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The fine control of synaptic function requires robust trans-synaptic molecular interactions. However, it remains poorly understood how the landscape of trans-synaptic bridges dynamically remodels to reflect functional states of the synapse. Here we developed novel optical tools to visualize in firing synapses the molecular behavior of a particular secreted trans-synaptic protein, LGI1, and its presynaptic receptor, ADAM23, and discovered that neuronal activity acutely rearranges the abundance of these proteins at the synaptic cleft. Surprisingly, LGI1 in synapses was not secreted, as described elsewhere, but exo- and endocytosed through its interaction with ADAM23. Activity-driven translocation of LGI1 facilitated the formation of trans-synaptic connections proportionally to the history of activity of the synapse, modulating excitatory transmission correlatively to synaptic firing rates. Thus, our findings reveal that LGI1 abundance at the synaptic cleft can be acutely remodeled and serves as critical point of activity-dependent control of synaptic function.Highlights-Neuronal activity translocates LGI1 and ADAM23 to the presynaptic surface-LGI1 and ADAM23 are not located in synaptic vesicles-Stable cleft localization of LGI1 depends on the history of synaptic activity-LGI1 abundance at the synaptic cleft controls glutamate release

To determine whether dipoles are an appropriate simplified representation of neural sources for stereo-EEG (sEEG).We compared the distributions of voltages generated by a dipole, biophysically realistic cortical neuron models, and extended regions of cortex to determine how well a dipole represented neural sources at different spatial scales and at electrode to neuron distances relevant for sEEG. We also quantified errors introduced by the dipole approximation of neural sources in sEEG source localization using standardized low-resolution electrotomography (sLORETA).For pyramidal neurons, the coefficient of correlation between voltages generated by a dipole and neuron model were 0.9 for distances 1 mm. For small regions of cortex (∼0.1 cmSingle dipoles are an appropriate source model to represent both single neurons and small regions of active cortex, while multiple dipoles are required to represent large regions of cortex.Dipoles are computationally tractable and valid source models for sEEG.

Copyright © 2022 The Author(s) and International Federation of Clinical Neurophysiology. Transcranial (electro)magnetic stimulation (TMS) is currently the method of choice to non-invasively induce neural activity in the human brain. A single transcranial stimulus induces a time-varying electric field in the brain that may evoke action potentials in cortical neurons. The spatial relationship between the locally induced electric field and the stimulated neurons determines axonal depolarization. The induced electric field is influenced by the conductive properties of the tissue compartments and is strongest in the superficial parts of the targeted cortical gyri and underlying white matter. TMS likely targets axons of both excitatory and inhibitory neurons. The propensity of individual axons to fire an action potential in response to TMS depends on their geometry, myelination and spatial relation to the imposed electric field and the physiological state of the neuron. The latter is determined by its transsynaptic dendritic and somatic inputs, intrinsic membrane potential and firing rate. Modeling work suggests that the primary target of TMS is axonal terminals in the crown top and lip regions of cortical gyri. The induced electric field may additionally excite bends of myelinated axons in the juxtacortical white matter below the gyral crown. Neuronal excitation spreads ortho- and antidromically along the stimulated axons and causes secondary excitation of connected neuronal populations within local intracortical microcircuits in the target area. Axonal and transsynaptic spread of excitation also occurs along cortico-cortical and cortico-subcortical connections, impacting on neuronal activity in the targeted network. Both local and remote neural excitation depend critically on the functional state of the stimulated target area and network. TMS also causes substantial direct co-stimulation of the peripheral nervous system. Peripheral co-excitation propagates centrally in auditory and somatosensory networks, but also produces brain responses in other networks subserving multisensory integration, orienting or arousal. The complexity of the response to TMS warrants cautious interpretation of its physiological and behavioural consequences, and a deeper understanding of the mechanistic underpinnings of TMS will be critical for advancing it as a scientific and therapeutic tool. Aman S. Aberra was supported by a U. S. A. National Science Foundation Graduate Research Fellowship (No. DGF 1106401). Andrea Antal has been supported by a grant of the Federal Ministry of Education and Research (BMBF) of Germany (Grant 01GP2124B) and by a grant of the Lower Saxony Ministry of Science and Culture (Grant 76251-12-7/19 ZN 3456). Marco Davare has been supported by a BBSRC responsive mode grant. Klaus Funke has been supported by a grant of the Federal Ministry of Education and Research (BMBF) of Germany (Grant 01EE1403B) as part of the German Center for Brain Stimulation (GCBS) and by the Deutsche Forschungsgemeinschaft (DFG) (Grants FU256/3-2; 122679504–SFB874). Mark Hallett is supported by the NINDS Intramural Program. Anke N. Karabanov holds a 4-year Sapere Aude Fellowship which is sponsored by the Independent Research Fund Denmark (Grant Nr. 0169-00027B). The sponsor had no direct involvement in the collection, analysis and interpretation of data and in the writing of the manuscript. Giacomo Koch has been supported by na EU grant H2020-EU.1.2.2. - FET Proactive (Neurotwin ID: 101017716). Sabine Meunier is Emeritus Research Director at INSERM, this has no direct involvement in the collection, analysis and interpretation of data and in the writing of the manuscript. Carlo Miniussi has been supported by a grant of the Caritro Foundation, Italy. Walter Paulus received grants from the Deutsche Forschungsgemeinschaft and BMBF. Angel V. Peterchev was supported by grants from the U. S. A. National Institutes of Health (Grants Nos. R01NS117405, R01NS088674, RF1MH114268, R01MH111865). Traian Popa has been supported by the Defitech Foundation and NIBS-iCog grant from the Swiss National Science Foundation. Hartwig R. Siebner holds a 5-year professorship in precision medicine at the Faculty of Health Sciences and Medicine, University of Copenhagen which is sponsored by the Lundbeck Foundation (Grant Nr. R186-2015-2138). The salary for Janine Kesselheim (PhD project) has been covered by a project grant “Biophysically adjusted state-informed cortex stimulation” (BASICS) funded by a synergy grant from Novo Nordisk Foundation (PI: Hartwig R Siebner, Interdisciplinary Synergy Program 2014; grant number NNF14OC001). Axel Thielscher has been supported by grants of the Lundbeck foundation (R118-A11308, R244-2017-196 and R313-2019-622). Yoshikazu Ugawa has been supported in part by grants from the Research Project Grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (Grants 15H05881, 16H05322, 19H01091, 20K07866). Ulf Ziemann received grants from the German Ministry of Education and Research (BMBF), European Research Council (ERC), and German Research Foundation (DFG).

ObjectiveTemporal interference stimulation (TIS) was proposed as a non-invasive, focal, and steerable deep brain stimulation method. However, the mechanisms underlying experimentally-observed suprathreshold TIS effects are unknown, and prior simulation studies had limitations in the representations of the TIS electric field (E-field) and cerebral neurons. We examined the E-field and neural response characteristics for TIS and related transcranial alternating current stimulation modalities.ApproachUsing the uniform-field approximation, we simulated a range of stimulation parameters in biophysically realistic model cortical neurons, including different orientations, frequencies, amplitude ratios, amplitude modulation, and phase difference of the E-fields, and obtained thresholds for both activation and conduction block.Main resultsFor two E-fields with similar amplitudes (representative of E-field distributions at the target region), TIS generated an amplitude-modulated total E-field. Due to the phase difference of the individual E-fields, the total TIS E-field vector also exhibited rotation where the orientations of the two E-fields were not aligned (generally also at the target region). TIS activation thresholds (75–230 V/m) were similar to those of high-frequency stimulation with or without modulation and/or rotation. For E-field dominated by the high-frequency carrier and with minimal amplitude modulation and/or rotation (typically outside the target region), TIS was less effective at activation and more effective at block. Unlike amplitude-modulated high-frequency stimulation, TIS generated conduction block with some orientations and amplitude ratios of individual E-field at very high amplitudes of the total E-field (>1700 V/m).SignificanceThe complex 3D properties of the TIS E-fields should be accounted for in computational and experimental studies. The mechanisms of suprathreshold cortical TIS appear to involve neural activity block and periodic activation or onset response, consistent with computational studies of peripheral axons. These phenomena occur at E-field strengths too high to be delivered tolerably through scalp electrodes and may inhibit endogenous activity in off-target regions, suggesting limited significance of suprathreshold TIS.

Transcranial stimulation induces or modulates neural activity in the brain through basic physical and biophysical processes. Transcranial electrical stimulation and transcranial magnetic stimulation impose an exogenous electric field in the brain that is determined by the stimulation device and the geometric and electric parameters of the head. The imposed electric field drives an electric current through the brain tissue, which macroscopically behaves as a volume conductor. The electric field polarizes neuronal membranes as described by the cable equation, resulting in direct activation of individual neurons and neural networks or indirect modulation of intrinsic activity. Computational modeling can estimate the delivered electric field as well as the resultant responses of individual neurons. This dosimetric information can be used to optimize and individualize stimulation targeting. The field distributions of transcranial stimulation are well understood and characterized, whereas analysis and modeling of the neural responses require further investigation, especially at the network level.

Objective We present a theory and computational methods to incorporate transverse polarization of neuronal membranes into the cable equation to account for the secondary electric field generated by the membrane in response to transverse electric fields. The effect of transverse polarization on nonlinear neuronal activation thresholds is quantified and discussed in the context of previous studies using linear membrane models. Approach The response of neuronal membranes to applied electric fields is derived under two time scales and a unified solution of transverse polarization is given for spherical and cylindrical cell geometries. The solution is incorporated into the cable equation re-derived using an asymptotic model that separates the longitudinal and transverse dimensions. Two numerical methods are proposed to implement the modified cable equation. Several common neural stimulation scenarios are tested using two nonlinear membrane models to compare thresholds of the conventional and modified cable equations. Main results The implementations of the modified cable equation incorporating transverse polarization are validated against previous results in the literature. The test cases show that transverse polarization has limited effect on activation thresholds. The transverse field only affects thresholds of unmyelinated axons for short pulses and in low-gradient field distributions, whereas myelinated axons are mostly unaffected. Significance The modified cable equation captures the membrane's behavior on different time scales and models more accurately the coupling between electric fields and neurons. It addresses the limitations of the conventional cable equation and allows sound theoretical interpretations. The implementation provides simple methods that are compatible with current simulation approaches to study the effect of transverse polarization on nonlinear membranes. The minimal influence by transverse polarization on axonal activation thresholds for the nonlinear membrane models indicates that predictions of stronger effects in linear membrane models with a fixed activation threshold are inaccurate. Thus, the conventional cable equation works well for most neuroengineering applications, and the presented modeling approach is well suited to address the exceptions.

Scalable, high-throughput DNA sequencing is a prerequisite for precision medicine and biomedical research. Recently, we presented a nanopore-based sequencing-by-synthesis (Nanopore-SBS) approach, which used a set of nucleotides with polymer tags that allow discrimination of the nucleotides in a biological nanopore. Here, we designed and covalently coupled a DNA polymerase to an α-hemolysin (αHL) heptamer using the SpyCatcher/SpyTag conjugation approach. These porin-polymerase conjugates were inserted into lipid bilayers on a complementary metal oxide semiconductor (CMOS)-based electrode array for high-throughput electrical recording of DNA synthesis. The designed nanopore construct successfully detected the capture of tagged nucleotides complementary to a DNA base on a provided template. We measured over 200 tagged-nucleotide signals for each of the four bases and developed a classification method to uniquely distinguish them from each other and background signals. The probability of falsely identifying a background event as a true capture event was less than 1.2%. In the presence of all four tagged nucleotides, we observed sequential additions in real time during polymerase-catalyzed DNA synthesis. Single-polymerase coupling to a nanopore, in combination with the Nanopore-SBS approach, can provide the foundation for a low-cost, single-molecule, electronic DNA-sequencing platform.

Introduction Accurate modeling of neural activation provides mechanistic understanding of non-invasive brain stimulation and means for optimization of stimulus parameters. The cable equation is commonly used to couple extracellular electric fields to neuronal models. However, its conventional form does not account for some aspects of the neuronal membranes’ response, such as polarization of soma or fibers by transverse electric fields, and has limitations in the theoretical foundation for coupling inductive magnetic stimulation. Until now, the membranes’ detailed interactions with the electric fields could only be modeled by computationally expensive finite element simulation of fine neural structures. Objectives This modeling study incorporates initial polarization into the cable equation to improve the accuracy of estimating neural activation of both electrical and magnetic stimulation. Materials and methods The initial polarization of axon segments and somas was derived analytically and incorporated into the cable equation. Test cases were simulated for neuron models with either linear or nonlinear membrane to evaluate the influence of initial polarization on polarization rate and action potential thresholds. Results Initial polarization can reduce the neural firing threshold by 5–50% for typical axon radii, electrode distances, and pulse widths. Short pulse widths and large electrode distance, such as those in non-invasive stimulation, result in larger decreases in threshold. The depolarization rates of nonlinear membrane models showed that the initial polarization mechanism has activation strength similar to the spatial gradient of the applied field, and contributes significantly to activating the soma and axon initial segment. Initial polarization reduces stimulation thresholds and may potentially shift the spike initiation site from axon terminals to the initial segments. This could be an important effect in transcranial stimulation due to the low spatial gradients of the applied fields. Conclusion Initial polarization may contribute significantly to neural activation. It is captured by the proposed modified cable equation, which could give more accurate estimation of the site and threshold for neural activation with exogenous electric fields. Download : Download high-res image (190KB) Download : Download full-size image