Electrical stimulation of the central and peripheral nervous systems - such as deep brain stimulation, spinal cord stimulation, and epidural cortical stimulation are common therapeutic options increasingly used to treat a large variety of neurological and psychiatric conditions. Despite their remarkable success, there are limitations which if overcome, could enhance outcomes and potentially reduce common side-effects. Micromagnetic stimulation (μMS) was introduced to address some of these limitations. One of the most remarkable properties is that μMS is theoretically capable of activating neurons with specific axonal orientations. Here, we used computational electromagnetic models of the μMS coils adjacent to neuronal tissue combined with axon cable models to investigate μMS orientation-specific properties. We found a 20-fold reduction in the stimulation threshold of the preferred axonal orientation compared to the orthogonal direction. We also studied the directional specificity of μMS coils by recording the responses evoked in the inferior colliculus of rodents when a pulsed magnetic stimulus was applied to the surface of the dorsal cochlear nucleus. The results confirmed that the neuronal responses were highly sensitive to changes in the μMS coil orientation. Accordingly, our results suggest that μMS has the potential of stimulating target nuclei in the brain without affecting the surrounding white matter tracts.

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Mitochondrial Ca 2+ handling is accomplished by balancing Ca 2+ uptake, primarily via the Ru360-sensitive mitochondrial calcium uniporter (MCU), Ca 2+ buffering in the matrix and Ca 2+ efflux mainly via Ca 2+ ion exchangers, such as the Na + /Ca 2+ exchanger (NCLX) and the Ca 2+ /H + exchanger (CHE). The mechanism of CHE in cardiac mitochondria is not well-understood and its contribution to matrix Ca 2+ regulation is thought to be negligible, despite higher expression of the putative CHE protein, LETM1, compared to hepatic mitochondria. In this study, Ca 2+ efflux via the CHE was investigated in isolated rat cardiac mitochondria and permeabilized H9c2 cells. Mitochondria were exposed to (a) increasing matrix Ca 2+ load via repetitive application of a finite CaCl 2 bolus to the external medium and (b) change in the pH gradient across the inner mitochondrial membrane (IMM). Ca 2+ efflux at different matrix Ca 2+ loads was revealed by inhibiting Ca 2+ uptake or reuptake with Ru360 after increasing number of CaCl 2 boluses. In Na +-free experimental buffer and with Ca 2+ uptake inhibited, the rate of Ca 2+ efflux and steady-state free matrix Ca 2+ [mCa 2+ ] ss increased as the number of administered CaCl 2 boluses increased. ADP and cyclosporine A (CsA), which are known to increase Ca 2+ buffering while maintaining a constant [mCa 2+ ] ss , decreased the rate of Ca 2+ efflux via the CHE, with a significantly greater decrease in the presence of ADP. ADP also increased Ca 2+ buffering rate and decreased [mCa 2+ ] ss. A change in the pH of the external medium to a more acidic value from 7.15 to 6.8∼6.9 caused a twofold increase in the Ca 2+ efflux rate, while an alkaline change in pH from 7.15 to 7.4∼7.5 did not change the Ca 2+ efflux rate. In addition, CHE activation was associated with membrane depolarization. Targeted transient knockdown of LETM1 in permeabilized H9c2 cells modulated Ca 2+ efflux. The results indicate that Ca 2+ efflux via the CHE in cardiac mitochondria is modulated by acidic buffer pH and by total matrix Ca 2+. A mechanism is proposed whereby activation of CHE is sensitive to changes in both the matrix Ca 2+ buffering system and the matrix free Ca 2+ concentration.