Comprehensive Simulation of Ca2+ Transients in the Continuum of Mouse Skeletal Muscle Fiber Types

Mag-Fluo-4 has revealed differences in the kinetics of the Ca2+ transients of mammalian fiber types (I, IIA, IIX, and IIB). We simulated the changes in [Ca2+] through the sarcomere of these four fiber types, considering classical (troponin –Tn–, parvalbumin –Pv–, adenosine triphosphate –ATP–, sarcoplasmic reticulum Ca2+ pump –SERCA–, and dye) and new (mitochondria –MITO–, Na+/Ca2+ exchanger –NCX–, and store-operated calcium entry –SOCE–) Ca2+ binding sites, during single and tetanic stimulation. We found that during a single twitch, the sarcoplasmic peak [Ca2+] for fibers type IIB and IIX was around 16 µM, and for fibers type I and IIA reached 10–13 µM. The release rate in fibers type I, IIA, IIX, and IIB was 64.8, 153.6, 238.8, and 244.5 µM ms−1, respectively. Both the pattern of change and the peak concentrations of the Ca2+-bound species in the sarcoplasm (Tn, PV, ATP, and dye), the sarcolemma (NCX, SOCE), and the SR (SERCA) showed the order IIB ≥ IIX > IIA > I. The capacity of the NCX was 2.5, 1.3, 0.9, and 0.8% of the capacity of SERCA, for fibers type I, IIA, IIX, and IIB, respectively. MITO peak [Ca2+] ranged from 0.93 to 0.23 µM, in fibers type I and IIB, respectively, while intermediate values were obtained in fibers IIA and IIX. The latter numbers doubled during tetanic stimulation. In conclusion, we presented a comprehensive mathematical model of the excitation–contraction coupling that integrated most classical and novel Ca2+ handling mechanisms, overcoming the limitations of the fast- vs. slow-fibers dichotomy and the use of slow dyes.

A Deep Reinforcement Learning Algorithm Based on Tetanic Stimulation and Amnesic Mechanisms for Continuous Control of Multi-DOF Manipulator

Deep Reinforcement Learning (DRL) has been an active research area in view of its capability in solving large-scale control problems. Until presently, many algorithms have been developed, such as Deep Deterministic Policy Gradient (DDPG), Twin-Delayed Deep Deterministic Policy Gradient (TD3), and so on. However, the converging achievement of DRL often requires extensive collected data sets and training episodes, which is data inefficient and computing resource consuming. Motivated by the above problem, in this paper, we propose a Twin-Delayed Deep Deterministic Policy Gradient algorithm with a Rebirth Mechanism, Tetanic Stimulation and Amnesic Mechanisms (ATRTD3), for continuous control of a multi-DOF manipulator. In the training process of the proposed algorithm, the weighting parameters of the neural network are learned using Tetanic stimulation and Amnesia mechanism. The main contribution of this paper is that we show a biomimetic view to speed up the converging process by biochemical reactions generated by neurons in the biological brain during memory and forgetting. The effectiveness of the proposed algorithm is validated by a simulation example including the comparisons with previously developed DRL algorithms. The results indicate that our approach shows performance improvement in terms of convergence speed and precision.

Tetanic stimulation of the pudendal nerve prior to transcranial electrical stimulation augments the amplitude of motor evoked potentials during pediatric neurosurgery

OBJECTIVE Reportedly, tetanic stimulation prior to transcranial electrical stimulation (TES) facilitates elicitation of motor evoked potentials (MEPs) by a mechanism involving increased corticomotoneuronal excitability in response to somatosensory input. However, the posttetanic MEP following stimulation of a pure sensory nerve has never been reported. Furthermore, no previous reports have described posttetanic MEPs in pediatric patients. The aim of this study was to investigate the efficacy of posttetanic MEPs in pediatric neurosurgery patients and to compare the effects on posttetanic MEP after tetanic stimulation of the sensory branch of the pudendal nerve versus the standard median and tibial nerves, which contain a mixture of sensory and motor fibers. METHODS In 31 consecutive pediatric patients with a mean age of 6.0 ± 5.1 years who underwent lumbosacral surgery, MEPs were elicited by TES without tetanic stimulation (conventional MEPs [c-MEPs]) and following tetanic stimulation of the unilateral median and tibial nerves (mt-MEPs) and the sensory branch of the pudendal nerve (p-MEP). Compound muscle action potentials were elicited from abductor pollicis brevis (APB), gastrocnemius (Gc), tibialis anterior (TA), and adductor hallucis (AH) muscles. The success rate of monitoring each MEP and the increases in the ratios of mt-MEP and p-MEP to c-MEP were investigated. RESULTS The success rate of monitoring p-MEPs was higher than those of mt-MEPs and c-MEPs (87.5%, 72.6%, and 63.3%, respectively; p < 0.01, adjusted by Bonferroni correction). The mean increase in the ratio of p-MEP to c-MEP for all muscles was significantly higher than that of mt-MEP to c-MEP (3.64 ± 4.03 vs 1.98 ± 2.23, p < 0.01). Subanalysis of individual muscles demonstrated significant differences in the increases in the ratios between p-MEP and mt-MEP in the APB bilaterally, as well as ipsilateral Gc, contralateral TA, and bilateral AH muscles. CONCLUSIONS Tetanic stimulation prior to TES can augment the amplitude of MEPs during pediatric neurosurgery, the effect being larger with pudendal nerve stimulation than tetanic stimulation of the unilateral median and tibial nerves. TES elicitation of p-MEPs might be useful in pediatric patients in whom it is difficult to elicit c-MEPs.

Reduced Thalamic Volume and Metabolites in Type 1 Diabetes with Polyneuropathy

Objective Thalamus is essential in processing of sensory information. This study explored the associations between thalamic volume and intra-thalamic metabolites and associations to clinical and experimental characteristics of sensory function in adults with diabetic polyneuropathy. Methods 48 adults with type 1 diabetes and confirmed distal symmetric peripheral neuropathy (DPSN) and 28 healthy controls participated in a cross-sectional study and underwent a brain magnetic resonance imaging scan. Estimates for thalamic volume were extracted using voxel-based morphometry and intra-thalamic N-acetylaspartate/creatine (NAA/cre) levels were assessed by magnetic resonance spectroscopy. Associations between thalamic volume and clinical measures, quantitative sensory testing and neuropathic phenotype were explored. Results In diabetes, reduced gray matter volume was identified including bilateral thalamus (all p≤0.001) in comparison to healthy participants. Thalamic volume estimates were positively associated to intra-thalamic NAA/cre (r=0.4; p=0.006), however not to diabetes duration (p=0.5), severity of DSPN (p=0.7), or presence of pain (p=0.3). Individuals with the lowest thalamic volume had greatest loss of protective sensation (light touch using von Frey-like filaments, p=0.037) and highest pain tolerance to electric stimulation (tetanic stimulation, p=0.008) compared to individuals with the highest thalamic volume. Conclusions In this cohort with type 1 diabetes and severe DSPN, thalamic atrophy was present and associated with reduced NAA/cre, indicating thalamic structural loss and dysfunction. Thalamic atrophy was associated to reduced sensory function involving large fiber neuropathy and sensation to tetanic stimulation that may reflect synaptic transmission. This may ultimately contribute to the current understanding of the pathophysiology behind the perception changes evident in DSPN.

Evaluation of Nociception Using Quantitative Pupillometry and Skin Conductance in Critically Ill Unconscious Patients: A Pilot Study

Background: Pain assessment is a challenge in critically ill patients, in particular those who are unable to express movements in reaction to noxious stimuli. The purpose of the study was to compare the pupillary response and skin conductance to pain stimulation in critically ill unconscious patients. Methods: This observational study included adult patients admitted to the intensive care unit (ICU) with acute brain injury (Glasgow Coma Scale < 9 with a motor response < 5) and/or requirements for deep level of sedation. Automated pupillometry (Algiscan, ID-MED, Marseille, France) was used to determine pupillary reflex dilation during tetanic stimulation. The maximum intensity of the stimulation value allowed the determination of a pupillary pain index score ranging from 1 (no nociception) to 9 (high nociception): a pupillary pain index (PPI) score of ≤4 was used to reflect adequate pain control. For skin conductance (SC), the number of SC peaks per second (NSCF) was collected concomitantly to tetanic stimulation. An NSCF of ≤0.07 peak/second was used to reflect adequate pain control. Results: Of the 51 included patients, there were 32 with brain injury and 19 receiving deep sedation. Mean PPI score was 5 (Interquartile Range= 2–7); a total of 28 (55%) patients showed inadequate control of the nociceptive stimulation according to the PPI assessment. Only 15 (29%) patients showed a detectable skin conductance, with NSCF values from 0.07 to 0.47/s. No correlation was found between skin conductance algesimeter (SCA)-derived variables and PPI score or pupillary dilation to pain. Conclusions: Detection of inadequate pain control might vary according to the method used to assess nociception in ICU patients. A poor agreement between quantitative pupillometry and skin conductance was observed.

Post-tetanic potentiation lowers the energy barrier for synaptic vesicle fusion independently of Synaptotagmin-1

Previously, we showed that modulation of the energy barrier for synaptic vesicle fusion boosts release rates supralinearly (Schotten, 2015). Here we show that mouse hippocampal synapses employ this principle to trigger Ca2+-dependent vesicle release and post-tetanic potentiation (PTP). We assess energy barrier changes by fitting release kinetics in response to hypertonic sucrose. Mimicking activation of the C2A domain of the Ca2+-sensor Synaptotagmin-1 (Syt1), by adding a positive charge (Syt1D232N) or increasing its hydrophobicity (Syt14W), lowers the energy barrier. Removing Syt1 or impairing its release inhibitory function (Syt19Pro) increases spontaneous release without affecting the fusion barrier. Both phorbol esters and tetanic stimulation potentiate synaptic strength, and lower the energy barrier equally well in the presence and absence of Syt1. We propose a model where tetanic stimulation activates Syt1-independent mechanisms that lower the energy barrier and act additively with Syt1-dependent mechanisms to produce PTP by exerting multiplicative effects on release rates.