably, the measured spike amplitudes and signal-to-noise ratios at different implantation sites show no statistically significant differences. Multisite stitching implantation of flexible electronics in the brain opens up new opportunities for both fundamental neuroscience research and electrotherapeutic applications.

Conditional deletion of KCC2 impairs synaptic plasticity and both spatial and nonspatial memory.

The postsynaptic inhibition through GABAA receptors (GABAAR) relies on two mechanisms, a shunting effect due to an increase in the postsynaptic membrane conductance and, in mature neurons, a hyperpolarization effect due to an entry of chloride into postsynaptic neurons. The second effect requires the action of the K+-Cl- cotransporter KCC2 which extrudes Cl- from the cell and maintains its cytosolic concentration very low. Neuronal chloride equilibrium seems to be dysregulated in several neurological and psychiatric conditions such as epilepsy, anxiety, schizophrenia, Down syndrome, or Alzheimer's disease. In the present study, we used the KCC2 Cre-lox knockdown system to investigate the role of KCC2 in synaptic plasticity and memory formation in adult mice. Tamoxifen-induced conditional deletion of KCC2 in glutamatergic neurons of the forebrain was performed at 3 months of age and resulted in spatial and nonspatial learning impairment. On brain slices, the stimulation of Schaffer collaterals by a theta burst induced long-term potentiation (LTP). The lack of KCC2 did not affect potentiation of field excitatory postsynaptic potentials (fEPSP) measured in the stratum radiatum (dendrites) but increased population spike (PS) amplitudes measured in the CA1 somatic layer, suggesting a reinforcement of the EPSP-PS potentiation, i.e., an increased ability of EPSPs to generate action potentials. At the cellular level, KCC2 deletion induced a positive shift in the reversal potential of GABAAR-driven Cl- currents (EGABA), suggesting an intracellular accumulation of chloride subsequent to the downregulation of KCC2. After treatment with bumetanide, an antagonist of the Na+-K+-Cl- cotransporter NKCC1, spatial memory impairment, chloride accumulation, and EPSP-PS potentiation were rescued in mice lacking KCC2. The presented results emphasize the importance of chloride equilibrium and GABA-inhibiting ability in synaptic plasticity and memory formation.

The retinal pigment epithelium displays electrical excitability and lateral signal spreading

BackgroundThe non-neuronal retinal pigment epithelium (RPE) functions in intimate association with retinal photoreceptors, performing a multitude of tasks critical for maintaining retinal homeostasis and collaborating with retinal glial cells to provide metabolic support and ionic buffering. Accordingly, the RPE has recently been shown to display dynamic properties mediated by an array of ion channels usually more characteristic of astrocytes and excitable cells. The recent discovery of canonical voltage-activated Na+ channels in the RPE and their importance for phagocytosis of photoreceptor outer segments raises a question about their electrogenic function. Here, we performed a detailed electrophysiological analysis related to the functioning of these channels in human embryonic stem cell (hESC)-derived RPE.ResultsOur studies examining the electrical properties of the hESC-RPE revealed that its membrane mainly displays passive properties in a broad voltage range, with the exception of depolarization-induced spikes caused by voltage-activated Na+ current (INa). Spike amplitude depended on the availability of INa and spike kinetics on the membrane time constant, and the spikes could be largely suppressed by TTX. Membrane resistance fluctuated rapidly and strongly, repeatedly changing over the course of recordings and causing closely correlated fluctuations in resting membrane potential. In a minority of cells, we found delayed secondary INa-like inward currents characterized by comparatively small amplitudes and slow kinetics, which produced secondary depolarizing spikes. Up to three consecutive delayed inward current waves were detected. These currents could be rapidly and reversibly augmented by applying L-type Ca2+ channel blocker nifedipine to diminish influx of calcium and thus increase gap junctional conductance.ConclusionsThis work shows, for the first time, that INa and INa-mediated voltage spikes can spread laterally through gap junctions in the monolayer of cells that are traditionally considered non-excitable. Our findings support a potential role of the RPE that goes beyond giving homeostatic support to the retina.

Geraniol improves passive avoidance memory and hippocampal synaptic plasticity deficits in a rat model of Alzheimer's disease

Alzheimer's disease (AD) is the most progressive and irreversible neurodegenerative disease that leads to synaptic loss and cognitive decline. The present study was designed to evaluate the effects of geraniol (GR), a valuable acyclic monoterpene alcohol, with protective and therapeutic effects, on passive avoidance memory, hippocampal synaptic plasticity, and amyloid-beta (Aβ) plaques formation in an AD rat model induced by intracerebroventricular (ICV) microinjection of Aβ1-40. Seventy male Wistar rats were randomly into sham, control, control-GR (100 mg/kg; P.O. (orally), AD, GR-AD (100 mg/kg; P.O.; pretreatment), AD-GR (100 mg/kg; P.O.; treatment), and GR-AD-GR (100 mg/kg; P.O.; pretreatment & treatment). Administration of GR was continued for four consecutive weeks. Training for the passive avoidance test was carried out on the 36th day and a memory retention test was performed 24 h later. On day 38, hippocampal synaptic plasticity (long-term potentiation; LTP) was recorded in perforant path-dentate gyrus (PP-DG) synapses to assess field excitatory postsynaptic potentials (fEPSPs) slope and population spike (PS) amplitude. Subsequently, Aβ plaques were identified in the hippocampus by Congo red staining. The results showed that Aβ microinjection increased passive avoidance memory impairment, suppressed of hippocampal LTP induction, and enhanced of Aβ plaque formation in the hippocampus. Interestingly, oral administration of GR improved passive avoidance memory deficit, ameliorated hippocampal LTP impairment, and reduced Aβ plaque accumulation in the Aβ-infused rats. The results suggest that GR mitigates Aβ-induced passive avoidance memory impairment, possibly through alleviation of hippocampal synaptic dysfunction and inhibition of Aβ plaque formation.

Dynamic of shock–bubble interactions and nonlinear evolution of ablative hydrodynamic instabilities initialed by capsule interior isolated defects

It is believed that isolated defects within the capsule (e.g., void, high-density inclusion) can be one of the essential factors for implosion performance degradation by seeding hydrodynamic instabilities in implosions. Nonetheless, a systematic study on how the isolated defects evolve and why they are not stabilized by ablation given the length scale comparable with the typical cutoff wavelength is still lacking. This paper addresses the above concerns by looking into a simplified model where a planar shell (without convergent geometry) is driven by laser direct-drive, with a single defect (low/high density) of micrometer or sub-micrometer scale residing at different locations inside. The underlying dynamics of two key physical processes are analyzed, i.e., the shock–bubble interactions as well as the subsequent nonlinear evolution of ablative hydrodynamic instabilities initiated by the direct interaction of the deformed defect and ablation front, revealing that compressibility and baroclinic effects drive vorticity production during the interactions between the shock wave and the isolated defect. In the “light-bubble” case, the vortex pair generated in the first process is further strengthened by the laser ablation. Hence, a directed flow is formed in companion with the persistent flow entering the bubble of the surrounding ablator. The bubble exhibits a remarkable growth both laterally and deeply, seriously threatening the shell's integrity. The positive feedback mechanism of the vortex pair is absent in the “heavy-bubble” counterpart, and the ablation stabilization manifested itself in the reduction of spike amplitude. A systematic study of localized perturbation growth as a function of defect placement, size, and preheating intensity is presented.

Plasma formation in holmium:YAG laser lithotripsy.

Duringholmium:yttrium-aluminum-garnet(holmium:YAG) laser lithotripsy to break urinary stones, urologists frequently see flashes of light. As infrared laser pulses are invisible, what is the source of light? Here we studied the origin, characteristics, and some effects of flashes of light in laser lithotripsy. Ultrahigh-speed video-microscopy was used to record single laser pulses at 0.2-1.0 J energy lasered with 242 µm glass-core-diameter fibers in contact with whole surgically retrieved urinary stones and hydroxyapatite (HA)-coated glass slides in air and water. Acoustic transients were measured with a hydrophone. Visible-light and infrared photodetectors resolved temporal profiles of visible-light emission and infrared-laser pulses. Temporal profiles of laser pulses showed intensity spikes of various duration and amplitude. The pulses were seen to produce dim light and bright sparks with submicrosecond risetime. The spark produced by the intensity spike at the beginning of laser pulse generated a shock wave in the surrounding liquid. The subsequent sparks were in a vapor bubble and generated no shock waves. Sparks enhanced absorption of laser radiation, indicative of plasma formation and optical breakdown. The occurrence and number of sparks varied even with the same urinary stone. Sparks were consistently observed at laser energy >0.5 J with HA-coated glass slides. The slides broke or cracked by cavitation with sparks in 63 ± 15% of pulses (1.0 J, N = 60). No glass-slide breakage occurred without sparks (1.0 J, N = 500). Unappreciated in previous studies, plasma formation with free-running long-pulse holmium:YAG lasers can be an additional physical mechanism of action in laser procedures.

GABAA receptor subunit modulation reversed electrophysiological network alterations after blast exposure in rat organotypic hippocampal slice cultures

Throughout training and deployment, some military service members are frequently exposed to shock waves due to blasts, and some complain of myriad neurological symptoms. In rat organotypic hippocampal slice cultures (OHSCs), blast-induced traumatic brain injury (bTBI) causes deficits in some electrophysiological measures, like long term potentiation, a neuronal correlate for learning and memory. In this study, we further characterized the alterations in the hippocampal network of OHSCs following a single moderate blast exposure. Connectivity and clustering coefficients were reduced across the hippocampal network following bTBI, despite the lack of changes in the firing rate, spike amplitude, spike duration, or inter-spike interval. However, interrogation with the GABAA receptor antagonist, bicuculline, revealed additional significant differences between injured and control slices in measures of spike amplitude, spike duration, connectivity, and clustering. bTBI also significantly reduced expression of the α1 and α5 GABAA receptor subunits. Treatment with the FDA-approved histone deacetylase inhibitor suberanilohydroxamic acid (SAHA) restored the α1 subunit and attenuated deficits in network measures, like connectivity and clustering coefficients. These findings suggest that GABAA receptors may be implicated in neuronal network changes in OHSCs following bTBI, and their recovery may be a viable therapeutic intervention to mitigate injury-induced neurological symptoms.

High Amplitude Spike Generator in Au Nanodot-Incorporated NbOx Mott Memristor.

NbOx-based Mott memristors exhibit fast threshold switching behaviors, making them suitable for spike generators in neuromorphic computing and stochastic clock generators in security devices. In these applications, a high output spike amplitude is necessary for threshold level control and accurate signal detection. Here, we propose a materialwise solution to obtain the high amplitude spikes by inserting Au nanodots into the NbOx device. The Au nanodots enable increasing the threshold voltage by modulating the oxygen contents at the electrode-oxide interface, providing a higher ON current compared to nanodot-free NbOx devices. Also, the reduction of the local switching region volume decreases the thermal capacitance of the system, allowing the maximum spike amplitude generation. Consequently, the Au nanodot incorporation increases the spike amplitude of the NbOx device by 6 times, without any additional external circuit elements. The results are systematically supported by both a numerical model and a finite-element-method-based multiphysics model.

Post-explant profiling of subcellular-scale carbon fiber intracortical electrodes and surrounding neurons enables modeling of recorded electrophysiology

Objective. Characterizing the relationship between neuron spiking and the signals that electrodes record is vital to defining the neural circuits driving brain function and informing clinical brain-machine interface design. However, high electrode biocompatibility and precisely localizing neurons around the electrodes are critical to defining this relationship. Approach. Here, we demonstrate consistent localization of the recording site tips of subcellular-scale (6.8 µm diameter) carbon fiber electrodes and the positions of surrounding neurons. We implanted male rats with carbon fiber electrode arrays for 6 or 12+ weeks targeting layer V motor cortex. After explanting the arrays, we immunostained the implant site and localized putative recording site tips with subcellular-cellular resolution. We then 3D segmented neuron somata within a 50 µm radius from implanted tips to measure neuron positions and health and compare to healthy cortex with symmetric stereotaxic coordinates. Main results. Immunostaining of astrocyte, microglia, and neuron markers confirmed that overall tissue health was indicative of high biocompatibility near the tips. While neurons near implanted carbon fibers were stretched, their number and distribution were similar to hypothetical fibers placed in healthy contralateral brain. Such similar neuron distributions suggest that these minimally invasive electrodes demonstrate the potential to sample naturalistic neural populations. This motivated the prediction of spikes produced by nearby neurons using a simple point source model fit using recorded electrophysiology and the mean positions of the nearest neurons observed in histology. Comparing spike amplitudes suggests that the radius at which single units can be distinguished from others is near the fourth closest neuron (30.7 ± 4.6 µm, ± S) in layer V motor cortex. Significance. Collectively, these data and simulations provide the first direct evidence that neuron placement in the immediate vicinity of the recording site influences how many spike clusters can be reliably identified by spike sorting.

Neuroprotective effects of vinpocetine, as a phosphodiesterase 1 inhibitor, on long-term potentiation in a rat model of Alzheimer’s disease

BackgroundVinpocetine (Vin) is known as a phosphodiesterase 1 inhibitor (PDE1-I) drug with multilateral effects, including antioxidant and anti-inflammatory activity. In this research, we investigated the neuroprotective and therapeutic effects of Vin through hippocampal synaptic plasticity on a rat’s model of Alzheimer’s disease (AD) induced by an intracerebroventricular (ICV) injection of beta-amyloid (Aβ).MethodsSixty adult male Wistar rats were randomly divided into six groups: 1. control, 2. sham, 3. Aβ, 4. pretreatment (Vin + Aβ): Vin (4 mg/kg, gavage) for 30 days and then, inducing an AD model by an ICV injection of Aβ(1–42), 5. treatment (Aβ + Vin): inducing an AD model and then receiving Vin for 30 days by gavage, and 7. pretreatment + treatment (Vin + Aβ + Vin): receiving Vin by gavage for 30 days before and 30 days after the induction of an AD model. After these procedures, via stereotaxic surgery, the stimulating electrodes were placed at the perforant pathway (PP) and the recording electrodes were implanted in the dentate gyrus.ResultsExcitatory postsynaptic potential (EPSP) slope and population spike (PS) amplitude in the Aβ group meaningfully diminished compared to the control group after the induction of long-term potentiation (LTP).ConclusionsVin could significantly prevent the Aβ effects on LTP. It can be concluded that pretreatment and treatment with Vin can be neuroprotective against harmful consequences of Aβ on hippocampal synaptic plasticity.

The Fifth Bioelectronic Medicine Summit Hosted by the Feinstein Institutes for Medical Research (Manhasset, NY) and Columbia Engineering (NY, NY) at The Garden City Hotel, Garden City, NY 11530 on October 11-12th, 2022- Bioelectronic Medicine: Today’s Tools, Tomorrow’s Therapies

The Fifth Bioelectronic Medicine Summit Hosted by the Feinstein Institutes for Medical Research (Manhasset, NY) and Columbia Engineering (NY, NY) at The Garden City Hotel, Garden City, NY 11530 on October 11-12th, 2022- Bioelectronic Medicine: Today’s Tools, Tomorrow’s Therapies

Injectable contraceptive Depo-Provera induces erratic beating patterns in patient-specific induced pluripotent stem cell–derived cardiomyocytes with long QT syndrome type 2

Long QT syndrome type 2 (LQT2) is caused by pathogenic variants in KCNH2. LQT2 may manifest as QT prolongation on an electrocardiogram and present with arrhythmic syncope/seizures and sudden cardiac arrest/death. Progestin-based oral contraceptives may increase the risk of LQT2-triggered cardiac events in women. We previously reported on a woman with LQT2 and recurrent cardiac events temporally related and attributed to the progestin-based contraceptive medroxyprogesterone acetate ("Depo-Provera" [Depo] MilliporeSigma, Catalog# 1378001, St. Louis, MO). The purpose of this study was to evaluate the arrhythmic risk of Depo in a patient-specific induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) model of LQT2. An iPSC-CM line was generated from a 40-year-old woman with p.G1006Afs∗49-KCNH2. A CRISPR/Cas9 gene-edited/variant-corrected isogenic control iPSC-CM line was generated. FluoVolt (Invitrogen, F10488, Waltham, MA) was used to measure the action potential duration after treatment with 10 μM Depo. Erratic beating patterns characterized as alternating spike amplitudes, alternans, or early afterdepolarization-like phenomena were assessed using multielectrode array (MEA) after 10 μM Depo, 1 μM isoproterenol (ISO), or combined Depo + ISO treatment. Depo treatment shortened the action potential duration at 90% repolarization of G1006Afs∗49 iPSC-CMs from 394 ± 10 to 303 ± 10 ms (P < .0001). Combined Depo + ISO treatment increased the percentage of electrodes displaying erratic beating in G1006Afs∗49 iPSC-CMs (baseline: 18% ± 5% vs Depo + ISO: 54% ± 5%; P < .0001) but not in isogenic control iPSC-CMs (baseline: 0% ± 0% vs Depo + ISO: 10% ± 3%; P = .9659). This cell study provides a potential mechanism for the patient's clinically documented Depo-associated episodes of recurrent ventricular fibrillation. This invitro data should prompt a large-scale clinical assessment of Depo's potential proarrhythmic effect in women with LQT2.

A Novel Analysis of Compound Muscle Action Potential Scan: Staircase Function Fitting and StairFit Motor Unit Number Estimation.

Compound muscle action potential (CMAP) scan provides a detailed stimulus-response curve for examination of neuromuscular disease. The objective of the study is to develop a novel CMAP scan analysis to extract motor unit number estimation (MUNE) and other physiological or diagnostic information. A staircase function was used as the basic mathematical model of the CMAP scan. An optimal staircase function fitting model was estimated for each given number of motor units, and the fitting model with the minimum number of motor units that meets a predefined error requirement was accepted. This yields MUNE as well as the spike amplitude and activation threshold of each motor unit that contributes to the CMAP scan. The significance of the staircase function fit was confirmed using simulated CMAP scans with different motor unit number (20, 50, 100 and 150) and baseline noise (1 µV, 5 µV and 10 µV) inputs, in terms of MUNE performance, repeatability, and the test-retest reliability. For experimental data, the average MUNE of the first dorsal interosseous muscle derived from the staircase function fitting was 57.5 ± 26.9 for the tested spinal cord injury subjects, which was significantly lower than 101.2 ± 16.9, derived from the control group (p < 0.001). The staircase function fitting provides an appropriate approach to CMAP scan processing, yielding MUNE and other useful parameters for examination of motor unit loss and muscle fiber reinnervation.

Effects of sesamin on Aβ1-42-induced oxidative stress and LTP impairment in a rat model of Alzheimer's disease.

The present study examined the protective effect of sesamin (Ses) on β-amyloid (Aβ)-induced long-term potentiation (LTP) impairment at the PP-DG synapses in male rats. Wistar rats were randomly assigned to seven groups: control, sham, Aβ; ICV Aβ1-42 microinjection, Ses, Aβ + Ses; first, ICV Aβ injections and then receiving Ses, Ses + Aβ: four weeks of pretreatment with Ses and then Aβ injection, and Ses + Aβ + Ses: pre (four weeks) and post (four weeks) treatment with Ses. Ses-treated groups received 30mg/kg of Ses once a day by oral gavage for four weeks. After the treatment period, the animals were positioned in a stereotaxic device for surgery and field potential recording. The population spike (PS) amplitude and slope of excitatory postsynaptic potentials (EPSP) were evaluated in the DG region. Serum oxidative stress biomarkers (total oxidant status (TOS) and total antioxidant capacity (TAC)) were measured. Aβ impaired LTP induction at the PP-DG synapses evidenced by a decrease in EPSP slope and PS amplitude of LTP. In Aβ rats, Ses increased EPSP slope and PS amplitude of LTP in the DG granular cells. Also, an increase in TOS and a reduction in TAC caused by Aβ were significantly corrected by Ses. Ses could prevent Aβ-induced LTP impairment at the PP-DG synapses in male rats, which can be due to its preventive effects on oxidative stress.

Anti-glutamatergic Effects of Three Lignan Compounds: Arctigenin, Matairesinol and Trachelogenin - An ex vivo Study on Rat Brain Slices.

Arctigenin is a bioactive dibenzylbutyrolactone-type lignan exhibiting various pharmacological activities. The neuroprotective effects of arctigenin were demonstrated to be mediated via inhibition of AMPA and KA type glutamate receptors in the somatosensory cortex of the rat brain. The aim of this study was to compare the effects of arctigenin with matairesinol and trachelogenin on synaptic activity in ex vivo rat brain slices. Arctigenin, matairesinol and trachelogenin were isolated from Arctium lappa, Centaurea scabiosa and Cirsium arvense, respectively, and applied on brain slices via perfusion medium at the concentration range of 0.5 - 40 µM. The effects of the lignans were examined in the CA1 hippocampus and the somatosensory cortex by recording electrically evoked field potentials. Arctigenin and trachelogenin caused a significant dose-dependent decrease in the amplitude of hippocampal population spikes (POPS) and the slope of excitatory postsynaptic potentials (EPSPs), whereas matairesinol (1 µM and 10 µM) decreased EPSP slope but had no effect on POPS amplitude. Trachelogenin effect (0.5 µM, 10 µM, 20 µM) was comparable to arctigenin (1 µM, 20 µM, 40 µM) (p > 0.05). In the neocortex, arctigenin (10 µM, 20 µM) and trachelogenin (10 µM) significantly decreased the amplitude of evoked potential early component, while matairesinol (1 µM and 10 µM) had no significant effect (p > 0.05). The results suggest that trachelogenin and arctigenin act via inhibition of AMPA and KA receptors in the brain and trachelogenin has a higher potency than arctigenin. Thus, trachelogenin and arctigenin could serve as lead compounds in the development of neuroprotective drugs.

Comparative analysis of the cardiomyocyte differentiation potential of induced pluripotent stem cells reprogrammed from human atrial or ventricular fibroblasts.

Background: We had shown that cardiomyocytes (CMs) were more efficiently differentiated from human induced pluripotent stem cells (hiPSCs) when the hiPSCs were reprogrammed from cardiac fibroblasts rather than dermal fibroblasts or blood mononuclear cells. Here, we continued to investigate the relationship between somatic-cell lineage and hiPSC-CM production by comparing the yield and functional properties of CMs differentiated from iPSCs reprogrammed from human atrial or ventricular cardiac fibroblasts (AiPSC or ViPSC, respectively). Methods: Atrial and ventricular heart tissues were obtained from the same patient, reprogrammed into AiPSCs or ViPSCs, and then differentiated into CMs (AiPSC-CMs or ViPSC-CMs, respectively) via established protocols. Results: The time-course of expression for pluripotency genes (OCT4, NANOG, and SOX2), the early mesodermal marker Brachyury, the cardiac mesodermal markers MESP1 and Gata4, and the cardiovascular progenitor-cell transcription factor NKX2.5 were broadly similar in AiPSC-CMs and ViPSC-CMs during the differentiation protocol. Flow-cytometry analyses of cardiac troponin T expression also indicated that purity of the two differentiated hiPSC-CM populations (AiPSC-CMs: 88.23% ± 4.69%, ViPSC-CMs: 90.25% ± 4.99%) was equivalent. While the field-potential durations were significantly longer in ViPSC-CMs than in AiPSC-CMs, measurements of action potential duration, beat period, spike amplitude, conduction velocity, and peak calcium-transient amplitude did not differ significantly between the two hiPSC-CM populations. Yet, our cardiac-origin iPSC-CM showed higher ADP and conduction velocity than previously reported iPSC-CM derived from non-cardiac tissues. Transcriptomic data comparing iPSC and iPSC-CMs showed similar gene expression profiles between AiPSC-CMs and ViPSC-CMs with significant differences when compared to iPSC-CM derived from other tissues. This analysis also pointed to several genes involved in electrophysiology processes responsible for the physiological differences observed between cardiac and non-cardiac-derived cardiomyocytes. Conclusion: AiPSC and ViPSC were differentiated into CMs with equal efficiency. Detected differences in electrophysiological properties, calcium handling activity, and transcription profiles between cardiac and non-cardiac derived cardiomyocytes demonstrated that 1) tissue of origin matters to generate a better-featured iPSC-CMs, 2) the sublocation within the cardiac tissue has marginal effects on the differentiation process.

Extracting the Invisible: Mesial Temporal Source Detection in Simultaneous EEG and SEEG Recordings.

Epileptic source detection relies mainly on visual expertise of scalp EEG signals, but it is recognised that epileptic discharges can escape to this expertise due to a deep localization of the brain sources that induce a very low, even negative, signal to noise ratio. In this methodological study, we aimed to investigate the feasibility of extracting deep mesial temporal sources that were invisible in scalp EEG signals using blind source separation (BSS) methods (infomax ICA, extended infomax ICA, and JADE) combined with a statistical measure (kurtosis). We estimated the effect of different methodological and physiological parameters that could alter or improve the extraction. Using nine well-defined mesial epileptic networks (1949 spikes) obtained from seven patients and simultaneous EEG-SEEG recordings, the first independent component extracted from the scalp EEG signals was validated in mean from 46 to 80% according to the different parameters. The three BSS methods equally performed (no significant difference) and no influence of the number of scalp electrodes used was found. At the opposite, the number and amplitude of spikes included in the averaging before the extraction modified the performance. Anyway, despite their invisibility in scalp EEG signals, this study demonstrates that deep source extraction is feasible under certain conditions and with the use of common signal analysis toolboxes. This finding confirms the crucial need to continue the signal analysis of scalp EEG recordings which contains subcortical signals that escape to expert visual analysis but could be found by signal processing.

Policosanol protects against Alzheimer's disease-associated spatial cognitive decline in male rats: possible involved mechanisms.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by cognitive decline and synaptic failure. The present study was designed to explore the possible protective effects of policosanol (PCO) on spatial cognitive capacity, long-term potentiation (LTP) induction, oxidant/antioxidant status, and Aβ plaques formation in an AD rat model induced by intracerebroventricular (ICV) injection of Aβ1-40. Healthy adult male Wistar rats were randomly divided into control, sham (ICV injection of 5µl phosphate-buffered saline), AG (50mg/kg; P.O., as PCO vehicle), PCO (50mg/kg; P.O.), AD model (ICV injection of 5µl Aβ), AD + AG (50mg/kg; P.O.), and AD + PCO (50mg/kg; P.O.). Treatments were performed for eight consecutive weeks. At the end of the treatment course, spatial learning and memory functions, hippocampal long-term potentiation (LTP) induction, malondialdehyde (MDA), and total thiol group (TTG) levels, as well as the formation of Aβ plaques, were examined. The results showed that injection of Aβ reduced spatial learning and memory abilities in the Barnes maze test, which was accompanied by decreases in field excitatory postsynaptic potential (fEPSP) slope, population spike (PS) amplitude, and TTG level and increases in Aβ plaque accumulation and MDA content. In contrast, PCO treatment improved all the above-mentioned changes in the Aβ-infused rats. The results suggest that amelioration of hippocampal synaptic plasticity impairment, modulation of oxidant/antioxidant status, and inhibition of Aβ plaque formation by PCO may be the mechanisms behind its protective effect against AD-associated spatial cognitive decline.

Curcumin attenuates memory impairments and long-term potentiation deficits by damping hippocampal inflammatory cytokines in lipopolysaccharide-challenged rats.

Neuroinflammation is a key pathological event triggering neurodegenerative process, resulting in neurologic sequelae. Curcumin (cur) has recently received increasing attention due to its anti-inflammatory properties. Therefore, we investigated the protective effects of curcumin on lipopolysaccharide (LPS)-induced memory impairments, long-term potentiation (LTP) deficits, hippocampal inflammatory cytokines, and neuronal loss in male rats. Rats were randomly divided into four groups as follows: (1) Vehicle; (2) cur; (3) LPS; and (4) cur/LPS. Following curcumin pretreatment (50mg/kg, per oral via gavage, 14 consecutive days), animals received a single dose of LPS (1mg/kg, intraperitoneally) or saline. Twenty-four hours after LPS/or saline administration, passive avoidance test (PAT), hippocampal LTP, inflammatory cytokines (TNFα, IL-1β), and neuronal loss were assessed in hippocampal tissue of rats. Our results indicated that pretreatment with curcumin in LPS-challenged rats attenuates memory impairment in PAT, which was accompanied by significant increase in the field excitatory post-synaptic potential (fEPSP) slope and population spike (PS) amplitude. Hence, pretreatment with curcumin in LPS-treated rats decreased hippocampal concentration of tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β), as well as reduced neuronal loss in the hippocampal tissue. This study provide evidence that pretreatment with curcumin attenuates LPS-induced memory impairment and LTP deficiency, which may be partly related to the amelioration of inflammatory cytokines and neuronal loss in the hippocampal tissue.