Head-to-nerve analysis of electromechanical impairments of diffuse axonal injury

The aim was to investigate mechanical and functional failure of diffuse axonal injury (DAI) in nerve bundles following frontal head impacts, by finite element simulations. Anatomical changes following traumatic brain injury are simulated at the macroscale by using a 3D head model. Frontal head impacts at speeds of 2.5-7.5 m/s induce mild-to-moderate DAI in the white matter of the brain. Investigation of the changes in induced electromechanical responses at the cellular level is carried out in two scaled nerve bundle models, one with myelinated nerve fibres, the other with unmyelinated nerve fibres. DAI occurrence is simulated by using a real-time fully coupled electromechanical framework, which combines a modulated threshold for spiking activation and independent alteration of the electrical properties for each three-layer fibre in the nerve bundle models. The magnitudes of simulated strains in the white matter of the brain model are used to determine the displacement boundary conditions in elongation simulations using the 3D nerve bundle models. At high impact speed, mechanical failure occurs at lower strain values in large unmyelinated bundles than in myelinated bundles or small unmyelinated bundles; signal propagation continues in large myelinated bundles during and after loading, although there is a large shift in baseline voltage during loading; a linear relationship is observed between the generated plastic strain in the nerve bundle models and the impact speed and nominal strains of the head model. The myelin layer protects the fibre from mechanical damage, preserving its functionalities

Spontaneous excitation patterns computed for axons with injury-like impairments of sodium channels and Na/K pumps.

In injured neurons, "leaky" voltage-gated sodium channels (Nav) underlie dysfunctional excitability that ranges from spontaneous subthreshold oscillations (STO), to ectopic (sometimes paroxysmal) excitation, to depolarizing block. In recombinant systems, mechanical injury to Nav1.6-rich membranes causes cytoplasmic Na(+)-loading and "Nav-CLS", i.e., coupled left-(hyperpolarizing)-shift of Nav activation and availability. Metabolic injury of hippocampal neurons (epileptic discharge) results in comparable impairment: left-shifted activation and availability and hence left-shifted I(Na-window). A recent computation study revealed that CLS-based I(Na-window) left-shift dissipates ion gradients and impairs excitability. Here, via dynamical analyses, we focus on sustained excitability patterns in mildly damaged nodes, in particular with more realistic Gaussian-distributed Nav-CLS to mimic "smeared" injury intensity. Since our interest is axons that might survive injury, pumps (sine qua non for live axons) are included. In some simulations, pump efficacy and system volumes are varied. Impacts of current noise inputs are also characterized. The diverse modes of spontaneous rhythmic activity evident in these scenarios are studied using bifurcation analysis. For "mild CLS injury", a prominent feature is slow pump/leak-mediated E(Ion) oscillations. These slow oscillations yield dynamic firing thresholds that underlie complex voltage STO and bursting behaviors. Thus, Nav-CLS, a biophysically justified mode of injury, in parallel with functioning pumps, robustly engenders an emergent slow process that triggers a plethora of pathological excitability patterns. This minimalist "device" could have physiological analogs. At first nodes of Ranvier and at nociceptors, e.g., localized lipid-tuning that modulated Nav midpoints could produce Nav-CLS, as could co-expression of appropriately differing Nav isoforms

The Role of Plasma Membrane ATPase Pumps in the Regulation of Rhythmic Activity in Electrically Excitable Cells

Membrane bound ion pumps have long been studied in a housekeeping role, and it is well known that they play a major part in creating the ionic gradients which determine the electrical excitability in a cell. Recent work has begun to highlight other, more direct roles for ion pumps in rhythm generation and information processing. As many pumps obtain energy for active ion transport from adenosine triphosphate (ATP) hydrolysis, they can exchange ions in an electrically asymmetric manner, generating an outward current, which along with ion channel currents, drives the membrane potential of the cell. Membrane potential is a major determining characteristic for how information is transferred between neurons, and so in persistently active excitable cells, pumps can provide a considerable contribution to neuron dynamics. Specialized networks of neurons and non-neural cells which drive rhythmic behaviors such as breathing and locomotion, must robustly produce useful patterns for the animal under dynamic behavioral goals in a highly variable environment. Here we will focus on two well-studied classes of ATPase pumps (the plasma membrane calcium ATPase pump (PMCA) and the sodium-potassium ATPase pump (Na+/K+ pump)) and investigate the role of these pumps in two rhythm generating biological subsystems with a combination of modeling and experimental approaches. In a model of a leech heartbeat central pattern generator, we demonstrate how the neuromodulator myomodulin can regulate the temporal properties of rhythm generation through effects on the hyperpolarization-activated current and the Na+/K+ pump current, and discuss the benefits of modulators which target multiple currents. With this model, we also show how synaptic inhibition can support a functional pattern when pump current is downregulated. Then, in a model of interstitial cells of Cajal (ICC) in the muscular syncytium of the intestinal walls, we demonstrate that due to the importance of complex intracellular calcium oscillations in the generation of ICC rhythms, the PMCA pump can play a major role in regulating the temporal properties of rhythm generation. We discuss rhythm generation mechanisms in both systems and predict parameter domains of multistability which correspond to both functional and pathological states of rhythm generation