KV7 channels are potential regulators of the exercise pressor reflex.

The exercise pressor reflex (EPR) originates in skeletal muscle and is activated by exercise-induced signals to increase arterial blood pressure and cardiac output. Muscle ischemia can elicit the EPR, which can be inappropriately activated in patients with peripheral vascular disease or heart failure to increase the incidence of myocardial infarction. We seek to better understand the receptor/channels that control excitability of group III and group IV muscle afferent fibers that give rise to the EPR. Bradykinin (BK) is released within contracting muscle and can evoke the EPR. However, the mechanism is incompletely understood. KV7 channels strongly regulate neuronal excitability and are inhibited by BK. We have identified KV7 currents in muscle afferent neurons by their characteristic activation/deactivation kinetics, enhancement by the KV7 activator retigabine, and block by KV7 specific inhibitor XE991. The blocking of KV7 current by different XE991 concentrations suggests that the KV7 current is generated by both KV7.2/7.3 (high affinity) and KV7.5 (low affinity) channels. The KV7 current was inhibited by 300 nM BK in neurons with diameters consistent with both group III and group IV afferents. The inhibition of KV7 by BK could be a mechanism by which this metabolic mediator generates the EPR. Furthermore, our results suggest that KV7 channel activators such as retigabine, could be used to reduce cardiac stress resulting from the exacerbated EPR in patients with cardiovascular disease.NEW & NOTEWORTHY KV7 channels control neuronal excitability. We show that these channels are expressed in muscle afferents and generate currents that are blocked by XE991 and bradykinin (BK). The XE991 block suggests that KV7 current is generated by KV7.2/3 and KV7.5 channels. The BK inhibition of KV7 channels may explain how BK activates the exercise pressor reflex (EPR). Retigabine can enhance KV7 current, which could help control the inappropriately activated EPR in patients with cardiovascular disease.

NaV1.9 channels in muscle afferent neurons and axons.

The exercise pressor reflex (EPR) is activated by muscle contractions to increase heart rate and blood pressure during exercise. While this reflex is beneficial in healthy individuals, the reflex activity is exaggerated in patients with cardiovascular disease, which is associated with increased mortality. Group III and IV afferents mediate the EPR and have been shown to express both tetrodotoxin-sensitive (TTX-S, NaV1.6, and NaV1.7) and -resistant (TTX-R, NaV1.8, and NaV1.9) voltage-gated sodium (NaV) channels, but NaV1.9 current has not yet been demonstrated. Using a F--containing internal solution, we found a NaV current in muscle afferent neurons that activates at around -70 mV with slow activation and inactivation kinetics, as expected from NaV1.9 current. However, this current ran down with time, which resulted, at least in part, from increased steady-state inactivation since it was slowed by both holding potential hyperpolarization and a depolarized shift of the gating properties. We further show that, following NaV1.9 current rundown (internal F-), application of the NaV1.8 channel blocker A803467 inhibited significantly more TTX-R current than we had previously observed (internal Cl-), which suggests that NaV1.9 current did not rundown with that internal solution. Using immunohistochemistry, we found that the majority of group IV somata and axons were NaV1.9 positive. The majority of small diameter myelinated afferent somata (putative group III) were also NaV1.9 positive, but myelinated muscle afferent axons were rarely labeled. The presence of NaV1.9 channels in muscle afferents supports a role for these channels in activation and maintenance of the EPR. NEW & NOTEWORTHY Small diameter muscle afferents signal pain and muscle activity levels. The muscle activity signals drive the cardiovascular system to increase muscle blood flow, but these signals can become exaggerated in cardiovascular disease to exacerbate cardiac damage. The voltage-dependent sodium channel NaV1.9 plays a unique role in controlling afferent excitability. We show that NaV1.9 channels are expressed in muscle afferents, which supports these channels as a target for drug development to control hyperactivity of these neurons.

A Method for Locomotion Mode Identification Using Muscle Synergies.

Active lower limb transfemoral prostheses have enabled amputees to perform different locomotion modes such as walking, stair ascent, stair descent, ramp ascent and ramp descent. To achieve seamless mode transitions, these devices either rely on neural information from the amputee's residual limbs or sensors attached to the prosthesis to identify the intended locomotion modes or both. We present an approach for classification of locomotion modes based on the framework of muscle synergies underlying electromyography signals. Neural information at the critical instances (e.g., heel contact and toe-off) was decoded for this purpose. Non-negative matrix factorization was used to extract the muscles synergies from the muscle feature matrix. The estimation of the neural command was done using non-negative least squares. The muscle synergy approach was compared with linear discriminant analysis (LDA), support vector machine (SVM), and neural network (NN) and was tested on seven able-bodied subjects. There was no significant difference ( p > 0.05 ) in transitional and steady state classification errors during stance phase. The muscle synergy approach performed significantly better ( ) than NN and LDA during swing phase while results were similar to SVM. These results suggest that the muscle synergy approach can be used to discriminate between locomotion modes involving transitions.

Limited efficacy of α-conopeptides, Vc1.1 and RgIA, to inhibit sensory neuron CaV current.

Chronic pain is very difficult to treat. Thus, novel analgesics are a critical area of research. Strong pre-clinical evidence supports the analgesic effects of α-conopeptides, Vc1.1 and RgIA, which block α9α10 nicotinic acetylcholine receptors (nAChRs). However, the analgesic mechanism is controversial. Some evidence supports the block of α9α10 nAChRs as an analgesic mechanism, while other evidence supports the inhibition of N-type CaV (CaV2.2) current via activation of GABAB receptors. Here we reassess the effect of Vc1.1 and RgIA on CaV current in rat sensory neurons. Unlike the previous findings, we found highly variable effects among individual sensory neurons, but on average only minimal inhibition induced by Vc1.1, and no significant effect on the current by RgIA. We also investigated the potential involvement of GABAB receptors in the Vc1.1 induced inhibition, and found no correlation between the size of CaV current inhibition induced by baclofen (GABAB agonist) vs. that induced by Vc1.1. Thus, GABAB receptors are unlikely to mediate the Vc1.1 induced CaV current inhibition. Based on the present findings, CaV current inhibition in dorsal root ganglia is unlikely to be the predominant mechanism by which either Vc1.1 or RgIA induce analgesia. SIGNIFICANCE STATEMENT: Better analgesic drugs are desperately needed to help physicians to treat pain. While many pre-clinical studies support the analgesic effects of α-conopeptides, Vc1.1 and RgIA, the mechanism is controversial. The development of improved α-conopeptide analgesics would be greatly facilitated by a complete understanding of the analgesic mechanism. However, we show that we cannot reproduce one of the proposed analgesic mechanisms, which is an irreversible inhibition of CaV current in a majority of sensory neurons.

Task discrimination for non-weight-bearing movements using muscle synergies.

Myoelectric control of lower limb prostheses requires discrimination of task-specific muscle patterns. In this paper we present a method based on the notion of muscle synergies to discriminate between various non-weight-bearing movements such as knee extension/flexion, femur rotation in/out, tibia rotation in/out and ankle dorsiflexion/plantarflexion. Data is recorded from eight targeted muscle sites on the thigh. Non-negative matrix factorization is used to identify the muscle synergies using multiple features and estimation of electromyographic (EMG) patterns is done using non-negative least squares (NNLS). Classification accuracy for the movements involving the knee joint was higher than the movements involving the ankle joint. The proposed algorithm performs at par with the common machine learning algorithm Linear Discriminant Analysis (LDA) in offline analysis.

Locomotion mode identification for lower limbs using neuromuscular and joint kinematic signals.

Recent development in lower limb prosthetics has seen an emergence of powered prosthesis that have the capability to operate in different locomotion modes. However, these devices cannot transition seamlessly between modes such as level walking, stair ascent and descent and up slope and down slope walking. They require some form of user input that defines the human intent. The purpose of this study was to develop a locomotion mode detection system and evaluate its performance for different sensor configurations and to study the effect of locomotion mode detection with and without electromyography (EMG) signals while using kinematic data from hip joint of non-dominant/impaired limb and an accelerometer. Data was collected from four able bodied subjects that completed two circuits that contained standing, level-walking, ramp ascent and descent and stair ascent and descent. By using only the kinematic data from the hip joint and accelerometer data the system was able to identify the transitions, stance and swing phases with similar performance as compared to using only EMG and accelerometer data. However, significant improvement in classification error was observed when EMG, kinematic and accelerometer data were used together to identify the locomotion modes. The higher recognition rates when using the kinematic data along with EMG shows that the joint kinematics could be beneficial in intent recognition systems of locomotion modes.