diff --git a/Frontiers_manuscript/Koch_frontiers.tex b/Frontiers_manuscript/Koch_frontiers.tex index 3d8ea3c..09d5e65 100644 --- a/Frontiers_manuscript/Koch_frontiers.tex +++ b/Frontiers_manuscript/Koch_frontiers.tex @@ -1,21 +1,4 @@ -%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% -% This is just an example/guide for you to refer to when submitting manuscripts to Frontiers, it is not mandatory to use Frontiers .cls files nor frontiers.tex % -% This will only generate the Manuscript, the final article will be typeset by Frontiers after acceptance. -% % -% % -% When submitting your files, remember to upload this *tex file, the pdf generated with it, the *bib file (if bibliography is not within the *tex) and all the figures. -%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% - -%%% Version 3.4 Generated 2022/06/14 %%% -%%% You will need to have the following packages installed: datetime, fmtcount, etoolbox, fcprefix, which are normally inlcuded in WinEdt. %%% -%%% In http://www.ctan.org/ you can find the packages and how to install them, if necessary. %%% -%%% NB logo1.jpg is required in the path in order to correctly compile front page header %%% - -\documentclass[utf8]{FrontiersinHarvard} % for articles in journals using the Harvard Referencing Style (Author-Date), for Frontiers Reference Styles by Journal: https://zendesk.frontiersin.org/hc/en-us/articles/360017860337-Frontiers-Reference-Styles-by-Journal -%\documentclass[utf8]{FrontiersinVancouver} % for articles in journals using the Vancouver Reference Style (Numbered), for Frontiers Reference Styles by Journal: https://zendesk.frontiersin.org/hc/en-us/articles/360017860337-Frontiers-Reference-Styles-by-Journal -%\documentclass[utf8]{frontiersinFPHY_FAMS} % Vancouver Reference Style (Numbered) for articles in the journals "Frontiers in Physics" and "Frontiers in Applied Mathematics and Statistics" - -%\setcitestyle{square} % for articles in the journals "Frontiers in Physics" and "Frontiers in Applied Mathematics and Statistics" +\documentclass[utf8]{FrontiersinHarvard} \DeclareUnicodeCharacter{03B2}{\(\beta\)} \DeclareUnicodeCharacter{03B1}{\(\alpha\)} \DeclareUnicodeCharacter{00C5}{\AA} @@ -38,10 +21,6 @@ \externaldocument{Koch_SupplementaryMaterial} - - -%\newcommand{\Kv}{\(\textrm{K}_{\textrm{V}}\textrm{1.1}\)\xspace} -%\newcommand{\IKv}{\(\textrm{I}_{\textrm{K}_{\textrm{V}}\textrm{1.1}}\)\xspace} \newcommand{\Kv}{\(\text{K}_{\text{V}}\text{1.1}\)\xspace} \newcommand{\IKv}{\(\text{I}_{\text{K}_{\text{V}}\text{1.1}}\)\xspace} \newcommand{\drheo}{\(\Delta\)rheobase\xspace} @@ -54,17 +33,9 @@ \linenumbers - -% Leave a blank line between paragraphs instead of using \\ - - \def\keyFont{\fontsize{8}{11}\helveticabold } \def\firstAuthorLast{Koch {et~al.}} %use et al only if is more than 1 author \def\Authors{Nils A. Koch\,$^{1,2}$, Lukas Sonnenberg\,$^{1,2}$, Ulrike B.S. Hedrich\,$^{3}$, Stephan Lauxmann\,$^{1,3}$ and Jan Benda\,$^{1,2,*}$} -% Affiliations should be keyed to the author's name with superscript numbers and be listed as follows: Laboratory, Institute, Department, Organization, City, State abbreviation (USA, Canada, Australia), and Country (without detailed address information such as city zip codes or street names). -% If one of the authors has a change of address, list the new address below the correspondence details using a superscript symbol and use the same symbol to indicate the author in the author list. -%\def\Address{$^{1}$Laboratory X, Institute X, Department X, Organization X, City X , State XX (only USA, Canada and Australia), Country X \\ -%$^{2}$Laboratory X, Institute X, Department X, Organization X, City X , State XX (only USA, Canada and Australia), Country X } \def\Address{$^{1}$Institute for Neurobiology, University of T{\"u}bingen, 72072 T{\"u}bingen, Germany \\ $^{2}$Bernstein Center for Computational Neuroscience T{\"u}bingen, 72076 T{\"u}bingen, Germany \\ $^{3}$Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of T{\"u}bingen, 72076 T{\"u}bingen, Germany} @@ -86,34 +57,23 @@ $^{3}$Department of Neurology and Epileptology, Hertie Institute for Clinical Br \author[\firstAuthorLast ]{\Authors} %This field will be automatically populated \address{} %This field will be automatically populated \correspondance{} %This field will be automatically populated - -\extraAuth{}% If there are more than 1 corresponding author, comment this line and uncomment the next one. -%\extraAuth{corresponding Author2 \\ Laboratory X2, Institute X2, Department X2, Organization X2, Street X2, City X2 , State XX2 (only USA, Canada and Australia), Zip Code2, X2 Country X2, email2@uni2.edu} +\extraAuth{} \maketitle \begin{abstract} - -%%% Leave the Abstract empty if your article does not require one, please see the Summary Table for full details. \section{} -%For full guidelines regarding your manuscript please refer to \href{https://www.frontiersin.org/guidelines/author-guidelines}{Author Guidelines}. -% -%As a primary goal, the abstract should render the general significance and conceptual advance of the work clearly accessible to a broad readership. References should not be cited in the abstract. Leave the Abstract empty if your article does not require one, please see the Article Types on every Frontiers journal page for full details Clinically relevant mutations to voltage-gated ion channels, called channelopathies, alter ion channel function, properties of ionic currents and neuronal firing. The effects of ion channel mutations are routinely assessed and characterized as loss of function (LOF) or gain of function (GOF) at the level of ionic currents. However, emerging personalized medicine approaches based on LOF/GOF characterization have limited therapeutic success. Potential reasons are among others that the translation from this binary characterization to neuronal firing is currently not well understood --- especially when considering different neuronal cell types. Here we investigate the impact of neuronal cell type on the firing outcome of ion channel mutations with simulations of a diverse collection of conductance-based neuron models. We systematically analyzed the effects of changes in ion current properties on firing in different neuronal types. Additionally, we simulated the effects of known mutations in the \textit{KCNA1} gene encoding the \Kv potassium channel subtype associated with episodic ataxia type~1 (EA1). These simulations revealed that the outcome of a given change in ion channel properties on neuronal excitability is depends on neuron type, i.e. the properties and expression levels of the unaffected ionic currents. Consequently, neuron-type specific effects are vital to a full understanding of the effects of channelopathies on neuronal excitability and are an important step towards improving the efficacy and precision of personalized medicine approaches. -% present an opportunity to further the efficacy and precision of personalized medicine approaches. \tiny - \keyFont{ \section{Keywords:} Channelopathy, Epilepsy, Ataxia, Potassium Current, Neuronal Simulations, Conductance-based Models, Neuronal heterogeneity } %All article types: you may provide up to 8 keywords; at least 5 are mandatory. + \keyFont{ \section{Keywords:} Channelopathy, Epilepsy, Ataxia, Potassium Current, Neuronal Simulations, Conductance-based Models, Neuronal heterogeneity } \end{abstract} - \section{Introduction} -% -%For Original Research Articles \citep{conference}, Clinical Trial Articles \citep{article}, and Technology Reports \citep{patent}, the introduction should be succinct, with no subheadings \citep{book}. For Case Reports the Introduction should include symptoms at presentation \citep{chapter}, physical exams and lab results \citep{dataset}. The properties and combinations of voltage-gated ion channels are vital in determining neuronal excitability \citep{bernard_channelopathies_2008, carbone_ion_2020, rutecki_neuronal_1992, pospischil_minimal_2008}. However, ion channel function can be disturbed, for instance through genetic alterations, resulting in altered neuronal firing behavior \citep{carbone_ion_2020}. In recent years, next generation sequencing has led to an increase in the discovery of clinically relevant ion channel mutations and has provided the basis for pathophysiological studies of genetic epilepsies, pain disorders, dyskinesias, intellectual disabilities, myotonias, and periodic paralyses \citep{bernard_channelopathies_2008, carbone_ion_2020}. Ongoing efforts of many research groups have contributed to the current understanding of underlying disease mechanism in channelopathies, however a complex pathophysiological landscape has emerged for many channelopathies and is likely a reason for limited therapeutic success with standard care. @@ -126,12 +86,9 @@ Taken together, these examples demonstrate the need to study the effects of ion In this study, we therefore investigated how the outcome of ionic current kinetic changes on firing depend on neuronal cell type by (1) characterizing firing responses with two measures, (2) simulating the response of a repertoire of different neuronal models to changes in single current parameters as well as (3) to more complex changes in this case as they were observed for specific \textit{KCNA1} mutations that are associated with episodic ataxia type~1 \citep{Browne1994, Browne1995, lauxmann_therapeutic_2021}. \section{Material and Methods} - All modelling and simulation was done in parallel with custom written Python 3.8 (Python Programming Language; RRID:SCR\_008394) software, run on a Cent-OS 7 server with an Intel(R) Xeon (R) E5-2630 v2 CPU. - % @ 2.60 GHz Linux 3.10.0-123.e17.x86_64. \subsection{Different Neuron Models} - A group of neuronal models representing the major classes of cortical and thalamic neurons including regular spiking pyramidal (RS pyramidal; model D), regular spiking inhibitory (RS inhibitory; model B), and fast spiking (FS; model C) neurons were used \citep{pospischil_minimal_2008}. Additionally, a \Kv current (\IKv; \citealt{ranjan_kinetic_2019}) was added to each of these models (RS pyramidal +\Kv; model H, RS inhibitory +\Kv; model E, and FS +\Kv; model G respectively). A cerebellar stellate cell model from \citet{alexander_cerebellar_2019} is used (Cb stellate; model A) in this study. This neuron model was also extended by a \Kv current \citep{ranjan_kinetic_2019}, either in addition to the A-type potassium current (Cb stellate +\Kv; model F) or by replacing the A-type potassium current (Cb stellate \(\Delta\)\Kv; model J). A subthalamic nucleus (STN; model L) neuron model as described by \citet{otsuka_conductance-based_2004} was also used. The STN neuron model (model L) was additionally extended by a \Kv current \citep{ranjan_kinetic_2019}, either in addition to the A-type potassium current (STN +\Kv; model I) or by replacing the A-type potassium current (STN \(\Delta\)\Kv; model K). Model letter naming corresponds to panel lettering in Figure \ref{fig:diversity_in_firing}. The properties and maximal conductances of each model are detailed in Table \ref{tab:g} and the gating properties are unaltered from the original Cb stellate (model A) and STN (model L) models \citep{alexander_cerebellar_2019, otsuka_conductance-based_2004}. For enabling the comparison of models with the typically reported electrophysiological data fitting reported and for ease of further gating curve manipulations, a modified Boltzmann function \begin{equation}\label{eqn:Boltz} @@ -155,7 +112,6 @@ All models exhibited tonic steady-state firing with default parameters. In limit \subsection{Sensitivity Analysis and Comparison of Models} - Properties of ionic currents common to all models (\(\text{I}_{\text{Na}}\), \(\text{I}_{\text{Kd}}\), \(\text{I}_{\text{A}}\)/\IKv, and \(\text{I}_{\text{Leak}}\)) were systematically altered in a one-factor-at-a-time sensitivity analysis for all models. The gating curves for each current were shifted (\(\Delta V_{1/2}\)) from -10 to 10\,mV in increments of 1\,mV. The voltage dependence of the time constant associated with the shifted gating curve was correspondingly shifted. The slope (\(k\)) of the gating curves were altered from half to twice the initial slope. Similarly, the maximal current conductance (\(g\)) was also scaled from half to twice the initial value. For both slope and conductance alterations, alterations consisted of 21 steps spaced equally on a \(\textrm{log}_2\) scale. We neglected the variation of time constants for the practical reason that estimation and assessment of time constants and changes to them is not straightforward \citep{Clerx2019, Whittaker2020}. \subsection{Model Comparison} @@ -171,8 +127,7 @@ The Kendall's \(\tau\) coefficient, a non-parametric rank correlation, is used t Known episodic ataxia type~1 associated \textit{KCNA1} mutations and their electrophysiological characterization have been reviewed in \citet{lauxmann_therapeutic_2021}. The mutation-induced changes in \IKv amplitude and activation slope (\(k\)) were normalized to wild type measurements and changes in activation \(V_{1/2}\) were used relative to wild type measurements. Although initially described to lack fast activation, \Kv displays prominent inactivation at physiologically relevant temperatures \citep{ranjan_kinetic_2019}. The effects of a mutation were also applied to \(\text{I}_{\text{A}}\) when present as both potassium currents display inactivation. In all cases, the mutation effects were applied to half of the \Kv or \(\text{I}_{\text{A}}\) under the assumption that the heterozygous mutation results in 50\% of channels carrying the mutation. Frequency-current curves for each mutation in each model were obtained through simulation and used to characterize firing behavior as described above. For each model the differences in mutation AUC to wild type AUC were normalized by wild type AUC (\ndAUC) and mutation rheobases were compared to wild type rheobase values (\drheo). Pairwise Kendall rank correlations (Kendall \(\tau\)) were used to compare the correlation in the effects of \Kv mutations on AUC and rheobase between models. \subsection{Code Accessibility} -%The code/software described in the paper is freely available online at [URL redacted for double-blind review]. The code is available as \Cref{code_zip}. -The simulation and analysis code including full specification of the models is freely available online at \newline \href{https://github.com/nkoch1/LOFGOF2023}{https://github.com/nkoch1/LOFGOF2023}. %The code is available as \ref{code_zip}. +The simulation and analysis code including full specification of the models is freely available online at \href{https://github.com/nkoch1/LOFGOF2023}{https://github.com/nkoch1/LOFGOF2023}. %The code is available as \ref{code_zip}. \section{Results} @@ -182,8 +137,6 @@ To examine the role of neuron-type specific ionic current environments on the im \subsection{Variety of model neurons} Neuronal firing is heterogenous across the CNS and a set of neuronal models with heterogenous firing due to different ionic currents is desirable to reflect this heterogeneity. The set of single-compartment, conductance-based neuronal models used here has considerable diversity as evident in the variability seen across neuronal models both in spike trains and their fI curves (Figure \ref{fig:diversity_in_firing}). The models chosen for this study all fire tonically and do not exhibit bursting (see methods for details and naming of the models). Models are qualitatively sorted based on their firing curves and labeled model A through L accordingly. Some models, such as models A and B, display type I firing, whereas others such as models J and L exhibit type II firing. Type I firing is characterized by continuous fI curves (i.e. firing rate increases from 0 in a continuous fashion) whereas type II firing is characterized by a discontinuity in the fI curve (i.e. a jump occurs from no firing to firing at a certain frequency; \citealt{ermentrout_type_1996, Rinzel_1998}). The other models used here lie on a continuum between these prototypical firing classifications. Most neuronal models exhibit hysteresis with ascending and descending ramps eliciting spikes at different current thresholds. However, the models I, J, and K have large hysteresis (Figure \ref{fig:diversity_in_firing} and Supplementary Figure S1). Different types of underlying current dynamics are known to generate these different firing types and hysteresis \cite{ERMENTROUT2002, ermentrout_type_1996, Izhikevich2006}. This broad range of single-compartmental models represents the distinct dynamics of various neuron types across diverse brain regions. -% \textcolor{red}{ (Figure \ref{fig:diversity_in_firing} and Supplementary Figure \ref{ramp_firing})} - \subsection{Characterization of Neuronal Firing Properties} Neuronal firing is a complex phenomenon, and a quantification of firing properties is required for comparisons across neuron types and between different conditions. Here we focus on two aspects of firing that are routinely measured in clinical settings \citep{Bryson_2020}: rheobase, the smallest injected current at which the neuron fires an action potential, and the shape of the frequency-current (fI) curve as quantified by the area under the curve (AUC) for a fixed range of input currents above rheobase (Figure \ref{fig:firing_characterization}~A). The characterization of the firing properties of a neuron by using rheobase and AUC allows to characterize both a neuron's excitability in the sub-threshold regime (rheobase) and periodic firing in the super-threshold regime (AUC) by two independent measures. Note that AUC is essentially quantifying the slope of a neuron's fI curve. @@ -246,134 +199,12 @@ The effects of altered ion channel properties on firing is generally influenced With this study we suggest that neuron-type specific effects are vital to a full understanding of the effects of channelopathies at the level of neuronal firing. Furthermore, we highlight the use of modelling approaches to enable relatively fast and efficient insight into channelopathies. -%\section{Article types} -% -%For requirements for a specific article type please refer to the Article Types on any Frontiers journal page. Please also refer to \href{https://www.frontiersin.org/about/author-guidelines#sections}{Author Guidelines} for further information on how to organize your manuscript in the required sections or their equivalents for your field -% -%% For Original Research articles, please note that the Material and Methods section can be placed in any of the following ways: before Results, before Discussion or after Discussion. - -%\section{Manuscript Formatting} -% -%%\subsection{Heading Levels} -%% -%%%There are 5 heading levels -%% -%%\subsection{Level 2} -%%\subsubsection{Level 3} -%%\paragraph{Level 4} -%%\subparagraph{Level 5} -% -%%\subsection{Equations} -%%Equations should be inserted in editable format from the equation editor. -%% -%%\begin{equation} -%%\sum x+ y =Z\label{eq:01} -%%\end{equation} -% -%%\subsection{Figures} -%%Frontiers requires figures to be submitted individually, in the same order as they are referred to in the manuscript. Figures will then be automatically embedded at the bottom of the submitted manuscript. Kindly ensure that each table and figure is mentioned in the text and in numerical order. Figures must be of sufficient resolution for publication. Figures which are not according to the guidelines will cause substantial delay during the production process. Please see \href{https://www.frontiersin.org/guidelines/author-guidelines#figure-and-table-guidelines}{here} for full figure guidelines. Cite figures with subfigures as figure \ref{fig:Subfigure 1} and \ref{fig:Subfigure 2}. -%% -%% -%%\subsubsection{Permission to Reuse and Copyright} -%%Figures, tables, and images will be published under a Creative Commons CC-BY licence and permission must be obtained for use of copyrighted material from other sources (including re-published/adapted/modified/partial figures and images from the internet). It is the responsibility of the authors to acquire the licenses, to follow any citation instructions requested by third-party rights holders, and cover any supplementary charges. -%%%%Figures, tables, and images will be published under a Creative Commons CC-BY licence and permission must be obtained for use of copyrighted material from other sources (including re-published/adapted/modified/partial figures and images from the internet). It is the responsibility of the authors to acquire the licenses, to follow any citation instructions requested by third-party rights holders, and cover any supplementary charges. -%% -%% -%% -%% -%% -%%\subsection{Tables} -%%Tables should be inserted at the end of the manuscript. Please build your table directly in LaTeX.Tables provided as jpeg/tiff files will not be accepted. Please note that very large tables (covering several pages) cannot be included in the final PDF for reasons of space. These tables will be published as \href{https://www.frontiersin.org/guidelines/author-guidelines#supplementary-material}{Supplementary Material} on the online article page at the time of acceptance. The author will be notified during the typesetting of the final article if this is the case. -%% -% -%% -%%\subsection{Resource Identification Initiative} -%%To take part in the Resource Identification Initiative, please use the corresponding catalog number and RRID in your current manuscript. For more information about the project and for steps on how to search for an RRID, please click \href{http://www.frontiersin.org/files/pdf/letter_to_author.pdf}{here}. -%%\notenk{did this for Python in the methods} -%%\subsection{Life Science Identifiers} -%%Life Science Identifiers (LSIDs) for ZOOBANK registered names or nomenclatural acts should be listed in the manuscript before the keywords. For more information on LSIDs please see the \href{https://www.frontiersin.org/guidelines/author-guidelines#nomenclature}{Nomenclature} section of the guidelines. -%%\notenk{Not sure if we need to do this, or what to do?} -%% -%%\section{Additional Requirements} -%% -%%For additional requirements for specific article types and further information please refer to the individual Frontiers journal pages -%% -%%\notenk{Original Research articles are peer-reviewed, have a maximum word count of 12,000 and may contain no more than 15 Figures/Tables. Authors are required to pay a fee (A-type article) to publish an Original Research article. Original Research articles should have the following format: 1) Abstract, 2) Introduction, 3) Materials and Methods, 4) Results, 5) Discussion. All article types require a minimum of five and a maximum of eight keywords.} -% -%\subsection*{\textcolor{red}{Contribution to the field}} -%\notenk{Contribution to the field. Ahead of submission, you should prepare a statement summarizing in 200 words your manuscript’s contribution to, and position in, the existing literature of your field. This should be written avoiding any technical language or non-standard acronyms. The aim should be to convey the meaning and importance of this research to a non-expert. (Note that you will NOT be able to provide a traditional cover letter.)} -% -% -% -%Although the genetic nature of ion channel mutations as well as their effects on the biophysical properties of an ion channel are routinely assessed experimentally in the context of neurological disorders such as epilepsy and ataxia, determination of their role in altering neuronal firing is more difficult. -% -% However, neuron-type dependency of ion channel mutations on firing has been observed experimentally. Here we demonstrate that the neuron type in which a mutation occurs is an important determinant in the effects of neuronal firing. As a result classification of ion channel mutations as loss or gain of function is useful to describe the ionic current but should not be blindly extend to classification at the level of neuronal firing nor used to directly inform therapeutic approaches. The knowledge of whether a mutation increases or decreases neuronal excitability is vital in the context of state-of-the-art personalized medicine approaches in this area where treatments are mainly based on biophysical properties only. As such taking neuron-type dependence of the firing effects of ion channel mutations provides a promising direction to increase efficacy in personalized medicine approaches. -% -%Taken together, our findings highlight that neuronal type and the respective ionic current composition is of vital importance and must be considered when assessing the effects of mutations on neuronal firing and for determining therapeutic strategies for ion channal mutations. - - -%\textit{Significance statement from eNeuro}\\ -%\textit{Although the genetic nature of ion channel mutations as well as their effects on the biophysical properties of an ion channel are routinely assessed experimentally, determination of their role in altering neuronal firing is more difficult. In particular, cell-type dependency of ion channel mutations on firing has been observed experimentally, and should be accounted for. In this context, computational modelling bridges this gap and demonstrates that the cell type in which a mutation occurs is an important determinant in the effects of neuronal firing. As a result, classification of ion channel mutations as loss or gain of function is useful to describe the ionic current but should not be blindly extend to classification at the level of neuronal firing.} - -%\textit{Cover letter from eNeuro}\\ -%\textit{Dear Editors, -%the effects of ion channel mutations on biophysical properties are routinely assessed in expression systems. However, how these altered biophysical properties translate into changes in neuronal firing and network activity is not well understood yet. As a first step, our manuscript "Loss or Gain of Function? Neuronal Firing Effects of Ion Channel Mutations Depend on Cell Type" emphasizes how much the effects of ion channel mutations on neuronal firing may depend on the specific neuron type. The knowledge of whether a mutation increases or decreases neuronal excitability is vital in the context of state-of-the-art personalized medicine approaches in this area where treatments are mainly based on biophysical properties only. -% -%We extensively simulated 12 conductance-based models to explore the dependence of the effects of ion channel mutations on neuron type. We systematically varied properties (maximal conductance, position and slope of activation and inactivation curves) of voltage-gated ionic currents over ranges typically measured experimentally and assess the effect of changes on both threshold and sensitivity of firing. Secondly, we simulated the effects of reported episodic ataxia type 1 associated KCNA1 mutations in the models and assessed the dependence of firing changes on neuron type in a similar manner. Overall, we find that the effects of ion channel mutations, both generally and in the case of reported KCNA1 mutations, depends on neuron type. Our findings highlight that neuronal type and the respective ionic current composition is of vital importance and must be considered when assessing the effects of mutations on neuronal firing. -% -%Our manuscript addresses clinicians investigating channelopathies, systemic neuroscientists as well as computational neuroscientists, all readers of eNeuro. -% -%We hope that you find our manuscript convincing and exciting, and look forward to hearing from you.} - -%\section*{Conflict of Interest Statement} -%%All financial, commercial or other relationships that might be perceived by the academic community as representing a potential conflict of interest must be disclosed. If no such relationship exists, authors will be asked to confirm the following statement: -% -%The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. - -%\section*{Author Contributions} -%% -%%The Author Contributions section is mandatory for all articles, including articles by sole authors. If an appropriate statement is not provided on submission, a standard one will be inserted during the production process. The Author Contributions statement must describe the contributions of individual authors referred to by their initials and, in doing so, all authors agree to be accountable for the content of the work. Please see \href{https://www.frontiersin.org/guidelines/policies-and-publication-ethics#authorship-and-author-responsibilities}{here} for full authorship criteria. -% -%NK, LS, UBSH, SL, JB contributed to conception and design of the study. NK performed simulation and wrote the first draft of the manuscript. NK, LS analyzed simulation data. All authors wrote sections of the manuscript and contributed to manuscript revision, read and approved the submitted version. - - - -%\section*{Funding} -%%Details of all funding sources should be provided, including grant numbers if applicable. Please ensure to add all necessary funding information, as after publication this is no longer possible. -% -%This work was supported by the German Research Foundation in the Frame of the Research Unit FOR-2715 (DFG, grants Le1030/15-1/2 and HE 8155/1-2) and the Network for Rare Ion Channel Disorders Treat-ION of the Federal Ministry for Education and Research (BMBF, grants 01GM1907A and 01GM2210A). SL was supported with an Otfrid-Foerster stipend from the German Society for Epileptology (DGfE). - - -%\section*{Acknowledgments} -%This is a short text to acknowledge the contributions of specific colleagues, institutions, or agencies that aided the efforts of the authors. - -%\section*{Supplemental Data} -% \href{https://www.frontiersin.org/guidelines/author-guidelines#supplementary-material}{Supplementary Material} should be uploaded separately on submission, if there are Supplementary Figures, please include the caption in the same file as the figure. LaTeX Supplementary Material templates can be found in the Frontiers LaTeX folder. -% \notenk{See ./Koch\_SupplementaryMaterial.tex} - -%\section*{Data Availability Statement} -%%The datasets [GENERATED/ANALYZED] for this study can be found in the [NAME OF REPOSITORY] [LINK]. -% -%The datasets generated for this study as well as the code/software described in this study are publicly available. This data and software can be found here: \href{https://github.com/nkoch1/LOFGOF2023}{https://github.com/nkoch1/LOFGOF2023}. -%The original contributions presented in the study are publicly available. This data can be found here: [link/accession number]. -% Please see the availability of data guidelines for more information, at https://www.frontiersin.org/guidelines/policies-and-publication-ethics#materials-and-data-policies - -\bibliographystyle{Frontiers-Harvard} % Many Frontiers journals use the Harvard referencing system (Author-date), to find the style and resources for the journal you are submitting to: https://zendesk.frontiersin.org/hc/en-us/articles/360017860337-Frontiers-Reference-Styles-by-Journal. For Humanities and Social Sciences articles please include page numbers in the in-text citations -%\bibliographystyle{Frontiers-Vancouver} % Many Frontiers journals use the numbered referencing system, to find the style and resources for the journal you are submitting to: https://zendesk.frontiersin.org/hc/en-us/articles/360017860337-Frontiers-Reference-Styles-by-Journal -%\selectlanguage{en} -%\bibliography{test} -\bibliography{ref} -%%% Make sure to upload the bib file along with the tex file and PDF -%%% Please see the test.bib file for some examples of references +\bibliographystyle{Frontiers-Harvard} +\bibliography{Koch_ref} \newpage \section*{Figures} - -%%% Please be aware that for original research articles we only permit a combined number of 15 figures and tables, one figure with multiple subfigures will count as only one figure. -%%% Use this if adding the figures directly in the mansucript, if so, please remember to also upload the files when submitting your article -%%% There is no need for adding the file termination, as long as you indicate where the file is saved. In the examples below the files (logo1.eps and logos.eps) are in the Frontiers LaTeX folder -%%% If using *.tif files convert them to .jpg or .png %%% NB logo1.eps is required in the path in order to correctly compile front page header %%% @@ -421,38 +252,6 @@ Changes in firing as characterized by \(\Delta\)AUC and \(\Delta\)rheobase occup -%\begin{figure}[h!] -%\begin{center} -%\includegraphics[width=10cm]{logo1}% This is a *.eps file -%\end{center} -%\caption{ Enter the caption for your figure here. Repeat as necessary for each of your figures}\label{fig:1} -%\end{figure} -% -%\setcounter{figure}{2} -%\setcounter{subfigure}{0} -%\begin{subfigure} -%\setcounter{figure}{2} -%\setcounter{subfigure}{0} -% \centering -% \begin{minipage}[b]{0.5\textwidth} -% \includegraphics[width=\linewidth]{logo1.eps} -% \caption{This is Subfigure 1.} -% \label{fig:Subfigure 1} -% \end{minipage} -% -%\setcounter{figure}{2} -%\setcounter{subfigure}{1} -% \begin{minipage}[b]{0.5\textwidth} -% \includegraphics[width=\linewidth]{logo2.eps} -% \caption{This is Subfigure 2.} -% \label{fig:Subfigure 2} -% \end{minipage} -% -%\setcounter{figure}{2} -%\setcounter{subfigure}{-1} -% \caption{Enter the caption for your subfigure here. \textbf{(A)} This is the caption for Subfigure 1. \textbf{(B)} This is the caption for Subfigure 2.} -% \label{fig: subfigures} -%\end{subfigure} \FloatBarrier \section*{Tables} @@ -461,8 +260,4 @@ Changes in firing as characterized by \(\Delta\)AUC and \(\Delta\)rheobase occup \input{gating_table} -%%% If you don't add the figures in the LaTeX files, please upload them when submitting the article. -%%% Frontiers will add the figures at the end of the provisional pdf automatically -%%% The use of LaTeX coding to draw Diagrams/Figures/Structures should be avoided. They should be external callouts including graphics. - \end{document}