Technical development of transcutaneous electrical nerve inhibition using medium-frequency alternating current.

BACKGROUND: Innovative technical approaches to controlling undesired sensory and motor activity, such as hyperalgesia or spasticity, may contribute to rehabilitation techniques for improving neural plasticity in patients with neurologic disorders. To date, transcutaneous electrical stimulation has used low frequency pulsed currents for sensory inhibition and muscle activation. Yet, few studies have attempted to achieve motor nerve inhibition using transcutaneous electrical stimulation. This study aimed to develop a technique for transcutaneous electrical nerve inhibition (TENI) using medium-frequency alternating current (MFAC) to suppress both sensory and motor nerve activity in humans. METHODS: Surface electrodes were affixed to the skin of eight young adults to stimulate the median nerve. Stimulation intensity was increased up to 50% and 100% of the pain threshold. To identify changes in sensory perception by transcutaneous MFAC (tMFAC) stimulation, we examined tactile and pressure pain thresholds in the index and middle fingers before and after stimulation at 10 kHz. To demonstrate the effect of tMFAC stimulation on motor inhibition, stimulation was applied while participants produced flexion forces with the index and middle fingers at target forces (50% and 90% of MVC, maximum voluntary contraction). RESULTS: tMFAC stimulation intensity significantly increased tactile and pressure pain thresholds, indicating decreased sensory perception. During the force production task, tMFAC stimulation with the maximum intensity immediately reduced finger forces by ~ 40%. Finger forces recovered immediately after stimulation cessation. The effect on motor inhibition was greater with the higher target force (90% MVC) than with the lower target (50% MVC). Also, higher tMFAC stimulation intensity provided a greater inhibition effect on both sensory and motor nerve activity. CONCLUSION: We found that tMFAC stimulation immediately inhibits sensory and motor activity. This pre-clinical study demonstrates a novel technique for TENI using MFAC stimulation and showed that it can effectively inhibit both sensory perception and motor activity. The proposed technique can be combined with existing rehabilitation devices (e.g., a robotic exoskeleton) to inhibit undesired sensorimotor activities and to accelerate recovery after neurologic injury.

Extracellular Matrix Stiffness Regulates Osteogenic Differentiation through MAPK Activation.

Mesenchymal stem cell (MSC) differentiation is regulated by the extracellular matrix (ECM) through activation of intracellular signaling mediators. The stiffness of the ECM was shown to be an important regulatory factor for MSC differentiation, and transcriptional coactivator with PDZ-binding motif (TAZ) was identified as an effector protein for MSC differentiation. However, the detailed underlying mechanism regarding the role of ECM stiffness and TAZ in MSC differentiation is not yet fully understood. In this report, we showed that ECM stiffness regulates MSC fate through ERK or JNK activation. Specifically, a stiff hydrogel matrix stimulates osteogenic differentiation concomitant with increased nuclear localization of TAZ, but inhibits adipogenic differentiation. ERK and JNK activity was significantly increased in cells cultured on a stiff hydrogel. TAZ activation was induced by ERK or JNK activation on a stiff hydrogel because exposure to an ERK or JNK inhibitor significantly decreased the nuclear localization of TAZ, indicating that ECM stiffness-induced ERK or JNK activation is important for TAZ-driven osteogenic differentiation. Taken together, these results suggest that ECM stiffness regulates MSC differentiation through ERK or JNK activation.

Shear stress induced by an interstitial level of slow flow increases the osteogenic differentiation of mesenchymal stem cells through TAZ activation.

Shear stress activates cellular signaling involved in cellular proliferation, differentiation, and migration. However, the mechanisms of mesenchymal stem cell (MSC) differentiation under interstitial flow are not fully understood. Here, we show the increased osteogenic differentiation of MSCs under exposure to constant, extremely low shear stress created by osmotic pressure-induced flow in a microfluidic chip. The interstitial level of shear stress in the proposed microfluidic system stimulated nuclear localization of TAZ (transcriptional coactivator with PDZ-binding motif), a transcriptional modulator of MSCs, activated TAZ target genes such as CTGF and Cyr61, and induced osteogenic differentiation. TAZ-depleted cells showed defects in shear stress-induced osteogenic differentiation. In shear stress induced cellular signaling, Rho signaling pathway was important forthe nuclear localization of TAZ. Taken together, these results suggest that TAZ is an important mediator of interstitial flow-driven shear stress signaling in osteoblast differentiation of MSCs.