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In this work, we are interested in solving large linear systems stemming from the extra-membrane-intra model, which is employed for simulating excitable tissues at a cellular scale. After setting the related systems of partial differential equations equipped with proper boundary conditions, we provide its finite element discretization and focus on the resulting large linear systems. We first give a relatively complete spectral analysis using tools from the theory of Generalized Locally Toeplitz matrix sequences. The obtained spectral information is used for designing appropriate preconditioned Krylov solvers. Through numerical experiments, we show that the presented solution strategy is robust w.r.t. problem and discretization parameters, efficient and scalable.

In this work, we are interested in solving large linear systems stemming from the extra-membrane-intra model, which is employed for simulating excitable tissues at a cellular scale. After setting the related systems of partial differential equations equipped with proper boundary conditions, we provide its finite element discretization and focus on the resulting large linear systems. We first give a relatively complete spectral analysis using tools from the theory of Generalized Locally Toeplitz matrix sequences. The obtained spectral information is used for designing appropriate preconditioned Krylov solvers. Through numerical experiments, we show that the presented solution strategy is robust w.r.t. problem and discretization parameters, efficient and scalable.

In this work, we are interested in solving large linear systems stemming from the extra-membrane-intra model, which is employed for simulating excitable tissues at a cellular scale. After setting the related systems of partial differential equations equipped with proper boundary conditions, we provide its finite element discretization and focus on the resulting large linear systems. We first give a relatively complete spectral analysis using tools from the theory of Generalized Locally Toeplitz matrix sequences. The obtained spectral information is used for designing appropriate preconditioned Krylov solvers. Through numerical experiments, we show that the presented solution strategy is robust w.r.t. problem and discretization parameters, efficient and scalable.

In this work, we are interested in solving large linear systems stemming from the extra-membrane-intra model, which is employed for simulating excitable tissues at a cellular scale. After setting the related systems of partial differential equations equipped with proper boundary conditions, we provide its finite element discretization and focus on the resulting large linear systems. We first give a relatively complete spectral analysis using tools from the theory of Generalized Locally Toeplitz matrix sequences. The obtained spectral information is used for designing appropriate preconditioned Krylov solvers. Through numerical experiments, we show that the presented solution strategy is robust w.r.t. problem and discretization parameters, efficient and scalable.

BACKGROUND: Brugada syndrome is associated with loss-of-function SCN5A variants, yet these account for only ≈20% of cases. A recent genome-wide association study identified a novel locus within MAPRE2, which encodes EB2 (microtubule end-binding protein 2), implicating microtubule involvement in Brugada syndrome. METHODS: A mapre2 knockout zebrafish model was generated using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat–associated protein 9) and validated by Western blot. Larval hearts at 5 days post-fertilization were isolated for voltage mapping and immunocytochemistry. Adult fish hearts were used for ECG, patch clamping, and immunocytochemistry. Morpholinos were injected into embryos at 1-cell stage for knockdown experiments. A transgenic zebrafish line with cdh2 tandem fluorescent timer was used to study adherens junctions. Microtubule plus-end tracking and patch clamping were performed in human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) with MAPRE2 knockdown and knockout, respectively. RESULTS: Voltage mapping of mapre2 knockout hearts showed a decrease in ventricular maximum upstroke velocity of the action potential and conduction velocity, suggesting loss of cardiac voltage-gated sodium channel function. ECG showed QRS prolongation in adult knockout fish, and patch clamping showed decreased sodium current density in knockout ventricular myocytes and arrhythmias in knockout iPSC-CMs. Confocal imaging showed disorganized adherens junctions and mislocalization of mature Ncad (N-cadherin) with mapre2 loss of function, associated with a decrease of detyrosinated tubulin. MAPRE2 knockdown in iPSC-CMs led to an increase in microtubule growth velocity and distance, indicating changes in microtubule dynamics. Finally, knockdown of ttl encoding tubulin tyrosine ligase in mapre2 knockout larvae rescued tubulin detyrosination and ventricular

Neuroimmune signals within the brain have a dual role in modulating neurophysiology both at baseline and in response to injury and infection. The primary focus of existing literature is on how inflammatory cascades affect network excitability following injury or in disease states. In these studies, we focus on the innate immune receptor, Toll-Like Receptor 4 (TLR4), and identify its novel neurophysiological roles in regulating hippocampal dentate excitatory and inhibitory networks under basal conditions and after fluid percussion injury (FPI) which impact working memory and behavior. Using CLI-095, a specific TLR4 antagonist, and a combination of local field potential recordings in the presence of glial metabolic inhibitors and whole cell voltage clamp recordings, we demonstrate a constitutive role of TLR4 in the uninjured dentate gyrus. This basal TLR4 signaling is absent in the presence of glial metabolic inhibitors and selectively modulates granule cell GABAergic inhibitory currents. In uninjured mice, blocking TLR4 decreased input driven evoked inhibitory post synaptic currents (eIPSCs) and impaired both working memory function in a Morris Water Maze task and spatial pattern separation in a Novel Object Location Task. In contrast, glial signaling is not required for TLR4 modulation of dentate excitability after brain injury. Specifically, neuronal expression of TLR4 enhances excitatory calcium permeable AMPA currents and reduces inhibitory GABA currents one week after brain injury. FPI resulted in early hilar somatostatin (SST) neuron loss, decreased eIPSC amplitude, and impaired working memory and spatial pattern separation at one week. Consistent with our finding that TLR4 is expressed on SST, but not parvalbumin interneurons, cell-type specific deletion of TLR4 in SST neurons identified that TLR4 expression in SST neurons as crucial for the injury-induced decrease in dentate eIPSC and behavioral deficits. These results indicate a differential role for cell-ty

BACKGROUND: Movement and tone disorders in children and young adults with cerebral palsy are a great source of disability. Deep brain stimulation (DBS) of basal ganglia targets has a major role in the treatment of isolated dystonias, but its efficacy in dyskinetic cerebral palsy (DCP) is lower, due to structural basal ganglia and thalamic damage and lack of improvement of comorbid choreoathetosis and spasticity. The cerebellum is an attractive target for DBS in DCP since it is frequently spared from hypoxic ischemic damage, it has a significant role in dystonia network models, and small studies have shown promise of dentate stimulation in improving CP-related movement and tone disorders. METHODS: Ten children and young adults with DCP and disabling movement disorders with or without spasticity will undergo bilateral DBS in the dorsal dentate nucleus, with the most distal contact ending in the superior cerebellar peduncle. We will implant Medtronic Percept, a bidirectional neurostimulator that can sense and store brain activity and deliver DBS therapy. The efficacy of cerebellar DBS in improving quality of life and motor outcomes will be tested by a series of N-of-1 clinical trials. Each N-of-1 trial will consist of three blocks, each consisting of one month of effective stimulation and one month of sham stimulation in a random order with weekly motor and quality of life scales as primary and secondary outcomes. In addition, we will characterize abnormal patterns of cerebellar oscillatory activity measured by local field potentials from the intracranial electrodes related to clinical assessments and wearable monitors. Pre- and 12-month postoperative volumetric structural and functional MRI and diffusion tensor imaging will be used to identify candidate imaging markers of baseline disease severity and response to DBS. DISCUSSION: Our goal is to test a cerebellar neuromodulation therapy that produces meaningful changes in function and well-being for people with CP, obt

Prediction plays a critical role in comprehending human language. Many theoretical and computational models have attempted to characterize how we use context to facilitate language processing in noisy environments either with or without relying on predictive processing. Despite these attempts, we do not yet have a complete understanding of the role of prediction in language processing. Predictive coding models have recently gained popularity as potential architectures for the role of prediction during language comprehension. These models suggest that predictions about bottom-up inputs are continuously generated from higher cortical levels to lower levels in a hierarchical manner – i.e., a particular level generates predictions about the next lower level. As bottom-up input is encounter by each level of processing, prediction error is computed by comparing the input with the top-down prediction. The goal of this dissertation was to assess whether predictive coding models can account for the time course of information retrieval during predictive language processing. Specifically, the studies described examine the time course of pre-activations of lexical and sub-lexical features in both monolinguals and bilinguals using a combination of decoding electroencephalogram (EEG) with machine-learning classifiers and mass univariate event-related potential analysis. Chapter 1 describes an experiment that compared three frequently used models for signal classification – support vector machines (SVM), linear discriminant analysis (LDA), and random forest (RF) to determine which is best-suited for analyzing word pair prediction paradigms. Results showed that SVM was the best performing classifier of the three within two data sets from separate visual word priming paradigms. Chapter 2 describes an experiment which used EEG decoding with SVM classifiers and mass univariate ERP analyses to identify the time course of information retrieval prior to the onset of accurately predicted

We present an unusual case of alternating left anterior and left posterior fascicular block. Given the known risk for progression to complete atrioventricular block with alternating right bundle and left bundle branch block, we performed an electrophysiological study. Findings were consistent with infra-Hisian disease, and the patient underwent pacemaker implantation.

MicroRNAs (miRs) are short, evolutionarily conserved noncoding RNAs that canonically downregulate expression of target genes. The miR family composed of miR-204 and miR-211 is among the most highly expressed miRs in the retinal pigment epithelium (RPE) in both mouse and human and also retains high sequence identity. To assess the role of this miR family in the developed mouse eye, we generated two floxed conditional KO mouse lines crossed to the RPE65-ERT2-Cre driver mouse line to perform an RPE-specific conditional KO of this miR family in adult mice. After Cre-mediated deletion, we observed retinal structural changes by optical coherence tomography; dysfunction and loss of photoreceptors by retinal imaging; and retinal inflammation marked by subretinal infiltration of immune cells by imaging and immunostaining. Single-cell RNA sequencing of diseased RPE and retinas showed potential miR-regulated target genes, as well as changes in noncoding RNAs in the RPE, rod photoreceptors, and Müller glia. This work thus highlights the role of miR-204 and miR-211 in maintaining RPE function and how the loss of miRs in the RPE exerts effects on the neural retina, leading to inflammation and retinal degeneration.

The complexity of information processing in the brain requires the development of technologies that can provide spatial and temporal resolution by means of dense electrode arrays paired with high-channel-count signal acquisition electronics. In this work, we present an ultra-low noise modular 512-channel neural recording circuit that is scalable to up to 4096 simultaneously recording channels. The neural readout application-specific integrated circuit (ASIC) uses a dense 8.2 mm × 6.8 mm 2D layout to enable high-channel count, creating an ultra-light 350 mg flexible module. The module can be deployed on headstages for small animals like rodents and songbirds, and it can be integrated with a variety of electrode arrays. The chip was fabricated in a TSMC 0.18 µm 1.8 V CMOS technology and dissipates a total of 125 mW. Each DC-coupled channel features a gain and bandwidth programmable analog front-end along with 14 b analog-to-digital conversion at speeds up to 30 kS/s. Additionally, each front-end includes programmable electrode plating and electrode impedance measurement capability. We present both standalone and in vivo measurements results, demonstrating the readout of spikes and field potentials that are modulated by a sensory input.

Analysis of mitochondrial structure and function is increasingly being recognized as central to understanding human health and disease. Mitochondria ultrastructure has been extensively characterized with transmission electron microscopy (TEM) and CryoTEM in fixed cells. Yet mitochondria within tissue cells can have markedly different structures and functions. Only through imaging functional, intact mitochondria can one ascertain information about the electrophysiology of the organelle. Hence, there is a critical need to be able to characterize the structure and function of the individual isolated mitochondrion.Our work aims to delve into procedures for characterizing the mitochondrial structure and function of isolated, functional mitochondria using super-resolution microscopy. This revealed that we can use super-resolution quantification of mitochondrial membrane potential using lipophilic cationic dye fluorescence to characterize the respiratory function of individual isolated, functional mitochondria in a way not possible in whole cells, potentially permitting elucidation of differences between individual mitochondria. Finally, by careful analysis of structure dyes and voltage dyes (lipophilic cations), we demonstrate that most of the fluorescent signal seen from voltage dyes is due to membrane-bound dyes, and develop a model for the membrane potential dependence of the fluorescence contrast for the case of super-resolution imaging, and how it relates to membrane potential. This quantitative voltage-dependent membrane binding model explains why super-resolution images of lipophilic cationic dyes show strong intensity near the cristae and not in the matrix. This model enables quantitative imaging of super-resolution voltages inside functional, intact mitochondria with super-resolution.

Studies have demonstrated alcohol-related deficits in LTP associated with histaminergic and glutamatergic impairments. The histaminergic H3R inverse agonist ABT-239 has shown promise in reversing these deficits. The present study focuses on another H3R inverse agonist, SAR-152594, and its impact on LTP deficits following moderate PAE. The findings reveal that systemic administration of 1 mg/kg of SAR-152594 reverses deficits in potentiation fEPSPs in adult male rats exposed to moderate PAE. Time-frequency analyses of evoked responses indicate PAE-related reductions in power during the fEPSP and increased power during later components of evoked responses, both reversed by SAR-152594. These results provide further evidence that H3R inverse agonism is a potential therapeutic strategy to address deficits in synaptic plasticity associated with PAE. This study also investigated extracellular glutamate levels with a glutamate biosensor in vivo. Following HFS stimulation, the results show differences in fractional change in amplitude of the evoked responses in PAE animals when compared with controls. These results support the alcohol-related deficits in LTP and support the hypothesis that there is a disruption in glutamate release from the presynaptic terminal.

This thesis focused on two brain areas in the visual system of the mouse: superior colliculus (SC) and the primary visual cortex (V1). Both these areas belong to the early visual system and encode features like luminance contrast and orientation. The ability to encode such simple features is highly relevant: first of all, this information is necessary to compute representations of more complex visual features. Secondly, even simple features can trigger behaviours. In this thesis, we aimed to answer some fundamental questions regarding feature integration in the early visual system. Figure-ground modulation is the phenomenon where visual neurons respond more strongly to visual patches that have a different orientation than their surround. Although SC shows figure-ground modulation, its role in object detection is not quite clear. In Chapter 2, we investigated the role of the superior colliculus in object detection in mice. When we inhibited sSC by activating its inhibitory neurons, the object detection performance of mice was decreased, indicating a causal role for the sSC. Electrophysiological recordings of sSC during task performance showed 1) an increased firing rate for contrast- and orientation-defined figures; 2) statistically significant decoding of the orientation- and phase-defined stimulus from the population firing rates; 3) higher discriminability of the neural code during correct vs. incorrect trials. Superior colliculus is also known to be involved in visually-guided behaviours like freezing and fleeing. The brain mechanisms underlying habituation of visually-guided behaviours are still under investigation. In Chapter 3, we investigated the responses of SC upon repeated exposure to a moving dot inside and outside of the receptive field of the recorded neurons. We discovered a novel type of feature integration in sSC, where neurons show adaptation to the out-of-RF dots. When we inhibited the wide-field neurons in SC during the adaptation protocol, the ad

2023 Medical Technologies Congress, TIPTEKNO 2023 -- 10 November 2023 through 12 November 2023 -- 195703, Panic Disorder (PD) is a debilitating condition marked by sudden, intense fear episodes with physical symptoms. Swift and accurate PD detection is crucial for effective intervention. This study aimed to propose an optimal combination of spectral features of the Alpha band to detect PD. For this purpose, 21 PD-diagnosed individuals and 26 healthy controls attended a 5-minute eyes-closed resting state Electroencephalography (EEG) recording session. Welch method was applied to calculate the power spectral density of EEG signals and then the sum, average, maximum, relative power of alpha band, and individual alpha frequency (IAF) were extracted. Relief and nearest component analysis (NCA) methods were performed to select highly relevant features. The maximum average accuracy was reached when commonly selected features between two selection methods were used as inputs of classifiers. Adaboost classifier reached the highest average accuracy with $89.03 ±6.73% rate. © 2023 IEEE.

2023 Medical Technologies Congress, TIPTEKNO 2023 -- 10 November 2023 through 12 November 2023 -- 195703, Panic Disorder (PD) is a debilitating condition marked by sudden, intense fear episodes with physical symptoms. Swift and accurate PD detection is crucial for effective intervention. This study aimed to propose an optimal combination of spectral features of the Alpha band to detect PD. For this purpose, 21 PD-diagnosed individuals and 26 healthy controls attended a 5-minute eyes-closed resting state Electroencephalography (EEG) recording session. Welch method was applied to calculate the power spectral density of EEG signals and then the sum, average, maximum, relative power of alpha band, and individual alpha frequency (IAF) were extracted. Relief and nearest component analysis (NCA) methods were performed to select highly relevant features. The maximum average accuracy was reached when commonly selected features between two selection methods were used as inputs of classifiers. Adaboost classifier reached the highest average accuracy with $89.03 ±6.73% rate. © 2023 IEEE.

This thesis primarily focuses on investigating atrial remodeling using cardiovascular MRI (CMR) in patients scheduled for an atrial fibrillation (AF) ablation procedure. Atrial remodeling refers to changes in atrial function, shape, and structure, which contribute to the development and perpetuation of AF. Our studies examined various imaging markers of atrial remodeling, and their association with the success of the ablation procedure. One of the most promising novel CMR-based markers is the non-invasive visualization and quantification of atrial fibrosis, as fibrotic tissue transformation is considered to be directly related to the mechanisms governing the development of AF. We performed a critical evaluation of this CMR-based atrial fibrosis detection. Furthermore, we explored the clinical feasibility of interventional CMR (iCMR) for performing flutter ablation procedures.

Orphan solute carrier (SLC) represents a group of membrane transporters whose exact functions and substrate specificities are not known. Elucidating the function and regulation of orphan SLC transporters is not only crucial for advancing our knowledge of cellular and molecular biology but can potentially lead to the development of new therapeutic strategies. Here, we provide evidence for the biological function of a ubiquitous orphan lysosomal SLC, the Major Facilitator Superfamily Domain-containing Protein 1 (MFSD1), which has remained phylogenetically unassigned. Targeted metabolomics revealed that dipeptides containing either lysine or arginine residues accumulate in lysosomes of cells lacking MFSD1. Whole-cell patch-clamp electrophysiological recordings of HEK293-cells expressing MFSD1 on the cell surface displayed transport affinities for positively charged dipeptides in the lower mM range, while dipeptides that carry a negative net charge were not transported. This was also true for single amino acids and tripeptides, which MFSD1 failed to transport. Our results identify MFSD1 as a highly selective lysosomal lysine/arginine/histidine-containing dipeptide exporter, which functions as a uniporter.

Background: Deep brain stimulation (DBS) is a highly efficient, evidence-based therapy to alleviate symptoms and improve quality of life in movement disorders such as Parkinson’s disease, essential tremor, and dystonia, which is also being applied in several psychiatric disorders, such as obsessive-compulsive disorder and depression, when they are otherwise resistant to therapy. Summary: At present, DBS is clinically applied in the so-called open-loop approach, with fixed stimulation parameters, irrespective of the patients’ clinical state(s). This approach ignores the brain states or feedback from the central nervous system or peripheral recordings, thus potentially limiting its efficacy and inducing side effects by stimulation of the targeted networks below or above the therapeutic level. Key Messages: The currently emerging closed-loop (CL) approaches are designed to adapt stimulation parameters to the electrophysiological surrogates of disease symptoms and states. CL-DBS paves the way for adaptive personalized DBS protocols. This review elaborates on the perspectives of the CL technology and discusses its opportunities as well as its potential pitfalls for both clinical and research use in neuropsychiatric disorders.

This thesis delves into the complex architecture of dynamic sensory information processing in the neocortex. Specifically, it asks how primary sensory cortical regions are influenced by local and widespread cortical state changes. Central to this question is the exploration of two historically opposing information processing frameworks emphasizing a local and global information processing principle respectively, i.e. the principle that certain areas of the brain are dedicated to specific functions and the principle that individual functions are distributed over a large network.Results were obtained through in vivo extracellular recordings in anesthetized rats while high-resolution spatiotemporal visual, tactile, and visuo-tactile input patterns were provided. Paper I showed that color input evokes rapid local state changes in primary visual cortex (V1) which result in unique temporal response patterns among neurons recorded within the same vertical axis, thereby challenging the historically popular idea of columnar organization. Paper II used field potential recordings as estimates of changes in the widespread and local cortical state and showed a significant differential effect on individual neuronal responses to haptic input in the primary somatosensory cortex (S1). In paper III, spontaneous activity among S1 neuron populations was defined as a high-dimensional state space that was found to shift in different ways when providing tactile, visual, and visuo-tactile input, questioning the idea of unimodal cortical regions. Together, the results suggest that both local and widespread internal brain states can impact processing of sensory information in primary sensory regions. It is concluded that the functional localization model cannot fully explain what we and other researchers have observed about cortical sensory information processing and that brain state dependence on the neuronal representation of sensory input is more likely a result of coordinated activity ac

Since birth, we learn about the perceptual and social world through our senses. Learning to appropriately bind multisensory information is key to effectively interact with our surroundings. In this chapter, we will review the behavioral, computational, and neurophysiological methods used to assess multisensory processing in healthy adult individuals. In the first part, we will provide an overview of fundamental principles governing the activity of multisensory neurons in the animal brain since these principles still provide an influential framework for the investigation of multisensory processing in humans too. In the second part, we will present a series of behavioral paradigms that have been adopted in the past 20 years to assess multisensory processing, particularly focusing on the difference between paradigms assessing multisensory integration and paradigms assessing crossmodal interactions, in which stimulation of one sensory system affects the experience in a different sense, typically leading to illusory percepts. The last part will provide a critical overview of electrophysiological and neuroimaging approaches to measure multisensory interactions in the human brain.

AMPA-type ionotropic glutamate receptors (AMPARs) are central to various neurological processes, including memory and learning. They assemble as homo- or heterotetramers of GluA1, GluA2, GluA3, and GluA4 subunits, each consisting of an N-terminal domain (NTD), a ligand-binding domain, a transmembrane domain, and a C-terminal domain. While AMPAR gating is primarily controlled by reconfiguration in the ligand-binding domain layer, our study focuses on the NTDs, which also influence gating, yet the underlying mechanism remains enigmatic. In this investigation, we employ molecular dynamics simulations to evaluate the NTD interface strength in GluA1, GluA2, and NTD mutants GluA2-H229N and GluA1-N222H. Our findings reveal that GluA1 has a significantly weaker NTD interface than GluA2. The NTD interface of GluA2 can be weakened by a single point mutation in the NTD dimer-of-dimer interface, namely H229N, which renders GluA2 more GluA1-like. Electrophysiology recordings demonstrate that this mutation also leads to slower recovery from desensitization. Moreover, we observe that lowering the pH induces more splayed NTD states and enhances desensitization in GluA2. We hypothesized that H229 was responsible for this pH sensitivity; however, GluA2-H229N was also affected by pH, meaning that H229 is not solely responsible and that protons exert their effect across multiple domains of the AMPAR. In summary, our work unveils an allosteric connection between the NTD interface strength and AMPAR desensitization., AMPA-type ionotropic glutamate receptors (AMPARs) are central to various neurological processes, including memory and learning. They assemble as homo- or heterotetramers of GluA1, GluA2, GluA3, and GluA4 subunits, each consisting of an N-terminal domain (NTD), a ligand-binding domain, a transmembrane domain, and a C-terminal domain. While AMPAR gating is primarily controlled by reconfiguration in the ligand-binding domain layer, our study focuses on the NTDs, which also influence gating, yet the underlying mechanism remains enigmatic. In this investigation, we employ molecular dynamics simulations to evaluate the NTD interface strength in GluA1, GluA2, and NTD mutants GluA2-H229N and GluA1-N222H. Our findings reveal that GluA1 has a significantly weaker NTD interface than GluA2. The NTD interface of GluA2 can be weakened by a single point mutation in the NTD dimer-of-dimer interface, namely H229N, which renders GluA2 more GluA1-like. Electrophysiology recordings demonstrate that this mutation also leads to slower recovery from desensitization. Moreover, we observe that lowering the pH induces more splayed NTD states and enhances desensitization in GluA2. We hypothesized that H229 was responsible for this pH sensitivity; however, GluA2-H229N was also affected by pH, meaning that H229 is not solely responsible and that protons exert their effect across multiple domains of the AMPAR. In summary, our work unveils an allosteric connection between the NTD interface strength and AMPAR desensitization.

Background: Focal pulsed field ablation (FPFA) is a novel and promising method of cardiac ablation. The aim of this study was to report the feasibility, short-term safety, and procedural findings for a broad spectrum of ablated atrial arrhythmias. Methods: Patients (n = 51) scheduled for ablation of atrial arrhythmias were prospectively included and underwent FPFA using the Galvanize CENTAURI generator with energy delivery through commercially available ablation catheters with ultrahigh-density (UHDx) 3D electroanatomic voltage/local activation time map evaluations. Workflow, procedural data, and peri-procedural technical errors and complications are described. Results: Planned ablation strategy was achieved with FPFA-only in 48/51 (94%) of the cases. Ablation strategy was first-time pulmonary vein isolation (PVI) in 17/51 (36%), repeat ablation in 18/51 (38%), PVI + in 13/51 (28%), and cavotricuspid isthmus block (CTI)-only in 3/51 (6%). The mean procedure time was 104 ± 31 min (first-time PVI), 114 ± 26 min (repeat procedure), 152 ± 36 min (PVI +), and 62 ± 17 min (CTI). Mean UHDx mapping time to assess lesion formation and block after ablation was 7 ± 4 min with 5485 ± 4809 points. First pass acute (linear) isolation with bidirectional block for anatomical lesion sets was 120/124 (97%) for all PVs, 17/17 (100%) for (any) isthmus, and 14/17 (82%) for left atrium posterior wall (LAPW). We observed several time-consuming integration errors with the used ablation system (mean 3.4 ± 3.7 errors/procedure), one transient inferior ST elevation when ablating CTI resolved by intravenous nitroglycerine and one transient AV block requiring temporary pacing for > 24 h. Conclusions: FPFA was a highly versatile method to treat atrial arrhythmias with high first-pass efficiency. UHDx revealed acute homogenous low-voltage lesions in ablated areas. More data is needed to establish lesion durability and limitations of FPFA.

AMPA-type ionotropic glutamate receptors (AMPARs) are central to various neurological processes, including memory and learning. They assemble as homo- or heterotetramers of GluA1, GluA2, GluA3, and GluA4 subunits, each consisting of an N-terminal domain (NTD), a ligand-binding domain, a transmembrane domain, and a C-terminal domain. While AMPAR gating is primarily controlled by reconfiguration in the ligand-binding domain layer, our study focuses on the NTDs, which also influence gating, yet the underlying mechanism remains enigmatic. In this investigation, we employ molecular dynamics simulations to evaluate the NTD interface strength in GluA1, GluA2, and NTD mutants GluA2-H229N and GluA1-N222H. Our findings reveal that GluA1 has a significantly weaker NTD interface than GluA2. The NTD interface of GluA2 can be weakened by a single point mutation in the NTD dimer-of-dimer interface, namely H229N, which renders GluA2 more GluA1-like. Electrophysiology recordings demonstrate that this mutation also leads to slower recovery from desensitization. Moreover, we observe that lowering the pH induces more splayed NTD states and enhances desensitization in GluA2. We hypothesized that H229 was responsible for this pH sensitivity; however, GluA2-H229N was also affected by pH, meaning that H229 is not solely responsible and that protons exert their effect across multiple domains of the AMPAR. In summary, our work unveils an allosteric connection between the NTD interface strength and AMPAR desensitization., AMPA-type ionotropic glutamate receptors (AMPARs) are central to various neurological processes, including memory and learning. They assemble as homo- or heterotetramers of GluA1, GluA2, GluA3, and GluA4 subunits, each consisting of an N-terminal domain (NTD), a ligand-binding domain, a transmembrane domain, and a C-terminal domain. While AMPAR gating is primarily controlled by reconfiguration in the ligand-binding domain layer, our study focuses on the NTDs, which also influence gating, yet the underlying mechanism remains enigmatic. In this investigation, we employ molecular dynamics simulations to evaluate the NTD interface strength in GluA1, GluA2, and NTD mutants GluA2-H229N and GluA1-N222H. Our findings reveal that GluA1 has a significantly weaker NTD interface than GluA2. The NTD interface of GluA2 can be weakened by a single point mutation in the NTD dimer-of-dimer interface, namely H229N, which renders GluA2 more GluA1-like. Electrophysiology recordings demonstrate that this mutation also leads to slower recovery from desensitization. Moreover, we observe that lowering the pH induces more splayed NTD states and enhances desensitization in GluA2. We hypothesized that H229 was responsible for this pH sensitivity; however, GluA2-H229N was also affected by pH, meaning that H229 is not solely responsible and that protons exert their effect across multiple domains of the AMPAR. In summary, our work unveils an allosteric connection between the NTD interface strength and AMPAR desensitization.

In this work, we are interested in solving large linear systems stemming from the extra-membrane-intra model, which is employed for simulating excitable tissues at a cellular scale. After setting the related systems of partial differential equations equipped with proper boundary conditions, we provide its finite element discretization and focus on the resulting large linear systems. We first give a relatively complete spectral analysis using tools from the theory of Generalized Locally Toeplitz matrix sequences. The obtained spectral information is used for designing appropriate preconditioned Krylov solvers. Through numerical experiments, we show that the presented solution strategy is robust w.r.t. problem and discretization parameters, efficient and scalable.

Background: Focal pulsed field ablation (FPFA) is a novel and promising method of cardiac ablation. The aim of this study was to report the feasibility, short-term safety, and procedural findings for a broad spectrum of ablated atrial arrhythmias. Methods: Patients (n = 51) scheduled for ablation of atrial arrhythmias were prospectively included and underwent FPFA using the Galvanize CENTAURI generator with energy delivery through commercially available ablation catheters with ultrahigh-density (UHDx) 3D electroanatomic voltage/local activation time map evaluations. Workflow, procedural data, and peri-procedural technical errors and complications are described. Results: Planned ablation strategy was achieved with FPFA-only in 48/51 (94%) of the cases. Ablation strategy was first-time pulmonary vein isolation (PVI) in 17/51 (36%), repeat ablation in 18/51 (38%), PVI + in 13/51 (28%), and cavotricuspid isthmus block (CTI)-only in 3/51 (6%). The mean procedure time was 104 ± 31 min (first-time PVI), 114 ± 26 min (repeat procedure), 152 ± 36 min (PVI +), and 62 ± 17 min (CTI). Mean UHDx mapping time to assess lesion formation and block after ablation was 7 ± 4 min with 5485 ± 4809 points. First pass acute (linear) isolation with bidirectional block for anatomical lesion sets was 120/124 (97%) for all PVs, 17/17 (100%) for (any) isthmus, and 14/17 (82%) for left atrium posterior wall (LAPW). We observed several time-consuming integration errors with the used ablation system (mean 3.4 ± 3.7 errors/procedure), one transient inferior ST elevation when ablating CTI resolved by intravenous nitroglycerine and one transient AV block requiring temporary pacing for > 24 h. Conclusions: FPFA was a highly versatile method to treat atrial arrhythmias with high first-pass efficiency. UHDx revealed acute homogenous low-voltage lesions in ablated areas. More data is needed to establish lesion durability and limitations of FPFA.

Background: The crista terminalis (CT) has been identified as the posterior boundary of typical atrial flutter (AFL) in the lateral wall (LW) of the right atrium (RA). To study conduction properties across the CT, rapid pacing was performed at both sides of the CT after bidirectional conduction block was achieved in the cavotricuspid isthmus by radiofrequency catheter ablation. Methods and results: In 22 patients (aged 61+/-7 years) with AFL (cycle length, 234+/-23 ms), CT was identified during AFL by double electrograms recorded between the LW and posterior wall (PW). After the ablation procedure, decremental pacing trains were delivered from 600 ms to 2-to-1 local capture at the LW and PW or coronary sinus ostium (CSO). At least 5 bipolar electrograms were recorded along the CT from the high to the low atrium next to the inferior vena cava. No double electrograms were recorded during sinus rhythm in that area. Complete transversal conduction block all along the CT (detected by the appearance of double electrograms at all recording sites and craniocaudal activation sequence on the side opposite to the pacing site) was observed in all patients during pacing from the PW or CSO (cycle length, 334+/-136 ms), but it was fixed in only 4 patients. During pacing from the LW, complete block appeared at a shorter pacing cycle length (281+/-125 ms; P<0.01) and was fixed in 2 patients. In 3 patients, complete block was not achieved. Conclusions: These data suggest the presence of rate-dependent transversal conduction block at the crista terminalis in patients with typical AFL. Block is usually observed at longer pacing cycle lengths with PW pacing than with LW pacing. This difference may be a critical determinant of the counterclockwise rotation of typical AFL, Depto. de Medicina, Fac. de Medicina, TRUE, pub

Background: RS morphology of the unipolar electrogram is associated with propagation of the wave front through the exploring electrode, whereas positive uniphasic (R) unipolar electrograms are characteristic of the end of activation. Methods and results: Unipolar electrograms were recorded in 45 consecutive patients with atrial flutter who were undergoing radiofrequency ablation (RFA). Bidirectional cavotricuspid isthmus (CTI) block was achieved in 44 patients. The unipolar electrogram obtained before RFA at the low anterolateral right atrium during coronary sinus pacing changed from RS, rS, or QS to R or Rs in all patients after clockwise CTI block was obtained. The morphology of unipolar electrograms recorded close to the coronary sinus during pacing from the low anterolateral right atrium changed from RS or rS to R or Rs in all but 4 patients after counterclockwise CTI block. In the patient in whom CTI block was not achieved, the RS morphology of the unipolar electrogram remained unchanged. In 18 patients, the results of the RFA were assessed with only the unipolar electrogram. The unipolar electrogram correctly predicted 100% and 89% of the cases of clockwise and counterclockwise CTI block, respectively. Conclusions: The creation of CTI block is associated with an easily detectable loss of negative components and development of an R or Rs pattern of the unipolar electrogram recorded close to the ablation line while pacing at the opposite side of the CTI., Depto. de Medicina, Fac. de Medicina, TRUE, pub

Objective: Microfluidic devices interfaced with microelectrode arrays have in recent years emerged as powerful platforms for studying and manipulating in vitro neuronal networks at the micro- and mesoscale. By segregating neuronal populations using microchannels only permissible to axons, neuronal networks can be designed to mimic the highly organized, modular topology of neuronal assemblies in the brain. However, little is known about how the underlying topological features of such engineered neuronal networks contribute to their functional profile. To start addressing this question, a key parameter is control of afferent or efferent connectivity within the network. Approach: In this study, we show that a microfluidic device featuring axon guiding channels with geometrical constraints inspired by a Tesla valve effectively promotes unidirectional axonal outgrowth between neuronal nodes, thereby enabling us to control afferent connectivity. Main results: Our results moreover indicate that these networks exhibit a more efficient network organization with higher modularity compared to single nodal controls. We verified this by applying designer viral tools to fluorescently label the neurons to visualize the structure of the networks, combined with extracellular electrophysiological recordings using embedded nanoporous microelectrodes to study the functional dynamics of these networks during maturation. We furthermore show that electrical stimulations of the networks induce signals selectively transmitted in a feedforward fashion between the neuronal populations. Significance: A key advantage with our microdevice is the ability to longitudinally study and manipulate both the structure and function of neuronal networks with high accuracy. This model system has the potential to provide novel insights into the development, topological organization, and neuroplasticity mechanisms of neuronal assemblies at the micro- and mesoscale in healthy and perturbed conditions.

BACKGROUND: Trace amine-associated receptor-1 (TAAR1) agonists have been proposed as potential antipsychotics, with ulotaront and ralmitaront having reached clinical trials. While ulotaront demonstrated efficacy in a recent Phase II trial, a corresponding study studies of ralmitaront failed to show efficacy as a monotherapy or as an adjunct to atypical antipsychotics. In addition to TAAR1 agonism, ulotaront is a partial agonist at the serotonin 1A receptor (5-HT1AR). However, little is known about ralmitaront. METHODS: We compared ulotaront and ralmitaront at TAAR1, 5-HT1AR, and dopamine D2 using luciferase complementation-based G protein recruitment, cAMP accumulation, and G protein-coupled inward rectifier potassium channel activation assays. RESULTS: Ralmitaront showed lower efficacy at TAAR1 in G protein recruitment, cAMP accumulation, and GIRK activation assays. Moreover, ralmitaront lacked detectable activity at 5-HT1AR and dopamine D2. CONCLUSIONS: Compared with ulotaront, ralmitaront shows lower efficacy and slower kinetics at TAAR1 and lacks efficacy at 5-HT1AR. These data may be relevant to understanding differences in clinical profiles of these 2 compounds.

Objective: Microfluidic devices interfaced with microelectrode arrays have in recent years emerged as powerful platforms for studying and manipulating in vitro neuronal networks at the micro- and mesoscale. By segregating neuronal populations using microchannels only permissible to axons, neuronal networks can be designed to mimic the highly organized, modular topology of neuronal assemblies in the brain. However, little is known about how the underlying topological features of such engineered neuronal networks contribute to their functional profile. To start addressing this question, a key parameter is control of afferent or efferent connectivity within the network. Approach: In this study, we show that a microfluidic device featuring axon guiding channels with geometrical constraints inspired by a Tesla valve effectively promotes unidirectional axonal outgrowth between neuronal nodes, thereby enabling us to control afferent connectivity. Main results: Our results moreover indicate that these networks exhibit a more efficient network organization with higher modularity compared to single nodal controls. We verified this by applying designer viral tools to fluorescently label the neurons to visualize the structure of the networks, combined with extracellular electrophysiological recordings using embedded nanoporous microelectrodes to study the functional dynamics of these networks during maturation. We furthermore show that electrical stimulations of the networks induce signals selectively transmitted in a feedforward fashion between the neuronal populations. Significance: A key advantage with our microdevice is the ability to longitudinally study and manipulate both the structure and function of neuronal networks with high accuracy. This model system has the potential to provide novel insights into the development, topological organization, and neuroplasticity mechanisms of neuronal assemblies at the micro- and mesoscale in healthy and perturbed conditions.

Objective. This paper presents a novel domain adaptation (DA) framework to enhance the accuracy of electroencephalography (EEG)-based auditory attention classification, specifically for classifying the direction (left or right) of attended speech. The framework aims to improve the performances for subjects with initially low classification accuracy, overcoming challenges posed by instrumental and human factors. Limited dataset size, variations in EEG data quality due to factors such as noise, electrode misplacement or subjects, and the need for generalization across different trials, conditions and subjects necessitate the use of DA methods. By leveraging DA methods, the framework can learn from one EEG dataset and adapt to another, potentially resulting in more reliable and robust classification models. Approach. This paper focuses on investigating a DA method, based on parallel transport, for addressing the auditory attention classification problem. The EEG data utilized in this study originates from an experiment where subjects were instructed to selectively attend to one of the two spatially separated voices presented simultaneously. Main results. Significant improvement in classification accuracy was observed when poor data from one subject was transported to the domain of good data from different subjects, as compared to the baseline. The mean classification accuracy for subjects with poor data increased from 45.84% to 67.92%. Specifically, the highest achieved classification accuracy from one subject reached 83.33%, a substantial increase from the baseline accuracy of 43.33%. Significance. The findings of our study demonstrate the improved classification performances achieved through the implementation of DA methods. This brings us a step closer to leveraging EEG in neuro-steered hearing devices. © 2023 The Author(s). Published by IOP Publishing Ltd.

BACKGROUND: Trace amine-associated receptor-1 (TAAR1) agonists have been proposed as potential antipsychotics, with ulotaront and ralmitaront having reached clinical trials. While ulotaront demonstrated efficacy in a recent Phase II trial, a corresponding study studies of ralmitaront failed to show efficacy as a monotherapy or as an adjunct to atypical antipsychotics. In addition to TAAR1 agonism, ulotaront is a partial agonist at the serotonin 1A receptor (5-HT1AR). However, little is known about ralmitaront. METHODS: We compared ulotaront and ralmitaront at TAAR1, 5-HT1AR, and dopamine D2 using luciferase complementation-based G protein recruitment, cAMP accumulation, and G protein-coupled inward rectifier potassium channel activation assays. RESULTS: Ralmitaront showed lower efficacy at TAAR1 in G protein recruitment, cAMP accumulation, and GIRK activation assays. Moreover, ralmitaront lacked detectable activity at 5-HT1AR and dopamine D2. CONCLUSIONS: Compared with ulotaront, ralmitaront shows lower efficacy and slower kinetics at TAAR1 and lacks efficacy at 5-HT1AR. These data may be relevant to understanding differences in clinical profiles of these 2 compounds.

Objective. This paper presents a novel domain adaptation (DA) framework to enhance the accuracy of electroencephalography (EEG)-based auditory attention classification, specifically for classifying the direction (left or right) of attended speech. The framework aims to improve the performances for subjects with initially low classification accuracy, overcoming challenges posed by instrumental and human factors. Limited dataset size, variations in EEG data quality due to factors such as noise, electrode misplacement or subjects, and the need for generalization across different trials, conditions and subjects necessitate the use of DA methods. By leveraging DA methods, the framework can learn from one EEG dataset and adapt to another, potentially resulting in more reliable and robust classification models. Approach. This paper focuses on investigating a DA method, based on parallel transport, for addressing the auditory attention classification problem. The EEG data utilized in this study originates from an experiment where subjects were instructed to selectively attend to one of the two spatially separated voices presented simultaneously. Main results. Significant improvement in classification accuracy was observed when poor data from one subject was transported to the domain of good data from different subjects, as compared to the baseline. The mean classification accuracy for subjects with poor data increased from 45.84% to 67.92%. Specifically, the highest achieved classification accuracy from one subject reached 83.33%, a substantial increase from the baseline accuracy of 43.33%. Significance. The findings of our study demonstrate the improved classification performances achieved through the implementation of DA methods. This brings us a step closer to leveraging EEG in neuro-steered hearing devices. © 2023 The Author(s). Published by IOP Publishing Ltd.

Introduction. Health education in patients with implantable cardiac devices is key due to the elevated number of patients, the changes in their psychological and personal environment, and the complications derived from inadequate management. In 2018 nurses from the Arrhythmia unit of the Hospital implemented monthly health talks for this population. Objectives. The aim was to analyze the sociodemographic characteristics, attendance rate and level of satisfaction with the lectures of the patients with the Health Education program and the educational value they provided.Methods. Observational cross-sectional and retrospective study describing the characteristics of patients with implantable cardiac devices who attended health talks imparted by nurses of this Unit.Results. Mean age was 72.97 years for the total population and 68.69 years for the participants. The attendance rate was 35% of all patients, 93% of whom were accompanied by a partner/family member, and 58% of patients lived near the hospital. Participants rated the satisfaction of the educational talks (content, knowledge, and organization) as «strongly agree» in a Likert-scale questionnaire and proposed future topics..Conclusions. The majority underwent a first cardiac device implantation, resided near the hospital (<10 km), and were pensioners/retired. They attended the talks accompanied by a partner and via a private vehicle. Questionnaires revealed a high level of patient satisfaction with the project. They proposed topics for future talks regarding medication, exercise, diet, and psychological suppor, Introducción. La educación sanitaria en pacientes portadores de dispositivos cardiacos implantables es clave debido al elevado número de pacientes, los cambios en su entorno psicológico y personal y las complicaciones derivadas de un manejo inadecuado. En 2018 enfermeras de la Unidad de Arritmias implantaron charlas mensuales de salud a esta población.Objetivos. Analizar las características sociodemográficas, tasa de asistencia y nivel de satisfacción de los pacientes con el programa de Educación para la Salud y el valor educativo que aportaron.Metodología. Estudio observacional transversal y retrospectivo que describe las características de los pacientes portadores de dispositivos cardiacos implantables que asistieron a charlas impartidas por enfermeras de dicha Unidad.Resultados. La edad media fue de 72,97 años para la población total y de 68,69 años para los participantes. La tasa de asistencia fue del 35% del total de pacientes, el 93% acudió acompañado de un familiar/acompañante, y el 58% residía cerca del hospital. Los participantes calificaron la satisfacción de las charlas educativas (contenido, conocimiento y organización) como «muy de acuerdo» en el cuestionario de escala Likert y propusieron temas futuros.Conclusiones. La mayoría se sometió a un primer implante de dispositivo cardiaco residía cerca del hospital (<10 km) y su situación laboral era pensionista/jubilado. Asistieron a las charlas acompañados y en vehículo particular. Los cuestionarios revelaron un alto nivel de satisfacción de los pacientes con el proyecto. Se propusieron temas para futuras ediciones sobre medicación, ejercicio, dieta y apoyo psicológico.

Alzheimers disease (AD) is a chronic neurodegenerative disorder characterized by memory loss and progressive cognitive impairments. In mouse models of AD pathology, studies have found neuronal and synaptic deficits in hippocampus, but less is known about changes in medial entorhinal cortex (MEC), which is the primary spatial input to the hippocampus and an early site of AD pathology. Here, we measured neuronal intrinsic excitability and synaptic activity in MEC layer II (MECII) stellate cells, MECII pyramidal cells, and MEC layer III (MECIII) excitatory neurons at 3 and 10 months of age in the 3xTg mouse model of AD pathology, using male and female mice. At 3 months of age, before the onset of memory impairments, we found early hyperexcitability in intrinsic properties of MECII stellate and pyramidal cells, but this was balanced by a relative reduction in synaptic excitation (E) compared with inhibition (I; E/I ratio), suggesting intact homeostatic mechanisms regulating MECII activity. Conversely, MECIII neurons had reduced intrinsic excitability at this early time point with no change in synaptic E/I ratio. By 10 months of age, after the onset of memory deficits, neuronal excitability of MECII pyramidal cells and MECIII excitatory neurons was largely normalized in 3xTg mice. However, MECII stellate cells remained hyperexcitable, and this was further exacerbated by an increased synaptic E/I ratio. This observed combination of increased intrinsic and synaptic hyperexcitability suggests a breakdown in homeostatic mechanisms specifically in MECII stellate cells at this postsymptomatic time point, which may contribute to the emergence of memory deficits in AD.SIGNIFICANCE STATEMENT AD causes cognitive deficits, but the specific neural circuits that are damaged to drive changes in memory remain unknown. Using a mouse model of AD pathology that expresses both amyloid and tau transgenes, we found that neurons in the MEC have altered excitability. Before the onset of memory

Cortical responses to visual stimuli are believed to rely on the geniculo-striate pathway. However, recent work has challenged this notion by showing that responses in the postrhinal cortex (POR), a visual cortical area, instead depend on the tecto-thalamic pathway, which conveys visual information to the cortex via the superior colliculus (SC). Does PORs SC-dependence point to a wider system of tecto-thalamic cortical visual areas? What information might this system extract from the visual world? We discovered multiple mouse cortical areas whose visual responses rely on SC, with the most lateral showing the strongest SC-dependence. This system is driven by a genetically defined cell type that connects the SC to the pulvinar thalamic nucleus. Finally, we show that SC-dependent cortices distinguish self-generated from externally generated visual motion. Hence, lateral visual areas comprise a system that relies on the tecto-thalamic pathway and contributes to processing visual motion as animals move through the environment.

AimsAtrial fibrillation (AF), the most prevalent clinical arrhythmia, is associated with atrial remodelling manifesting as acute and chronic alterations in expression, function, and regulation of atrial electrophysiological and Ca2+-handling processes. These AF-induced modifications crosstalk and propagate across spatial scales creating a complex pathophysiological network, which renders AF resistant to existing pharmacotherapies that predominantly target transmembrane ion channels. Developing innovative therapeutic strategies requires a systems approach to disentangle quantitatively the pro-arrhythmic contributions of individual AF-induced alterations.Methods and resultsHere, we built a novel computational framework for simulating electrophysiology and Ca2+-handling in human atrial cardiomyocytes and tissues, and their regulation by key upstream signalling pathways [i.e. protein kinase A (PKA), and Ca2+/calmodulin-dependent protein kinase II (CaMKII)] involved in AF-pathogenesis. Populations of atrial cardiomyocyte models were constructed to determine the influence of subcellular ionic processes, signalling components, and regulatory networks on atrial arrhythmogenesis. Our results reveal a novel synergistic crosstalk between PKA and CaMKII that promotes atrial cardiomyocyte electrical instability and arrhythmogenic triggered activity. Simulations of heterogeneous tissue demonstrate that this cellular triggered activity is further amplified by CaMKII- and PKA-dependent alterations of tissue properties, further exacerbating atrial arrhythmogenesis.ConclusionsOur analysis reveals potential mechanisms by which the stress-associated adaptive changes turn into maladaptive pro-arrhythmic triggers at the cellular and tissue levels and identifies potential anti-AF targets. Collectively, our integrative approach is powerful and instrumental to assemble and reconcile existing knowledge into a systems network for identifying novel anti-AF targets and innovative approaches mov

Background and Purpose: Cannabidiol (CBD) is used clinically as an anticonvulsant. Its precise mechanism of action has remained unclear. CBD was recently demonstrated to enhance the activity of the neuronal KV7.2/7.3 channel, which may be one important contributor to CBD anticonvulsant effect. Curiously, CBD inhibits the closely related cardiac KV7.1/KCNE1 channel. Whether and how CBD affects other KV7 subtypes remains uninvestigated and the CBD interaction sites mediating these diverse effects remain unknown. Experimental Approach: Here, we used electrophysiology, molecular dynamics simulations, molecular docking and site-directed mutagenesis to address these questions. Key Results: We found that CBD modulates the activity of all human KV7 subtypes and that the effects are subtype dependent. CBD enhanced the activity of KV7.2–7.5 subtypes, seen as a V50 shift towards more negative voltages or increased maximum conductance. In contrast, CBD inhibited the KV7.1 and KV7.1/KCNE1 channels, seen as a V50 shift towards more positive voltages and reduced conductance. In KV7.2 and KV7.4, we propose a CBD interaction site at the subunit interface in the pore domain that overlaps with the interaction site of other compounds, notably the anticonvulsant retigabine. However, CBD relies on other residues for its effects than the conserved tryptophan that is critical for retigabine effects. We propose a similar, though not identical CBD site in KV7.1, with a non-conserved phenylalanine being important. Conclusions and Implications: We identify novel targets of CBD, contributing to a better understanding of CBD clinical effects and provide mechanistic insights into how CBD modulates different KV7 subtypes., QC 20240625

Objective. This paper presents a novel domain adaptation (DA) framework to enhance the accuracy of electroencephalography (EEG)-based auditory attention classification, specifically for classifying the direction (left or right) of attended speech. The framework aims to improve the performances for subjects with initially low classification accuracy, overcoming challenges posed by instrumental and human factors. Limited dataset size, variations in EEG data quality due to factors such as noise, electrode misplacement or subjects, and the need for generalization across different trials, conditions and subjects necessitate the use of DA methods. By leveraging DA methods, the framework can learn from one EEG dataset and adapt to another, potentially resulting in more reliable and robust classification models. Approach. This paper focuses on investigating a DA method, based on parallel transport, for addressing the auditory attention classification problem. The EEG data utilized in this study originates from an experiment where subjects were instructed to selectively attend to one of the two spatially separated voices presented simultaneously. Main results. Significant improvement in classification accuracy was observed when poor data from one subject was transported to the domain of good data from different subjects, as compared to the baseline. The mean classification accuracy for subjects with poor data increased from 45.84% to 67.92%. Specifically, the highest achieved classification accuracy from one subject reached 83.33%, a substantial increase from the baseline accuracy of 43.33%. Significance. The findings of our study demonstrate the improved classification performances achieved through the implementation of DA methods. This brings us a step closer to leveraging EEG in neuro-steered hearing devices. © 2023 The Author(s). Published by IOP Publishing Ltd.

Ventricular arrhythmias (VAs) are a leading cause of cardiovascular morbidity and sudden cardiac death (SCD). It is estimated that SCD and VA account for 15-20% of all deaths worldwide. Despite the decline in cardiovascular deaths over recent decades, the incidence of sudden cardiac death as a proportion of overall cardiovascular mortality has increased. Medical therapy to prevent sudden arrhythmic death has been shown to be ineffective. Institution of implantable cardiac defibrillators has been shown to reduce mortality from malignant VAs, but these devices do nothing to prevent VAs from occurring. Subsequently catheter ablation for VAs, particularly ventricular tachycardia (VT), is now part of standard of care. Advancement in electroanatomical mapping and ablation technology has led to further insights into VT circuits and the functional nature of the substrate that sustains them. The aim of this thesis was to investigate the diagnostic, mechanistic, and therapeutic techniques used for the treatment of VAs occurring in the presence of structural heart disease. There was a particular focus on the functional assessment of the VT substrate, and how this provides insight into where critical sites of VT re-entry are harboured. Initially, novel therapies for treatment of VAs were reviewed, and a systemic review and meta-analysis was conducted on the role of renal denervation. Subsequently, assessment of the VT circuit was investigated using novel modalities such as an automated conduction velocity mapping algorithm and direct graph mapping (DGM). Analysis of the substrate was then performed using a novel retrospective window of interest (WOI) approach. Finally, a direct comparison of different techniques for annotating local activation time (LAT) was performed. Chapter 1 outlines current understanding of VT and ventricular fibrillation (VF) mechanisms and treatment. Contemporary methods for performing a substrate-based VT ablation are explored. The role of imaging in VA

Epilepsy is a disorder in which abnormal neuronal hyperexcitation causes several types of seizures. Because pharmacological and surgical treatments occasionally interfere with normal brain function, a more focused and on-demand approach is desirable. Here we examined the efficacy of a chemogenetic tool—designer receptors exclusively activated by designer drugs (DREADDs)—for treating focal seizure in a nonhuman primate model. Acute infusion of the GABAA receptor antagonist bicuculline into the forelimb region of unilateral primary motor cortex caused paroxysmal discharges with twitching and stiffening of the contralateral arm, followed by recurrent cortical discharges with hemi- and whole-body clonic seizures in two male macaque monkeys. Expression of an inhibitory DREADD (hM4Di) throughout the seizure focus, and subsequent on-demand administration of a DREADD-selective agonist, rapidly suppressed the wide-spread seizures. These results demonstrate the efficacy of DREADDs for attenuating cortical seizure in a nonhuman primate model.

Producción Científica, Voltage-dependent potassium channel Kv1.3 plays a key role on T-cell activation; however, lack of reliable antibodies has prevented its accurate detection under endogenous circumstances. To overcome this limitation, we created a Jurkat T-cell line with endogenous Kv1.3 channel tagged, to determine the expression, location, and changes upon activation of the native Kv1.3 channels. CRISPR-Cas9 technique was used to insert a Flag-Myc peptide at the C terminus of the KCNA3 gene. Basal or activated channel expression was studied using western blot analysis and imaging techniques. We identified two isoforms of Kv1.3 other than the canonical channel (54 KDa) differing on their N terminus: a longer isoform (70 KDa) and a truncated isoform (43 KDa). All three isoforms were upregulated after T-cell activation. We focused on the functional characterization of the truncated isoform (short form, SF), because it has not been previously described and could be present in the available Kv1.3−/− mice models. Overexpression of SF in HEK cells elicited small amplitude Kv1.3-like currents, which, contrary to canonical Kv1.3, did not induce HEK proliferation. To explore the role of endogenous SF isoform in a native system, we generated both a knockout Jurkat clone and a clone expressing only the SF isoform. Although the canonical isoform (long form) localizes mainly at the plasma membrane, SF remains intracellular, accumulating perinuclearly. Accordingly, SF Jurkat cells did not show Kv1.3 currents and exhibited depolarized resting membrane potential (VM), decreased Ca2+ influx, and a reduction in the [Ca2+]i increase upon stimulation. Functional characterization of these Kv1.3 channel isoforms showed their differential contribution to signaling pathways involved in formation of the immunological synapse. We conclude that alternative translation initiation generates at least three endogenous Kv1.3 channel isoforms in T cells that exhibit different functional roles. For some of these func, Ministerio de Economía y Competitividad (grant PID 2020‐118517RB‐I00), Junta de Castilla y León (grants VA172P20) and (CLU-2019-02), Funds from Institut Curie, INSERM,Agence Nationale de la Recherche RetroTact (ANR‐20CE15‐0009‐01,ANR‐10‐IDEX‐0001‐02 PSL*, and ANR‐11‐LABX‐0043), Fondation pour la Recherche Médicale FRM (EQU202003010280)

Producción Científica, Voltage-dependent potassium channel Kv1.3 plays a key role on T-cell activation; however, lack of reliable antibodies has prevented its accurate detection under endogenous circumstances. To overcome this limitation, we created a Jurkat T-cell line with endogenous Kv1.3 channel tagged, to determine the expression, location, and changes upon activation of the native Kv1.3 channels. CRISPR-Cas9 technique was used to insert a Flag-Myc peptide at the C terminus of the KCNA3 gene. Basal or activated channel expression was studied using western blot analysis and imaging techniques. We identified two isoforms of Kv1.3 other than the canonical channel (54 KDa) differing on their N terminus: a longer isoform (70 KDa) and a truncated isoform (43 KDa). All three isoforms were upregulated after T-cell activation. We focused on the functional characterization of the truncated isoform (short form, SF), because it has not been previously described and could be present in the available Kv1.3−/− mice models. Overexpression of SF in HEK cells elicited small amplitude Kv1.3-like currents, which, contrary to canonical Kv1.3, did not induce HEK proliferation. To explore the role of endogenous SF isoform in a native system, we generated both a knockout Jurkat clone and a clone expressing only the SF isoform. Although the canonical isoform (long form) localizes mainly at the plasma membrane, SF remains intracellular, accumulating perinuclearly. Accordingly, SF Jurkat cells did not show Kv1.3 currents and exhibited depolarized resting membrane potential (VM), decreased Ca2+ influx, and a reduction in the [Ca2+]i increase upon stimulation. Functional characterization of these Kv1.3 channel isoforms showed their differential contribution to signaling pathways involved in formation of the immunological synapse. We conclude that alternative translation initiation generates at least three endogenous Kv1.3 channel isoforms in T cells that exhibit different functional roles. For some of these func, Ministerio de Economía y Competitividad (grant PID 2020‐118517RB‐I00), Junta de Castilla y León (grants VA172P20) and (CLU-2019-02), Funds from Institut Curie, INSERM,Agence Nationale de la Recherche RetroTact (ANR‐20CE15‐0009‐01,ANR‐10‐IDEX‐0001‐02 PSL*, and ANR‐11‐LABX‐0043), Fondation pour la Recherche Médicale FRM (EQU202003010280)

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Technological advancements have facilitated the implementation of realistic, terrestrial-based complex 33-beam galactic cosmic radiation simulations (GCR Sim) to now probe central nervous system functionality. This work expands considerably on prior, simplified GCR simulations, yielding new insights into responses of male and female mice exposed to 40-50 cGy acute or chronic radiations relevant to deep space travel. Results of the object in updated location task suggested that exposure to acute or chronic GCR Sim induced persistent impairments in hippocampus-dependent memory formation and reconsolidation in female mice that did not manifest robustly in irradiated male mice. Interestingly, irradiated male mice, but not females, were impaired in novel object recognition and chronically irradiated males exhibited increased aggressive behavior on the tube dominance test. Electrophysiology studies used to evaluate synaptic plasticity in the hippocampal CA1 region revealed significant reductions in long-term potentiation after each irradiation paradigm in both sexes. Interestingly, network-level disruptions did not translate to altered intrinsic electrophysiological properties of CA1 pyramidal cells, whereas acute exposures caused modest drops in excitatory synaptic signaling in males. Ultrastructural analyses of CA1 synapses found smaller postsynaptic densities in larger spines of chronically exposed mice compared to controls and acutely exposed mice. Myelination was also affected by GCR Sim with acutely exposed mice exhibiting an increase in the percent of myelinated axons; however, the myelin sheathes on small calibur (< 0.3 mm) and larger (> 0.5 mm) axons were thinner when compared to controls. Present findings might have been predicted based on previous studies using single and mixed beam exposures and provide further evidence that space-relevant radiation exposures disrupt critical cognitive processes and underlying neuronal network-level plasti