Excitation Patterns Research Articles

Supercomputer framework for reverse engineering firing patterns of neuron populations to identify their synaptic inputs

In this study, we develop new reverse engineering (RE) techniques to identify the organization of the synaptic inputs generating firing patterns of populations of neurons. We tested these techniques in silico to allow rigorous evaluation of their effectiveness, using remarkably extensive parameter searches enabled by massively-parallel computation on supercomputers. We chose spinal motoneurons as our target neural system, since motoneurons process all motor commands and have well-established input-output properties. One set of simulated motoneurons was driven by 300,000+ simulated combinations of excitatory, inhibitory, and neuromodulatory inputs. Our goal was to determine if these firing patterns had sufficient information to allow RE identification of the input combinations. Like other neural systems, the motoneuron input-output system is likely non-unique. This non-uniqueness could potentially limit this RE approach, as many input combinations can produce similar outputs. However, our simulations revealed that firing patterns contained sufficient information to sharply restrict the solution space. Thus, our RE approach successfully generated estimates of the actual simulated patterns of excitation, inhibition, and neuromodulation, with variances accounted for ranging from 75–90%. It was striking that nonlinearities induced in firing patterns by the neuromodulation inputs did not impede RE, but instead generated distinctive features in firing patterns that aided RE. These simulations demonstrate the potential of this form of RE analysis. It is likely that the ever-increasing capacity of supercomputers will allow increasingly accurate RE of neuron inputs from their firing patterns from many neural systems.

Supercomputer framework for reverse engineering firing patterns of neuron populations to identify their synaptic inputs.

In this study, we develop new reverse engineering (RE) techniques to identify the organization of the synaptic inputs generating firing patterns of populations of neurons. We tested these techniques in silico to allow rigorous evaluation of their effectiveness, using remarkably extensive parameter searches enabled by massively-parallel computation on supercomputers. We chose spinal motoneurons as our target neural system, since motoneurons process all motor commands and have well-established input-output properties. One set of simulated motoneurons was driven by 300,000+ simulated combinations of excitatory, inhibitory, and neuromodulatory inputs. Our goal was to determine if these firing patterns had sufficient information to allow RE identification of the input combinations. Like other neural systems, the motoneuron input-output system is likely non-unique. This non-uniqueness could potentially limit this RE approach, as many input combinations can produce similar outputs. However, our simulations revealed that firing patterns contained sufficient information to sharply restrict the solution space. Thus, our RE approach successfully generated estimates of the actual simulated patterns of excitation, inhibition, and neuromodulation, with variances accounted for ranging from 75-90%. It was striking that nonlinearities induced in firing patterns by the neuromodulation inputs did not impede RE, but instead generated distinctive features in firing patterns that aided RE. These simulations demonstrate the potential of this form of RE analysis. It is likely that the ever-increasing capacity of supercomputers will allow increasingly accurate RE of neuron inputs from their firing patterns from many neural systems.

The association of intraoperative electric field and neural excitation patterns of the cochlear implant with patient-related factors of age, gender, cochlear diameter, and postoperative speech measures

The association of intraoperative electric field and neural excitation patterns of the cochlear implant with patient-related factors of age, gender, cochlear diameter, and postoperative speech measures

Interference patterns of two-photon excited fluorescence by spatial beam shaping

We report on two-photon excited fluorescence interference patterns produced by spatial laser beam shaping. Thereto, a focused spatially modulated laser beam component is overlapped with an unfocused Gaussian beam component, and both are directed on a cuvette filled with dye. The phase retardance between the two common path laser components is precisely adjusted by a 2D liquid crystal modulator. With this method it is possible to generate various fluorescence patterns which exhibit sharp features and a high contrast due to constructive and destructive interference of a two-photon excitation process. The developed spatial shaping interference technique with two-photon excitations has a high potential for optical and biophotonic imaging applications.

Atrial Fibrillation and Underlying Structural and Electrophysiological Heterogeneity.

As atrial fibrillation (AF) progresses from initial paroxysmal episodes to the persistent phase, maintaining sinus rhythm for an extended period through pharmacotherapy and catheter ablation becomes difficult. A major cause of the deteriorated treatment outcome is the atrial structural and electrophysiological heterogeneity, which AF itself can exacerbate. This heterogeneity exists or manifests in various dimensions, including anatomically segmental structural features, the distribution of histological fibrosis and the autonomic nervous system, sarcolemmal ion channels, and electrophysiological properties. All these types of heterogeneity are closely related to the development of AF. Recognizing the heterogeneity provides a valuable approach to comprehending the underlying mechanisms in the complex excitatory patterns of AF and the determining factors that govern the seemingly chaotic propagation. Furthermore, substrate modification based on heterogeneity is a potential therapeutic strategy. This review aims to consolidate the current knowledge on structural and electrophysiological atrial heterogeneity and its relation to the pathogenesis of AF, drawing insights from clinical studies, animal and cell experiments, molecular basis, and computer-based approaches, to advance our understanding of the pathophysiology and management of AF.

Local quenches in fracton field theory: Lieb-Robinson bound, noncausal dynamics and fractal excitation patterns

We study the out-of-equilibrium dynamics induced by a local perturbation in fracton field theory. For the Z4- and Z8-symmetric free fractonic theories, we compute the time dynamics of several observables such as the two-point Green’s function, ⟨ϕ2⟩ condensate, energy density, and the dipole momentum. The time-dependent considerations highlight that the free fractonic theory breaks causality and exhibits instantaneous signal propagation, even if an additional relativistic term is included to enforce a speed limit in the system. We show that it is related to the fact that the Lieb-Robinson bound does not hold in the continuum limit of the fracton field theory, and the effective bounded speed of light does not emerge. For the theory in finite volume, we show that the fracton wave front acquires fractal shape with nontrivial Hausdorff dimension and argue that this phenomenon cannot be explained by a simple self-interference effect. Published by the American Physical Society 2024

Mixtures of Dirichlet processes for joint spatial modelling of transcranial magnetic stimulation mapping data

Abstract A patient’s responses to Transcranial Magnetic Stimulation (TMS) pulses on the motor cortex have a complex spatial pattern, making it challenging to understand the response patterns across multiple patients. We developed a mixture of Dirichlet process models to distinguish between patient-specific and shared spatial patterns across multiple patients to provide insight into consistent response patterns essential for developing personalized treatment procedures. The Metropolis–Hastings within Gibbs sampler of the Markov Chain Monte Carlo algorithm was developed for estimation. The model was used to analyse the TMS data of 3 healthy subjects. The study revealed that the primary motor cortex of the hand consistently emerges as a promising region for eliciting optimal responses. This area serves as a key target for brain mapping using TMS to identify cortical hotspots. However, the excitability patterns in this region can vary significantly among patients.

Unpinning and elimination of spiral waves and turbulence through local optogenetical illumination.

Spiral waves in cardiac tissue have been identified as a significant factor leading to life-threatening arrhythmias and ventricular fibrillation. Consequently, understanding the mechanisms underlying the dynamics of such waves and exploring strategies for their elimination have garnered substantial interest and emerged as crucial research objectives. Spiral waves often become pinned (trapped) at anatomical obstacles in cardiac tissue, resulting in increased stability and posing challenges for their elimination. The unpinning of spiral waves can be achieved through the application of an external electric field and has been the subject of previous research. Recently, optogenetics has emerged as an alternative method to modulate electrical activity by illumination of cardiac tissue. In this paper, we employ mathematical modeling to investigate the potential of utilizing local illumination to unpin and eliminate spiral waves in cardiac tissue. We also extend this methodology to explore the effects of more complex turbulent excitation patterns. We conduct simulations using low-dimensional (Barkley) and ionic (Fenton-Karma) models of cardiac tissue, incorporating optogenetical channels. Our findings demonstrate that local suprathreshold illumination can successfully unpin spiral waves in 100% of cases. Notably, unlike unpinning by electrical field stimulation, this approach does not necessitate precise timing of stimulus application during a specific phase of rotation. Additionally, we demonstrate that periodic optogenetical stimulation can effectively eliminate both unpinned spiral waves and turbulence by moving them toward the boundary via an antitachycardia pacing mechanism.

Phases and dynamics of few fermionic impurities immersed in two-dimensional boson droplets

We unravel the ground state properties and emergent nonequilibrium dynamics of a mixture consisting of a few spin-polarized fermions embedded in a two-dimensional bosonic quantum droplet. For an increasingly attractive droplet-fermion interaction we find a transition from a spatially delocalized fermion configuration to a state where the fermions are highly localized and isolated. This process is accompanied by the rise of induced fermion-fermion interactions mediated by the droplet. Additionally, for increasing attractive droplet-fermion coupling, undulations in the droplet density occur in the vicinity of the fermions manifesting the back-action of the latter. Following interaction quenches from strong to weaker attractive droplet-fermion couplings reveals the spontaneous nucleation of complex excitation patterns in the fermion density such as ring- and cross-shaped structures. These stem from the enhanced interference of the fermions that remain trapped within the droplet, which emulates, to a good degree, an effective potential for the fermions. The non-negligible back-action of the droplet manifests itself in the fact that the effective potential predictions are less accurate at the level of the many-body wave function. Our results provide a paradigm for physics beyond the reduced single-component droplet model, unveiling the role of back-action in droplets and the effect of induced mediated interactions. Published by the American Physical Society 2024

The evolution of patch-clamp electrophysiology: robotic, multiplex, and dynamic.

The patch-clamp technique has been the gold standard for analysis of excitable cells. Since its development in the 1980s it has contributed immensely to our understanding of neurons, muscle cells, and cardiomyocytes, and the ion channels and receptors that reside within them. This technique, predicated on Ohm's law, enables precise measurements of macroscopic excitability patterns, and ionic and gating conductances that can be assessed even down to the single channel level. Over the years, patch-clamp electrophysiology has undergone extensive modifications, with the introduction of new applications that have enhanced its power and reach. The most recent evolution of this technique occurred with the introduction of robotic high throughput automated platforms that enable high quality simultaneous recordings, in both voltage- and current-clamp modes, from 10s to 100s of cells, including cells freshly isolated from their native tissues. Combined with new dynamic-clamp applications, these new methods provide increasingly powerful tools for studying the contributions of ion channels and receptors to electrogenesis. In this brief review, we provide an overview of these enhanced patch-clamp techniques, followed by some of the applications presently being pursued, and a perspective into the potential future of the patch-clamp method. Significance Statement The patch-clamp technique, introduced in the 1980s, has revolutionized understanding of electrogenesis. Predicated on Ohm's law, this approach facilitates exploration of ionic conductances, gating mechanisms of ion channels and receptors, and their roles in neuronal, muscular, and cardiac excitability. Robotic platforms for high-throughput patch-clamp, and dynamic-clamp, have recently expanded its reach. Here, we outline new advances in patch-clamp including high throughput analysis of freshly-isolated neurons, and discuss the increasingly powerful trajectory of new patch-clamp techniques.

Retigabine, a potassium channel opener, restores thalamocortical neuron functionality in a murine model of autoimmune encephalomyelitis

BackgroundMultiple Sclerosis (MS) is an autoimmune neurodegenerative disease, whose primary hallmark is the occurrence of inflammatory lesions in white and grey matter structures. Increasing evidence in MS patients and respective murine models reported an impaired ionic homeostasis driven by inflammatory-demyelination, thereby profoundly affecting signal propagation. However, the impact of a focal inflammatory lesion on single-cell and network functionality has hitherto not been fully elucidated. ObjectivesIn this study, we sought to determine the consequences of a localized cortical inflammatory lesion on the excitability and firing pattern of thalamic neurons in the auditory system. Moreover, we tested the neuroprotective effect of Retigabine (RTG), a specific Kv7 channel opener, on disease outcome. MethodsTo resemble the human disease, we focally administered pro-inflammatory cytokines, TNF-α and IFN-γ, in the primary auditory cortex (A1) of MOG35-55 immunized mice. Thereafter, we investigated the impact of the induced inflammatory milieu on afferent thalamocortical (TC) neurons, by performing ex vivo recordings. Moreover, we explored the effect of Kv7 channel modulation with RTG on auditory information processing, using in vivo electrophysiological approaches. ResultsOur results revealed that a cortical inflammatory lesion profoundly affected the excitability and firing pattern of neighboring TC neurons. Noteworthy, RTG restored control-like values and TC tonotopic mapping. ConclusionOur results suggest that RTG treatment might robustly mitigate inflammation-induced altered excitability and preserve ascending information processing.

Relativistic and quantum electrodynamics effects on NMR shielding tensors of TlX (X = H, F, Cl, Br, I, At) molecules.

The results of relativistic calculations of nuclear magnetic resonance shielding tensors (σ) for the thallium monocation (Tl+), thallium hydride (TlH), and thallium halides (TlF, TlCl, TlBr, TlI, and TlAt) are presented as obtained within a four-component polarization propagator formalism and a two-component linear response approach within the zeroth-order regular approximation. In addition to a detailed analysis of relativistic effects performed in this work, some quantum electrodynamical (QED) effects on those nuclear magnetic resonance shieldings and other small contributions are estimated. A strong dependence of σ(Tl) on the bonding partner is found, together with a very weak dependence of QED effects with them. In order to explain the trends observed, the excitation patterns associated with relativistic ee (or paramagnetic-like) and pp (or diamagnetic-like) contributions to σ are analyzed. For this purpose, the electronic spin-free and spin-dependent contributions are separated within the two-component zeroth-order regular approximation, and the influence of spin-orbit coupling on involved molecular orbitals is studied, which allows for a thorough understanding of the underlying mechanisms.

New patterns of localized excitations in (2+1)-dimensions: The fifth-order asymmetric Nizhnik–Novikov–Veselov equation

By applying the mastersymmetry of degree one to the time-independent symmetry K 1, the fifth-order asymmetric Nizhnik–Novikov–Veselov system is derived. The variable separation solution is obtained by using the truncated Painlevé expansion with a special seed solution. New patterns of localized excitations, such as dromioff, instanton moving on a curved line, and tempo-spatial breather, are constructed. Additionally, fission or fusion solitary wave solutions are presented, graphically illustrated by several interesting examples.

Scapula-Focused Exercises With or Without Biofeedback and Corticospinal Excitability in Recreational Overhead Athletes With Shoulder Impingement.

Individuals with shoulder impingement syndrome (SIS) exhibit changes in corticospinal excitability, scapular kinematics, and scapular muscle-activation patterns. To restore the scapular kinematics and muscle-activation patterns in individuals with SIS, treatment protocols usually include scapula-focused exercises, such as scapular-orientation and strength training. To investigate whether scapular-orientation and strength training can reverse the altered corticospinal excitability of recreational overhead athletes with SIS. Randomized controlled clinical trial. University laboratory. Forty-one recreational overhead athletes with SIS: 20 in the scapular-orientation group (age = 26.45 ± 4.13 years, height = 171.85 ± 7.88 cm, mass = 66.70 ± 10.68 kg) and 21 in the strengthening group (age = 26.43 ± 5.55 years, height = 171.62 ± 5.87 cm, mass = 68.67 ± 10.18 kg). Both groups performed a 30-minute training protocol consisting of 3 exercises to strengthen the lower trapezius (LT) and serratus anterior muscles without overactivating the upper trapezius muscles. Participants in the scapular-orientation group were instructed to consciously activate their scapular muscles with electromyographic biofeedback and cues, whereas the strengthening group did not receive biofeedback or cues for scapular motion. Corticospinal excitability was assessed using transcranial magnetic stimulation. Scapular kinematics and muscle activation during arm elevation were also measured. After training, both groups demonstrated an increase in motor-evoked potentials in the LT (P = .004) and increases in scapular upward rotation (P = .03), LT activation (P < .001), and serratus anterior activation (P < .001) during arm elevation. Moreover, the scapular-orientation group showed higher LT activation levels during arm elevation after training than the strengthening group (P = .03). With or without biofeedback and cues, scapula-focused exercises improved scapular control and increased corticospinal excitability. Adding biofeedback and cues for scapular control during exercise helped facilitate greater LT activation, so feedback and cues are recommended during scapula-focused training.

Organized patterns of excitation during persistent atrial fibrillation in humans relate to tissue structure and activation rate

Abstract Background The contribution of organized patterns of excitation as mechanisms maintaining persistent atrial fibrillation (PAF) is questioned. Purpose We aim to analyze the relationship of focal and reentrant activities, identified with the CARTO-Finder system, with tissue structure and activation rate to explain potential link with mechanisms and outcomes. Methods 33 patients with PAF of at least 6 months (24±4 months) were admitted for right and left atrial (RA &amp; LA) mapping with the CARTO-Finder system. The biatrial geometry, bipolar Penta-Ray`s signals (30 sec long) and activation patterns were exported for off-line analysis (MatLab environment). A fast-Fourier transform was computed on 30 sec bipolar signal length segments to compute dominant frequency (DF) and represented on atrial shells. Focal and reentrant patterns of activation were superimposed, and correlation with DF and bipolar voltage analyzed. Results Biatrial mapping was performed obtaining 15.3±5 Finder maps from the RA and 15.9±5 Finder maps from the LA. Focal activities (182±151 at the RA &amp; 270±21 at the LA) were documented in all patients at both atria. Rotational activities (more than 2 consecutive) were documented in the left atria in 4 patients (22.5±16.8 rotations) and in the right atria in 9 patients (35.5±32 rotations). 30 sec long activation rate was higher at places with focal activities compared with areas without organized patterns (DF: 6.11±0.09 Hz vs 5.7±0.09 Hz; p&amp;lt;0.001). The higher the number of consecutive focal activities, the higher the tissue activation rate (DF no focal activities 5.7±0.09 Hz vs DF 1-5 focal activities 6.0±0.14 Hz vs DF&amp;gt;5 focal activities 6.2±0.14 Hz; p&amp;lt;0.001). In addition, DF at focal activities strongly correlates with DF at areas without organized patterns (Pearson 0.91; p&amp;lt;0.001). The bipolar voltage was higher at places with focal activities compared with areas without organized patterns (1.0±0.04 mV vs 0.5±0.04 mV; p&amp;lt;0.001). None of the previous were observed at places with rotational activities (DF: 5.9±0.16 Hz vs 5.7±0.09 Hz; p=0.204 &amp; Volt: 0.6±0.08 mV vs 0.5±0.04 mV; p=0.364). During follow-up after ablation (24±7 months), a cox regression model including number of focal activities, number of rotations, mean tissue activation rate (mean DF) and bipolar voltage, identified bipolar voltage as a unique independent predictor of survival free of AF recurrence (p=0.04). Conclusions Focal activities identified with the CARTO Finder system during PAF in humans correlate with tissue structure and activation rate, suggesting a potential link with mechanisms.

α1-Adrenergic Receptors Control the Activity of Sinoatrial Node by Modulating Transmembrane Transport of Chloride Anions

Norepinephrine (NE), which is released by sympathetic nerve endings, causes an increase in the frequency of spontaneous action potentials in the pacemaker cardiomyocytes of the sinoatrial node (SAN), also known as the “pacemaker” of the heart. This results in an increase in heart rate (HR). It is known that two types of postsynaptic adrenoreceptors (ARs), α1-AR and β-AR, can mediate the effects of NE. The role of α1-AR in the sympathetic control of heart rate and SAN automaticity, as well as the membrane mechanisms mediation the effects of α1-AR on the pacemaker, have not yet been elucidated. In this study, we utilized immunofluorescence confocal microscopy to examine the distribution of α1A-AR in the SAN of rats. Additionally, we assessed the expression of α1A-AR mRNA in the SAN tissue using RT-PCR. Furthermore, we investigated the impact of α1-AR stimulation on key functional parameters of the pacemaker, including the corrected sinus node recovery time (SNRT/cSNRT) and the SAN accommodation, using the Langendorff perfused heart technique. We also used optical mapping of the electrical activity of perfused, isolated tissue preparations to study the effect of α1-AR stimulation on the spatiotemporal characteristics of SAN excitation. We tested the effects of chloride transmembrane conductance blockade on alteration of functional parameters and pattern of SAN excitation caused by α1-AR. Fluorescent signals corresponding to α1A-AR have been identified in SAN cardiomyocytes, indicating the presence of α1A-AR at protein level. The expression of α1A-AR in SAN has been also confirmed at the mRNA level. The stimulation of α1-AR affects SAN functioning Phenylephrine (PHE) utilized as α1A-AR agonist causes a decrease in SNRT/cSNRT, as well as an acceleration of SAN accommodation. These effects were rate dependent and were observed at a high frequency of pacemaker tissue stimulation. PHE induces changes in the excitation pattern of the SAN. The effects of PHE on functional parameters and SAN excitation pattern are attenuated by Ca2+-dependent chloride channel blocker NPPB but remains unaffected by the protein kinase C inhibitor BIM. Our results suggest that cardiac α1-ARs are important for maintaining function of SAN pacemaker at high heart rates and that α1-AR signalling cascades in the SAN target Ca2+-dependent chloride channels are involved in the α1-adrenergic modulation of the electrophysiological properties of the heart pacemaker.

Discrimination of rippled spectra with various ripple widths in listeners with normal and impaired hearing

In listeners aged 26 to 82 years with various degrees of hearing loss (from normal to moderate), the frequency resolving power (FRP) was assessed as the resolved ripple density resolution in rippled-spectrum signals at various ripple widths. In normal-hearing listeners, FRP increased with narrowing the ripple width. In impaired-hearing listeners, the effect of narrowing the ripple width was minor. The difference between the normal- and impaired-hearing listeners could not be explained by the excitation pattern model of the rippled spectrum resolution. The temporal analysis model did explain this difference on an assumption that in normal hearing listeners, enhancing the autocorrelation of the input signal resulted in prolongation of the delay at which the autocorrelation could be detected by the auditory system, whereas in impaired-hearing listeners this effect was reduced or absent.

The Rapid Decline in Interaural-Time-Difference Sensitivity for Pure Tones Can Be Explained by Peripheral Filtering.

The interaural time difference (ITD) is a primary horizontal-plane sound localization cue computed in the auditory brainstem. ITDs are accessible in the temporal fine structure of pure tones with a frequency of no higher than about 1400Hz. How listeners' ITD sensitivity transitions from very best sensitivity near 700Hz to impossible to detect within 1 octave currently lacks a fully compelling physiological explanation. Here, it was hypothesized that the rapid decline in ITD sensitivity is dictated not by a central neural limitation but by initial peripheral sound encoding, specifically, the low-frequency (apical) portion of the cochlear excitation pattern produced by a pure tone. ITD sensitivity was measured in 16 normal-hearing listeners as a joint function of frequency (900-1500Hz) and level (10-50dB sensation level). Performance decreased with increasing frequency and decreasing sound level. The slope of performance decline was 90dB/octave, consistent with the low-frequency slope of the cochlear excitation pattern. Fine-structure ITD sensitivity near 1400Hz may be conveyed primarily by "off-frequency" activation of neurons tuned to lower frequencies near 700Hz. Physiologically, this could be realized by having neurons sensitive to fine-structure ITD up to only about 700Hz. A more extreme model would have only a single narrow channel near 700Hz that conveys fine-structure ITDs. Such a model is a major simplification and departure from the classic formulation of the binaural display, which consists of a matrix of neurons tuned to a wide range of relevant frequencies and ITDs.

Evolution of Hyperventilation-Induced Nystagmus in Acute Unilateral Vestibulopathy-Interpretative Model and Etiopathogenetic Hypotheses.

Hyperventilation induces metabolic changes that can elicit nystagmus (hyperventilation-induced nystagmus, HVIN) in various vestibular disorders, revealing vestibular imbalance and bringing out central or peripheral asymmetries. In acute unilateral vestibulopathy (AUVP, namely vestibular neuritis), hyperventilation can induce different patterns of nystagmus (excitatory, inhibitory, or negative), disclosing or modifying existing static vestibular asymmetries through its ability to invalidate compensation or increase peripheral excitability. In this context, we followed the evolutionary stages of HVIN in AUVP across 35 consecutive patients, with the goal of assessing alterations in the oculomotor pattern caused by hyperventilation over time. In the acute phase, the incidence of the excitatory pattern (and the strongly excitatory one, consisting of a reversal nystagmus evoked by hyperventilation) was significantly higher compared to the inhibitory pattern; then, a progressive reduction in the incidence of the excitatory pattern and a concomitant gradual increase in the incidence of the inhibitory one were observed in the follow-up period. Assuming the role of the ephaptic effect and the transient loss of vestibular compensation as opposing mechanisms, i.e., excitatory and inhibitory, respectively, the oculomotor pattern evoked by hyperventilation is the result of the interaction of these two factors. The data obtained allowed us to hypothesize an interpretative model regarding the pathogenetic aspects of responses evoked by hyperventilation and the etiologies of the disease: according to our hypotheses, the excitatory pattern implies a neuritic (viral) form of AUVP; instead, the inhibitory (and negative) one can be an expression of both the neuritic (viral) and vascular forms of the disease.

Revisiting distinct nerve excitability patterns in patients with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a devastating neurodegenerative disease, characterized by loss of central and peripheral motor neurons. Although the disease is clinically and genetically heterogeneous, axonal hyperexcitability is a commonly observed feature that has been suggested to reflect an early pathophysiological step linked to the neurodegenerative cascade. Therefore, it is important to clarify the mechanisms causing axonal hyperexcitability and how these relate to the clinical characteristics of patients. Measures derived directly from a nerve excitability recording are frequently used as study end points, although their biophysical basis is difficult to deduce. Mathematical models can aid in the interpretation but are reliable only when applied to group-averaged recordings. Consequently, model estimates of membrane properties cannot be compared with clinical characteristics or treatment effects in individual patients, posing a considerable limitation in heterogeneous diseases, such as amyotrophic lateral sclerosis. To address these challenges, we revisited nerve excitability using a new pattern analysis-based approach (principal component analysis). We evaluated disease-specific patterns of excitability changes and established their biophysical origins. Based on the observed patterns, we developed new compound measures of excitability that facilitate the implementation of this approach in clinical settings. We found that excitability changes in amyotrophic lateral sclerosis patients (n = 161, median disease duration = 11 months) were characterized by four unique patterns compared with controls (n = 50, age and sex matched). These four patterns were best explained by changes in resting membrane potential (modulated by Na+/K+ currents), slow potassium and sodium currents (modulated by their gating kinetics) and refractory properties of the nerve. Consequently, we were able to show that altered gating of slow potassium channels was associated with, and predictive of, the rate of progression of the disease on the amyotrophic lateral sclerosis functional rating scale. Based on these findings, we designed four composite measures that capture these properties to facilitate implementation outside this study. Our findings demonstrate that changes in nerve excitability in patients with amyotrophic lateral sclerosis are dominated by four distinct patterns, each with a distinct biophysical origin. Based on this new approach, we provide evidence that altered slow potassium-channel function might play a role in the rate of disease progression. The magnitudes of these patterns, quantified using a similar approach or our new composite measures, have potential as efficient measures to study membrane properties directly in amyotrophic lateral sclerosis patients, and thus aid prognostic stratification and trial design.