Neurointerface with oscillator motifs for inhibitory effect over antagonist muscles.

The effect of inhibitory management is usually underestimated in artificial control systems, using biological analogy. According to our hypothesis, the muscle hypertonus could be effectively compensated via stimulation by bio-plausible patterns. We proposed an approach for the compensatory stimulation device as implementation of previously presented architecture of the neurointerface, where (1) the neuroport is implemented as a DAC and stimulator, (2) neuroterminal is used for neurosimulation of a set of oscillator motifs on one-board computer. In the set of experiments with five volunteers, we measured the efficacy of motor neuron inhibition via the antagonist muscle or nerve stimulation registering muscle force with and without antagonist stimulation. For the agonist activation, we used both voluntary activity and electrical stimulation. In the case of stimulation of both the agonist and the antagonist muscles and nerves, we experimented with delays between muscle stimulation in the range of 0-20 ms. We registered the subjective discomfort rate. We did not identify any significant difference between the antagonist muscle and nerve stimulation in both voluntary activity and electrical stimulation of cases showing agonist activity. We determined the most effective delay between the stimulation of the agonist and the antagonist muscles and nerves as 10-20 ms.

Memristive circuit-based model of central pattern generator to reproduce spinal neuronal activity in walking pattern.

Existing methods of neurorehabilitation include invasive or non-invasive stimulators that are usually simple digital generators with manually set parameters like pulse width, period, burst duration, and frequency of stimulation series. An obvious lack of adaptation capability of stimulators, as well as poor biocompatibility and high power consumption of prosthetic devices, highlights the need for medical usage of neuromorphic systems including memristive devices. The latter are electrical devices providing a wide range of complex synaptic functionality within a single element. In this study, we propose the memristive schematic capable of self-learning according to bio-plausible spike-timing-dependant plasticity to organize the electrical activity of the walking pattern generated by the central pattern generator.

Deciphering in silico the Role of Mutated Na V 1.1 Sodium Channels in Enhancing Trigeminal Nociception in Familial Hemiplegic Migraine Type 3.

Familial hemiplegic migraine type 3 (FHM3) is caused by gain-of-function mutations in the SCN1A gene that encodes the α1 subunit of voltage-gated NaV1.1 sodium channels. The high level of expression of NaV1.1 channels in peripheral trigeminal neurons may lead to abnormal nociceptive signaling thus contributing to migraine pain. NaV1.1 dysfunction is relevant also for other neurological disorders, foremost epilepsy and stroke that are comorbid with migraine. Here we used computer modeling to test the functional role of FHM3-mutated NaV1.1 channels in mechanisms of trigeminal pain. The activation of Aδ-fibers was studied for two algogens, ATP and 5-HT, operating through P2X3 and 5-HT3 receptors, respectively, at trigeminal nerve terminals. In WT Aδ-fibers of meningeal afferents, NaV1.1 channels efficiently participate in spike generation induced by ATP and 5-HT supported by NaV1.6 channels. Of the various FHM3 mutations tested, the L263V missense mutation, with a longer activation state and lower activation voltage, resulted in the most pronounced spiking activity. In contrast, mutations that result in a loss of NaV1.1 function largely reduced firing of trigeminal nerve fibers. The combined activation of P2X3 and 5-HT3 receptors and branching of nerve fibers resulted in very prolonged and high-frequency spiking activity in the mutants compared to WT. We identified, in silico, key determinants of long-lasting nociceptive activity in FHM3-mutated Aδ-fibers that naturally express P2X3 and 5-HT3 receptors and suggest mutant-specific correction options. Modeled trigeminal nerve firing was significantly higher for FHM3 mutations, compared to WT, suggesting that pronounced nociceptive signaling may contribute to migraine pain.

Modeling a Nociceptive Neuro-Immune Synapse Activated by ATP and 5-HT in Meninges: Novel Clues on Transduction of Chemical Signals Into Persistent or Rhythmic Neuronal Firing.

Extracellular ATP and serotonin (5-HT) are powerful triggers of nociceptive firing in the meninges, a process supporting headache and whose cellular mechanisms are incompletely understood. The current study aimed to develop, with the neurosimulator NEURON, a novel approach to explore in silico the molecular determinants of the long-lasting, pulsatile nature of migraine attacks. The present model included ATP and 5-HT release, ATP diffusion and hydrolysis, 5-HT uptake, differential activation of ATP P2X or 5-HT3 receptors, and receptor subtype-specific desensitization. The model also tested the role of branched meningeal fibers with multiple release sites. Spike generation and propagation were simulated using variable contribution by potassium and sodium channels in a multi-compartment fiber environment. Multiple factors appeared important to ensure prolonged nociceptive firing potentially relevant to long-lasting pain. Crucial roles were observed in: (i) co-expression of ATP P2X2 and P2X3 receptor subunits; (ii) intrinsic activation/inactivation properties of sodium Nav1.8 channels; and (iii) temporal and spatial distribution of ATP/5-HT release sites along the branches of trigeminal nerve fibers. Based on these factors we could obtain either persistent activation of nociceptive firing or its periodic bursting mimicking the pulsating nature of pain. In summary, our model proposes a novel tool for the exploration of peripheral nociception to test the contribution of clinically relevant factors to headache including migraine pain.