Holistic idealization: An artifactual standpoint.

Idealization is commonly understood as distortion: representing things differently than how they actually are. In this paper, we outline an alternative artifactual approach that does not make misrepresentation central for the analysis of idealization. We examine the contrast between the Hodgkin-Huxley (1952a, b, c) and the Heimburg-Jackson (2005, 2006) models of the nerve impulse from the artifactual perspective, and argue that, since the two models draw upon different epistemic resources and research programs, it is often difficult to tell which features of a system the central assumptions involved are supposed to distort. Many idealizations are holistic in nature. They cannot be locally undone without dismantling the model, as they occupy a central position in the entire research program. Nor is their holistic character mainly related to the use of mathematical and statistical modeling techniques as portrayed by Rice (2018, 2019). We suggest that holistic idealizations are implicit theoretical and representational assumptions that can only be understood in relation to the conceptual and representational tools exploited in modeling and experimental practices. Such holistic idealizations play a pivotal role not just in individual models, but also in defining research programs.

How is information transmitted in a nerve?

In the last 15 years, a debate has emerged about the validity of the famous Hodgkin-Huxley model for nerve impulse. Mechanical models have been proposed. This note reviews the experimental properties of the nerve impulse and discusses the proposed alternatives. The experimental data, which rule out some of the alternative suggestions, show that while the Hodgkin-Huxley model may not be complete, it nevertheless includes essential features that should not be overlooked in the attempts made to improve, or supersede, it.

Neurocomputational mechanisms underlying perception and sentience in the neocortex.

The basis for computation in the brain is the quantum threshold of "soliton," which accompanies the ion changes of the action potential, and the refractory membrane at convergences. Here, we provide a logical explanation from the action potential to a neuronal model of the coding and computation of the retina. We also explain how the visual cortex operates through quantum-phase processing. In the small-world network, parallel frequencies collide into definable patterns of distinct objects. Elsewhere, we have shown how many sensory cells are meanly sampled from a single neuron and that convergences of neurons are common. We also demonstrate, using the threshold and refractory period of a quantum-phase pulse, that action potentials diffract across a neural network due to the annulment of parallel collisions in the phase ternary computation (PTC). Thus, PTC applied to neuron convergences results in a collective mean sampled frequency and is the only mathematical solution within the constraints of the brain neural networks (BNN). In the retina and other sensory areas, we discuss how this information is initially coded and then understood in terms of network abstracts within the lateral geniculate nucleus (LGN) and visual cortex. First, by defining neural patterning within a neural network, and then in terms of contextual networks, we demonstrate that the output of frequencies from the visual cortex contains information amounting to abstract representations of objects in increasing detail. We show that nerve tracts from the LGN provide time synchronization to the neocortex (defined as the location of the combination of connections of the visual cortex, motor cortex, auditory cortex, etc.). The full image is therefore combined in the neocortex with other sensory modalities so that it receives information about the object from the eye and all the abstracts that make up the object. Spatial patterns in the visual cortex are formed from individual patterns illuminating the retina, and memory is encoded by reverberatory loops of computational action potentials (CAPs). We demonstrate that a similar process of PTC may take place in the cochlea and associated ganglia, as well as ascending information from the spinal cord, and that this function should be considered universal where convergences of neurons occur.

The creation of proton hopping from a drug-receptor encounter.

We extend recent modeling studies of proton hopping, used to describe the functioning of membrane channels and axon nerve conduction, to offer an explanation of the initiation of the nerve impulse at an effector-ligand encounter. This encounter is proposed to create a hydronium ion in the vicinity of the effector and ligand, which leads to a continuous flow of protons, called proton hopping, through water adjacent to this encounter. This proton hopping is proposed to be the message carried from the encounter to the axon of a particular nerve system associated with that particular effector-ligand system.

Thinking about the action potential: the nerve signal as a window to the physical principles guiding neuronal excitability.

Ever since the work of Edgar Adrian, the neuronal action potential has been considered as an electric signal, modeled and interpreted using concepts and theories lent from electronic engineering. Accordingly, the electric action potential, as the prime manifestation of neuronal excitability, serving processing and reliable "long distance" communication of the information contained in the signal, was defined as a non-linear, self-propagating, regenerative, wave of electrical activity that travels along the surface of nerve cells. Thus, in the ground-breaking theory and mathematical model of Hodgkin and Huxley (HH), linking Nernst's treatment of the electrochemistry of semi-permeable membranes to the physical laws of electricity and Kelvin's cable theory, the electrical characteristics of the action potential are presented as the result of the depolarization-induced, voltage- and time-dependent opening and closure of ion channels in the membrane allowing the passive flow of charge, particularly in the form of Na+ and K+ -ions, into and out of the neuronal cytoplasm along the respective electrochemical ion gradient. In the model, which treats the membrane as a capacitor and ion channels as resistors, these changes in ionic conductance across the membrane cause a sudden and transient alteration of the transmembrane potential, i.e., the action potential, which is then carried forward and spreads over long(er) distances by means of both active and passive conduction dependent on local current flow by diffusion of Na+ ion in the neuronal cytoplasm. However, although highly successful in predicting and explaining many of the electric characteristics of the action potential, the HH model, nevertheless cannot accommodate the various non-electrical physical manifestations (mechanical, thermal and optical changes) that accompany action potential propagation, and for which there is ample experimental evidence. As such, the electrical conception of neuronal excitability appears to be incomplete and alternatives, aiming to improve, extend or even replace it, have been sought for. Commonly misunderstood as to their basic premises and the physical principles they are built on, and mistakenly perceived as a threat to the generally acknowledged explanatory power of the "classical" HH framework, these attempts to present a more complete picture of neuronal physiology, have met with fierce opposition from mainstream neuroscience and, as a consequence, currently remain underdeveloped and insufficiently tested. Here we present our perspective that this may be an unfortunate state of affairs as these different biophysics-informed approaches to incorporate also non-electrical signs of the action potential into the modeling and explanation of the nerve signal, in our view, are well suited to foster a new, more complete and better integrated understanding of the (multi)physical nature of neuronal excitability and signal transport and, hence, of neuronal function. In doing so, we will emphasize attempts to derive the different physical manifestations of the action potential from one common, macroscopic thermodynamics-based, framework treating the multiphysics of the nerve signal as the inevitable result of the collective material, i.e., physico-chemical, properties of the lipid bilayer neuronal membrane (in particular, the axolemma) and/or the so-called ectoplasm or membrane skeleton consisting of cytoskeletal protein polymers, in particular, actin fibrils. Potential consequences for our view of action potential physiology and role in neuronal function are identified and discussed.

"Knowing It Before Blocking It," the ABCD of the Peripheral Nerves: Part A (Nerve Anatomy and Physiology).

Regional anesthesia (RA) is an interplay between the local anesthetic (LA) solution and the neural structures, resulting in nerve conduction blockade. For that, it is necessary to understand which hurdles the LA has to overcome and which components of the nerves are involved. Background knowledge of the neural and non-neural components of the nerve helps locate the safest area for LA deposition. In addition, knowledge of nerve physiology and the conduction process helps to understand the patterns of block onset, involved fibers, and block regression. Neural connective tissue protects the nerve on the one hand and influences the overall effect of the blockade and the occurrence of nerve injuries on the other. The arrangement of the nerve fibers explains the science behind the differential blockage after LA deposition. This article describes the important aspects of nerve anatomy (nerve formation and composition) and nerve physiology (impulse generation and propagation). It also provides insight into the physiological processes involved when a damaged neural structure leads to potential clinical symptoms. It will help readers sharpen their skills and knowledge to execute safe RA without damaging any vital structures in the nerve.

Normal Cortical Myelination in Galectin-4-Deficient Mice.

Myelin, critical for the correct function of the nervous system, is organized in different patterns that can include long non-myelinated axonal segments. How myelin patterning is regulated remains unexplained. The carbohydrate-binding protein galectin-4 (Gal-4) influences oligodendrocyte differentiation in vitro and is associated with non-myelinable axon segments (NMS) in cultured neurons. In consequence, Gal-4 has been proposed as a myelin patterning regulator, although no in vivo studies have corroborated this hypothesis. We used Gal-4-deficient mice (Lgals4-KO) to study the role of Gal-4 in cortical myelination in vivo. We show that cultured neurons of Lgals4-KO mice form NMS that are regulated as in control neurons. In addition, oligodendrocyte/myelin markers expression measured by biochemical and immunochemical means, and cortical myelin microstructure studied by in-depth image analysis appear unaltered in these animals. Consistently, myelin displays an essentially normal function assessed by in vivo electrophysiology and locomotion analyses. In conclusion, cortical myelin of Lgals4-KO mice does not show any significant defect in composition, organization or function, pointing to a negligible role of Gal-4 in myelination in vivo or, as discussed, to unknown mechanisms that compensate its absence.

On the Coupling between Mechanical Properties and Electrostatics in Biological Membranes.

Cell membrane structure is proposed as a lipid matrix with embedded proteins, and thus, their emerging mechanical and electrostatic properties are commanded by lipid behavior and their interconnection with the included and absorbed proteins, cytoskeleton, extracellular matrix and ionic media. Structures formed by lipids are soft, dynamic and viscoelastic, and their properties depend on the lipid composition and on the general conditions, such as temperature, pH, ionic strength and electrostatic potentials. The dielectric constant of the apolar region of the lipid bilayer contrasts with that of the polar region, which also differs from the aqueous milieu, and these changes happen in the nanometer scale. Besides, an important percentage of the lipids are anionic, and the rest are dipoles or higher multipoles, and the polar regions are highly hydrated, with these water molecules forming an active part of the membrane. Therefore, electric fields (both, internal and external) affects membrane thickness, density, tension and curvature, and conversely, mechanical deformations modify membrane electrostatics. As a consequence, interfacial electrostatics appears as a highly important parameter, affecting the membrane properties in general and mechanical features in particular. In this review we focus on the electromechanical behavior of lipid and cell membranes, the physicochemical origin and the biological implications, with emphasis in signal propagation in nerve cells.

Nerve impulse propagation: Mechanical wave model and HH model.

The Hodgkin-Huxley model (HH model) of nerve propagation from the middle of the 20th century has not remained untouched by criticism. Complementary as well as ambivalent views of this model have been published. A real breakthrough of another model does not exist yet. Many similarities as well as contradictions between the HH model and the alternative mechanical impulse model are shown.

Thinking About the Nerve Impulse: The Prospects for the Development of a Comprehensive Account of Nerve Impulse Propagation.

Currently, a scientific debate is ongoing about modeling nerve impulse propagation. One of the models discussed is the celebrated Hodgkin-Huxley model of the action potential, which is central to the electricity-centered conception of the nerve impulse that dominates contemporary neuroscience. However, this model cannot represent the nerve impulse completely, since it does not take into account non-electrical manifestations of the nerve impulse for which there is ample experimental evidence. As a result, alternative models of nerve impulse propagation have been proposed in contemporary (neuro)scientific literature. One of these models is the Heimburg-Jackson model, according to which the nerve impulse is an electromechanical density pulse in the neural membrane. This model is usually contrasted with the Hodgkin-Huxley model and is supposed to potentially be able to replace the latter. However, instead of contrasting these models of nerve impulse propagation, another approach integrates these models in a general unifying model. This general unifying model, the Engelbrecht model, is developed to unify all relevant manifestations of the nerve impulse and their interaction(s). Here, we want to contribute to the debate about modeling nerve impulse propagation by conceptually analyzing the Engelbrecht model. Combining the results of this conceptual analysis with insights from philosophy of science, we make recommendations for the study of nerve impulse propagation. The first conclusion of this analysis is that attempts to develop models that represent the nerve impulse accurately and completely appear unfeasible. Instead, models are and should be used as tools to study nerve impulse propagation for varying purposes, representing the nerve impulse accurately and completely enough to achieve the specified goals. The second conclusion is that integrating distinct models into a general unifying model that provides a consistent picture of nerve impulse propagation is impossible due to the distinct purposes for which they are developed and the conflicting assumptions these purposes often require. Instead of explaining nerve impulse propagation with a single general unifying model, it appears advisable to explain this complex phenomenon using a 'mosaic' framework of models in which each model provides a partial explanation of nerve impulse propagation.

Collision and annihilation of nonlinear sound waves and action potentials in interfaces.

Nerve impulses, previously proposed as manifestations of nonlinear acoustic pulses localized at the plasma membrane, can annihilate upon collision. However, whether annihilation of acoustic waves at interfaces takes place is unclear. We previously showed the propagation of nonlinear sound waves that propagate as solitary waves above a threshold (super-threshold) excitation in a lipid monolayer near a phase transition. Here we investigate the interaction of these waves. Sound waves were excited mechanically via a piezo cantilever in a lipid monolayer at the air-water interface and their amplitude is reported before and after a collision. The compression amplitude was observed via Förster resonance energy transfer between donor and acceptor dyes, measured at fixed points along the propagation path in the lipid monolayer. We provide direct experimental evidence for the annihilation of two super-threshold interfacial pulses upon head-on collision in a lipid monolayer and conclude that sound waves propagating in a lipid interface can interact linearly, nonlinearly, or annihilate upon collision depending on the state of the system. Thus we show that the main characteristics of nerve impulses, i.e. solitary character, velocity, couplings, all-or-none behaviour, threshold and even annihilation are also demonstrated by nonlinear sound waves in a lipid monolayer, where they follow directly from the thermodynamic principles applied to an interface. As these principles are equally unavoidable in a nerve membrane, our observations strongly suggest that the underlying physical basis of action potentials and the observed nonlinear-pules is identical.

Thinking about the nerve impulse: A critical analysis of the electricity-centered conception of nerve excitability.

Nerve impulse generation and propagation are often thought of as solely electrical events. The prevalence of this view is the result of long and intense study of nerve impulses in electrophysiology culminating in the introduction of the Hodgkin-Huxley model of the action potential in the 1950s. To this day, this model forms the physiological foundation for a broad area of neuroscientific research. However, the Hodgkin-Huxley model cannot account for non-electrical phenomena that accompany nerve impulse propagation, for which there is nevertheless ample evidence. This raises the question whether the Hodgkin-Huxley model is a complete model of the nerve impulse. Several alternative models have been proposed that do take into account non-electrical aspects of the nerve impulse and emphasize their importance in gaining a more complete understanding of the nature of the nerve impulse. In our opinion, these models deserve more attention in neuroscientific research, since, together with the Hodgkin-Huxley model, they will help in addressing and solving a number of questions in basic and applied neuroscience which thus far have remained outside our grasp. Here we provide a historico-scientific overview of the developments that have led to the current conception of the action potential as an electrical phenomenon, discuss some major objections against this conception, and suggest a number of scientific factors which have likely contributed to the enduring success of the Hodgkin-Huxley model and should be taken into consideration whilst contemplating the formulation of a more extensive and complete conception of the nerve impulse.

A contextual analysis of nervous force in medico-scientific and literary writings in English of the nineteenth and early-twentieth centuries.

This study concerns the context of use of the term "nervous force," as it appears in scientific and literary publications in English over the course of the nineteenth century and the first two decades of the twentieth century. The context of use, loss, or waste of nervous force and the context of nervous force as an expression of an attribute are analyzed in 189 scientific and 105 literary writings. Both contexts appeared in literary writings, where nervous force expresses the attributes of strength, forcefulness, vigor, or energy and use, loss or waste of nervous force explains such nonmorbid conditions as why someone is tired or needs rest. Only the context of use-loss-waste appeared in the medico-scientific literature, but here it explained both nonmorbid conditions (for example, effects of old age) and morbid conditions (like epilepsy). Changes in the number of these references give insights into the medico-scientific and the literary disciplines. Discussions include why nervous force is associated with explanation of disease, the persistence of its use in this capacity, and its influence on a similar use in literary writings.