Expression of interferon-γ and its effect on cough hypersensitivity in chronic refractory cough patients

Chronic refractory cough (CRC) is characterised by cough hypersensitivity. Interferon-γ (IFN-γ) has been reported to induce calcium influx, action potentials of vagal neurons in vitro and cough response in guinea pigs. While the effect of IFN-γ in CRC patients remains unknown. Here, via flow-cytometry and inhalation cough challenge, we found CRC patients had significantly increased levels of sputum IFN-γ+CD4+ T cells, IFN-γ+CD8+ T cells as well as supernatant of IFN-γ. The average number of coughs in CRC patients increased as the concentration of inhaled IFN-γ went up in IFN-γ cough challenge. Two or more coughs and five or more coughs elicited by inhaled IFN-γ in CRC patients occurred in 7 of 10 and 2 of 10, respectively. Preinhaled IFN-γ (100 µg/mL) increased the capsaicin cough sensitivity in CRC patients but not healthy volunteers. Targeting IFN-γ may be a potential effective anti-tussive strategy in CRC patients.

SK Current, Expressed During the Development and Regeneration of Chick Hair Cells, Contributes to the Patterning of Spontaneous Action Potentials

Chick hair cells display calcium (Ca2+)-sensitive spontaneous action potentials during development and regeneration. The role of this activity is unclear but thought to be involved in establishing proper synaptic connections and tonotopic maps, both of which are instrumental to normal hearing. Using an electrophysiological approach, this work investigated the functional expression of Ca2+-sensitive potassium [IK(Ca)] currents and their role in spontaneous electrical activity in the developing and regenerating hair cells (HCs) in the chick basilar papilla. The main IK(Ca) in developing and regenerating chick HCs is an SK current, based on its sensitivity to apamin. Analysis of the functional expression of SK current showed that most dramatic changes occurred between E8 and E16. Specifically, there is a developmental downregulation of the SK current after E16. The SK current gating was very sensitive to the availability of intracellular Ca2+ but showed very little sensitivity to T-type voltage-gated Ca2+ channels, which are one of the hallmarks of developing and regenerating hair cells. Additionally, apamin reduced the frequency of spontaneous electrical activity in HCs, suggesting that SK current participates in patterning the spontaneous electrical activity of HCs.

Diaphragmatic Compound Muscle Action Potentials Recorded From Over the Sternum and Lateral Chest Wall: a Comparative Study

Objectives:To report normative data for diaphragmatic compound muscle action potentials (DCMAPs) recorded from over the sternum and lateral chest wall (LCW).Method:The phrenic nerve of seventy-three healthy subjects was bilaterally stimulated at the posterior border of the sternocleidomastoid muscle. DCMAPs from over the sternum and LCW were recorded (inspiration/expiration). Results: Normative values of sternal and LCW DCMAPs were presented. Significant differences were found between sternal and LCW potentials in the mean latency, amplitude, and area (p<0.001). The duration did not differ between the two sites. Differences were found between inspiration and expiration, right and left sides, and men and women. Regression analysis showed a relation between latency of sternal and LCW potentials and age. Latency (LCW potentials) and amplitude and area (sternal/LCW potentials) were related to gender. Amplitude (LCW potentials/inspiration) and area (sternal potentials/inspiration) were related to chest circumference (p=0.023 and 0.013 respectively). Area (sternal potentials/expiration) was related to the BMI (p=0.019). Conclusions: Our normative values for sternal and LCW DCMAPs are provided. Notable differences in the DCMAPs parameters were detected between the two recording sites, inspiration and expiration, right and left, and men and women. Significance:The technique of phrenic nerve should be standardized.

High density single-unit human cortical recordings using the Neuropixels probe

A fundamental unit of neural computation is the action potential. While significant advances have been made in the ability to sample action potentials of large numbers of individual neurons in animal models, translation of these methodologies to humans has been lacking due to clinical time constraints, electrical noise in the operating room, and reliability of the methodology. Here we present a reliable method for intraoperative recording of dozens of neurons in humans using the Neuropixels probe, yielding up to ~100 simultaneously-recorded single-units (n=596 across 11 recordings in 8 participants). Most single-units were active within 1 minute of reaching target depth, compatible with clinical time constraints. Cell pairs active close in time were spatially closer in most recordings, demonstrating the power to resolve complex cortical dynamics. Altogether, this approach provides access to population single-unit activity across the depth of human neocortex at scales previously only accessible in animal models.

Neurophysiological Characterization of Posteromedial Hypothalamus in Anaesthetized Patients

Deep brain stimulation (DBS) requires a precise localization, which is especially difficult at the hypothalamus, because it is usually performed in anesthetized patients. We aimed to characterize the neurophysiological properties posteromedial hypothalamus (PMH), identified by the best neurophysiological response to electrical stimulation. We obtained microelectrode recordings from four patients with intractable aggressivity operated under general anesthesia. We pooled data from 1.5 mm at PMH, 1.5 mm upper (uPMH) and 1.5 mm lower (lPMH). We analyzed 178 units, characterized by the mean action potential (mAP). Only 11% were negative. We identified the next types of units: P1N1 (30.9%), N1P1N2 (29.8%), P1P2N1 (16.3%), N1P1 and N1N2P1 (6.2%) and P1N1P2 (5.0%). Besides, atypical action potentials (amAP) were recorded in 11.8%. PMH was highly different in cell composition from uPMH and lPMH, exhibiting also a higher percentage of amAP. Different kinds of cells shared similar features for the three hypothalamic regions. Although features for discharge pattern did not show region specificity, the probability mass function of inter-spike interval were different for all the three regions. Comparison of the same kind of mAP with thalamic neurons previously published demonstrate that most of cells are different for derivatives, amplitude and/or duration of repolarization and depolarization phases and also for the first phase, demonstrating a highly specificity for both brain centers. Therefore, the different properties described for PMH can be used to positively refine targeting, even under general anesthesia. Besides, we describe by first time the presence of atypical extracellular action potentials.

The N-linker region of hERG1a upregulates hERG1b potassium channels

A major physiological role of hERG1 (human Ether-a-go-go-Related Gene) potassium channels is to repolarize cardiac action potentials. Two isoforms, hERG1a and hERG1b, associate to form the native cardiac IKr current in vivo. Inherited mutations in hERG1a or hERG1b cause prolonged cardiac repolarization, Long QT Syndrome and sudden death arrhythmia. hERG1a subunits assemble with and enhance the number of hERG1b subunits at the plasma membrane, but the mechanism for the increase in hERG1b by hERG1a is not well understood. Here, we report that the hERG1a N-terminal PAS (Per-Arnt-Sim) domain-N-linker region expressed in trans with hERG1b markedly increased hERG1b currents and increased biotin-labelled hERG1b protein at the membrane surface. hERG1b channels with a deletion of the 1b domain did not have a measurable increase in current or biotinylated protein when co-expressed with hERG1a PAS domain-N-linker regions indicating that the 1b domain was required for the increase in hERG1b. Using a biochemical pull-down interaction assay and a FRET hybridization experiment, we detected a direct interaction between the hERG1a PAS domain-N-linker region and the hERG1b N-terminal 1b domain. Using engineered deletions and alanine mutagenesis, we identified a short span of amino acids at positions 216-220 within the hERG1a N-linker region that were necessary for the upregulation of hERG1b. Taken together, we propose that direct structural interactions between the hERG1a N-linker region and the hERG1b N-terminal 1b domain increase hERG1b at the plasma membrane. Mechanisms that enhance hERG1b current would be anticipated to shorten action potentials, which could be anti-arrhythmic, and may point toward hERG1b or the hERG1a N-linker as molecular targets for therapy for Long QT syndrome.

Effects of muscle shortening on single-fiber, motor unit, and compound muscle action potentials

Even under isometric conditions, muscle contractions are associated with some degree of fiber shortening. The effects of muscle shortening on extracellular electromyographic potentials have not been characterized in detail. Moreover, the anatomical, biophysical, and detection factors influencing the muscle-shortening effects have been neither identified nor understood completely. Herein, we investigated the effects of muscle shortening on the amplitude and duration characteristics of single-fiber, motor unit, and compound muscle action potentials. We found that, at the single-fiber level, two main factors influenced the muscle-shortening effects: (1) the electrode position and distance relative to the myotendinous zone and (2) the electrode distance to the maxima of the dipole field arising from the stationary dipole created at the fiber-tendon junction. Besides, at the motor unit and muscle level, two additional factors were involved: (3) the overlapping between the propagating component of some fibers with the non-propagating component of other fibers and (4) the spatial spreading of the fiber-tendon junctions. The muscle-shortening effects depend critically on the electrode longitudinal distance to the myotendinous zone. When the electrode was placed far from the myotendinous zone, muscle shortening resulted in an enlargement and narrowing of the final (negative) phase of the potential, and this enlargement became less pronounced as the electrode approached the fiber endings. For electrode locations close to the myotendinous zone, muscle shortening caused a depression of both the main (positive) and final (negative) phases of the potential. Beyond the myotendinous zone, muscle shortening led to a decrease of the final (positive) phase. The present results provide reference information that will help to identify changes in MUPs and M waves due to muscle shortening, and thus to differentiate these changes from those caused by muscle fatigue. Graphical abstract

Kink propagation in the artificial axon

The Artificial Axon is a unique synthetic system, based on biomolecular components, which supports action potentials. Here we consider, theoretically, the corresponding space extended system, and discuss the occurrence of solitary waves, or kinks. Such structures are indeed observed in living systems. In contrast to action potentials, stationary kinks are possible. We point out an analogy with the interface separating two condensed matter phases, though our kinks are always non-equilibrium, dissipative structures, even when stationary.

Critical behavior in the artificial axon

The Artificial Axon is a unique synthetic system, based on biomolecular components, which supports action potentials. Here we examine, experimentally and theoretically, the properties of the threshold for firing in this system. As in real neurons, this threshold corresponds to the critical point of a saddle-node bifurcation. We measure the delay time for firing as a function of the distance to threshold, recovering the expected scaling exponent of −1/2. We introduce a minimal model of the Morris-Lecar type, validate it on the experiments, and use it to extend analytical results obtained in the limit of ”fast” ion channel dynamics. In particular, we discuss the dependence of the firing threshold on the number of channels. The Artificial Axon is a simplified system, an Ur-neuron, relying on only one ion channel species for functioning. Nonetheless, universal properties such as the action potential behavior near threshold are the same as in real neurons. Thus we may think of the Artificial Axon as a cell-free breadboard for electrophysiology research.

Simplifying the hardware requirements for fast neural EIT of peripheral nerves

Objective: The main objective of this study was to assess the feasibility of lowering the hardware requirements for fast neural EIT in order to support the distribution of this technique. Specifically, the feasibility of replacing the commercial modules present in the existing high-end setup with compact and cheap customized circuitry was assessed. Approach: Nerve EIT imaging was performed on rat sciatic nerves with both our standard ScouseTom setup and a customized version in which commercial benchtop current sources were replaced by custom circuitry. Electrophysiological data and images collected in the same experimental conditions with the two setups were compared. Data from the customized setup was subject to a down-sampling analysis to simulate the use of a recording module with lower specifications. Main results: Compound action potentials (573±287µV and 487±279µV, p=0.28) and impedance changes (36±14µV and 31±16µV, p=0.49) did not differ significantly when measured using commercial high-end current sources or our custom circuitry, respectively. Images reconstructed from both setups showed neglibile (<1voxel, i.e. 40µm) difference in peak location and a high degree of correlation (R2=0.97). When down-sampling from 24 to 16 bits ADC resolution and from 100KHz to 50KHz sampling frequency, signal-to-noise ratio showed acceptable decrease (<-20%), and no meaningful image quality loss was detected (peak location difference <1voxel, pixel-by-pixel correlation R2=0.99). Significance: The technology developed for this study greatly reduces the cost and size of a fast neural EIT setup without impacting quality and thus promotes the adoption of this technique by the neuroscience research community.