Solomon Silas Senok

Despite the vagus nerve stimulator (VNS) being used in neuroscience, it has recently been highlighted that it has cardioprotective functions. However, many studies related to VNS are not mechanistic in nature. This systematic review aims to focus on the role of VNS in cardioprotective therapy, selective vagus nerve stimulators (sVNS), and their functional capabilities. A systemic review of the current literature was conducted on VNS, sVNS, and their ability to induce positive effects on arrhythmias, cardiac arrest, myocardial ischemia/reperfusion injury, and heart failure. Both experimental and clinical studies were reviewed and assessed separately. Of 522 research articles retrieved from literature archives, 35 met the inclusion criteria and were included in the review. Literature analysis proves that combining fiber-type selectivity with spatially-targeted vagus nerve stimulation is feasible. The role of VNS as a tool for modulating heart dynamics, inflammatory response, and structural cellular components was prominently seen across the literature. The application of transcutaneous VNS, as opposed to implanted electrodes, provides the best clinical outcome with minimal side effects. VNS presents a method for future cardiovascular treatment that can modulate human cardiac physiology. However, continued research is needed for further insight.

Merkel nerve endings are identified physiologically as slowly adapting type I mechanoreceptor units. They are important for fine acuity tactile perception. We examined the effect of age on the electrophysiological availability of different types of slowly adapting mechanoreceptor units. Using 6–50 week old rats, we observed an obvious decline with age in the probability of recording from St I units of the deep vibrissal nerve. The precipitous decline occurred between ages 6–14 weeks and then stabilized. By contrast, the prevalence of St II units, the other type of slowly adapting mechanoreceptor, remained constant over the age range studied. These observations correlate with anatomical findings reported elsewhere.

Objective . Direct stimulation of retinal ganglion cells in degenerate retinas by implanting epi-retinal prostheses is a recognized strategy for restoration of visual perception in patients with retinitis pigmentosa or age-related macular degeneration. Elucidating the best stimulus-response paradigms in the laboratory using multielectrode arrays (MEA) is complicated by the fact that the short-latency spikes (within 10 ms) elicited by direct retinal ganglion cell (RGC) stimulation are obscured by the stimulus artifact which is generated by the electrical stimulator. Approach . We developed an artifact subtraction algorithm based on topographic prominence discrimination, wherein the duration of prominences within the stimulus artifact is used as a strategy for identifying the artifact for subtraction and clarifying the obfuscated spikes which are then quantified using standard thresholding. Main results . We found that the prominence discrimination based filters perform creditably in simulation conditions by successfully isolating randomly inserted spikes in the presence of simple and even complex residual artifacts. We also show that the algorithm successfully isolated short-latency spikes in an MEA-based recording from degenerate mouse retinas, where the amplitude and frequency characteristics of the stimulus artifact vary according to the distance of the recording electrode from the stimulating electrode. By ROC analysis of false positive and false negative first spike detection rates in a dataset of one hundred and eight RGCs from four retinal patches, we found that the performance of our algorithm is comparable to that of a generally-used artifact subtraction filter algorithm which uses a strategy of local polynomial approximation (SALPA). Significance . We conclude that the application of topographic prominence discrimination is a valid and useful method for subtraction of stimulation artifacts with variable amplitudes and shapes. We propose that our algorithm may be used as stand-alone or supplementary to other artifact subtraction algorithms like SALPA.

Ahn J, et al. Korean J Physiol Pharmacol. 2017 Sep;21(5):555-563. https://doi.org/10.4196/kjpp.2017.21.5.555

Characterization of the electrical activity of the retina in the animal models of retinal degeneration has been carried out in part to understand the progression of retinal degenerative diseases like age-related macular degeneration (AMD) and retinitis pigmentosa (RP), but also to determine optimum stimulus paradigms for use with retinal prosthetic devices. The models most studied in this regard have been the two lines of mice deficient in the β-subunit of phosphodiesterase (rd1 and rd10 mice), where the degenerating retinas exhibit characteristic spontaneous hyperactivity and oscillatory local field potentials (LFPs). Additionally, there is a robust ~10 Hz rhythmic burst of retinal ganglion cell (RGC) spikes on the trough of the oscillatory LFP. In rd1 mice, the rhythmic burst of RGC spikes is always phase-locked with the oscillatory LFP and this phase-locking property is preserved regardless of postnatal ages. However, in rd10 mice, the frequency of the oscillatory rhythm changes according to postnatal age, suggesting that this rhythm might be a marker of the stage of degeneration. Furthermore when a biphasic current stimulus is applied to rd10 mice degenerate retina, distinct RGC response patterns that correlate with the stage of degeneration emerge. This review also considers the significance of these response properties.

Motivation: Emergence of aberrant spiking activity coupled with 5 ~15 Hz oscillatory rhythm has been reported in degenerate mouse retinas [1-2]. This rhythm has been regarded as noise which reduces the efficacy of prosthetic stimulation. In our previous study, ~5 Hz and ~10 Hz rhythms in rd10 mouse retina vary with postnatal ages [3]. Here, we investigated if oscillatory rhythms affect retinal ganglion cell (RGC) response to electrical stimulation in rd10 retina according to progression of degeneration. Material and Methods: Electrically-evoked RGC spikes were recorded using 8 ¡¿ 8 multi-electrode array (MEA) in rd10 mice (B6CXB1) at postnatal week (PNW) 2 ~34. Retinal patches were placed RGC layer down on MEA. Fifty cathodic phase-1st biphasic square pulses (duration: 500 ¥ìs, pulse amplitude: 5 ~60 ¥ìA) were applied at every 1 sec. Previously, 1st peak in post-stimulus time histogram (PSTH) showed better modulation efficacy than subsequently appeared remnant peaks [4]. Therefore, stimulus efficacy of PSTH 1st peak and remnant peaks was compared among different age groups to clarify potential information-carrying role of multiple peaks. Also, correlation between evoked spike numbers in PSTH peaks and oscillatory rhythm was calculated. Results: Modulation range of RGC response to electrical stimulus is narrower at PNW 6.5, 10, and 20, when power of ~ 5 Hz oscillation is much higher (PNW 6.5 and 20) or lower (PNW 10) than those in other age groups (Fig 1A,B). Remnant peaks show broader modulation range at PNW 8 and 26 than those at other ages (Fig 1C). Power of ~5 Hz oscillation has good correlation with evoked spike number in PSTH 1st peak at PNW 6.5 and 20 with high amplitude stimulation (>30 ¥ìA)(R¡Ö0.7, p0.05)(Fig 2). Groups of PNW 6.5 and 20 show the strongest power of ~5 Hz oscillation among all age groups (p<0.001). After excluding data points which have stronger oscillatory power than 3 ¡¿ 10^5 dB, the correlation between ~5 Hz oscillation and PSTH 1st peak spike became much weaker in these age groups. This result suggests that power of ~5 Hz oscillation may increase the electrically-evoked spike number when its power is stronger than 3 ¡¿ 10^5 dB (at PNW 6.5 and 20), but not when its power is weaker than 3 ¡¿ 10^5 dB (at PNW 10). Discussion: At PNW 6.5 and 20, evoked RGC spike number at 5 ¥ìA in PSTH 1st peak is much higher, but modulation range is much narrower than those at other ages (Fig 1B). This suggests that significant phosphenes can be induced even with low amplitude of electrical stimulation, but much difficulty with modulating evoked phosphenes. At PNW 10, evoked spike is much smaller in number and its modulation curve shows much narrower than those at other ages (Fig 1B). This result implies that many difficulties are expected to induce and modulate phosphenes for visual perception at PNW 10. Conclusion: Power of ~5 Hz oscillation in rd 10 retinas might modulate RGC spike response to electrical stimulation in PSTH 1st peak. High modulation efficacy of PSTH remnant peaks at PNW 8 and 26 may support the possibility that remnant peaks play an important role for carrying visual information (Fig 1C). Figure legend: Fig 1. Response curve of electrically-evoked PSTH peaks in rd 10 mouse RGCs. Each data point represents the electrically-evoked RGC spike number with various stimulus amplitude (5 ~ 60 ¥ìA). A, B : Response curve of PSTH 1st peak spikes. All other groups which were not shown in these graphs (PNW 3, 4.5, 15, 26, 34) show similar response curve with PNW 8. C : Response curve of PSTH remnant peak spikes. Response curve at PNW 26 is similar to that at PNW 8 (Data not shown). Fig 2. Correlation between power of ~5 Hz oscillation and PSTH 1st peak spikes at PNW 6.5 (A), PNW 10 (B), and PNW 20 (C). Amplitude of applied electric pulse is higher than 30 ¥ìA. Only the cells near to stimulus electrode (recording electrode distance: 200 ~ 400 ¥ìm) were used for correlation analysis. Reference: [1] Stasheff S.F. (2008) Emergence of sustained spontaneous hyperactivity and temporary preservation of OFF responses in ganglion cells of the retinal degeneration (rd1) mouse. J Neurophysiol 99, 1408-1421. [2] Margolis D.J, Newkirk G, Euler T, Detwiler P.B. (2008) Functional stability of retinal ganglion cells after degeneration-induced changes in synaptic input. J Neurosci 28, 6526-6536. [3] Goo Y.S, Ahn K.N, Song Y.J, Ahn S.H, Han S.K, Ryu S.B, Kim K.H. (2011) Spontaneous oscillatory rhythm in retinal activities of two retinal degeneration (rd1 and rd10) mice. Korean J Physiol Pharmacol 15, 415-422. [4] Ryu S.B, Ye J.H, Goo Y.S, Kim C.G, Kim K.H. (2010) Temporal response properties of retinal ganglion cells in rd1 mice evoked by amplitude-modulated electrical pulse trains. Invest Ophthalmol Vis Sci 51, 6762-6769.

It is known that with retinal degeneration there is rewiring of retinal networks. Consequently, electrical stimulation of the degenerating retina produces responses that differ according to the stage of retinal degeneration. We sought to delineate a degeneration stage-specific parameter for the response pattern of retinal ganglion cell (RGC) spikes as a strategy for stage-specific electrical stimulation for perceptual efficiency of prosthetic vision devices. Electrically-evoked RGC spikes were recorded at different degeneration stages in the rd10 mouse model for human retinitis pigmentosa (RP). Retinal explants mounted on an 8×8 multi-electrode array were stimulated by applying 1 Hz cathodic-phase first biphasic current pulses. RGC firing rate during the first 100 ms post-stimulus was compared to that during the 100 - 1000 ms period and a response ratio of 100 ms (RR _{100 ms} ) was calculated through the different postnatal weeks. Our results show that during post-stimulus 100 - 1000 ms, the degree of correlation between pulse amplitude and evoked RGC spikes drastically decreases at PNW 4.5. This pattern was closely matched by the RR _{100 ms} curve at this stage. We conclude that the RR _{100 ms} might be a good indicator of the therapeutic potential of a retinal electrical prosthesis.

Ahn KN, et al. Korean J Physiol Pharmacol. 2015 Mar;19(2):167-175. http://dx.doi.org/10.4196/kjpp.2015.19.2.167

Introduction. Clinical and experimental studies have reported the role of homocysteine in ventricular hypertrophy. Activation of the reninangiotensin system mediated by angiotensin II type 1 (AT1) receptor has also been suggested to contribute to the pathogenesis of ventricular hypertrophy. There are also reports suggesting the affect of angiotensin II (Ang II) on cardiac hypertrophy is mediated by hyperhomocysteinemia. However, there is limited information on the mechanisms of the possible relationship between homocysteine and Ang II in ventricular hypertrophy. In this study we tested the hypothesis that hyperhomocysteinemia induced ventricular hypertrophy and remodelling may be mediated through activation of Ang II AT₁-receptors in rats. Methods. This study was conducted on control non-treated rats (n=13), methionine-treated rats (1.5 mg/kg/day, n=18) and methionine plus oral AT1 antagonist (valsartan, 30 mg/kg/day, n=13) treated rats for 56 days. Systolic blood pressure (SBP) was determined in rats at baseline, 28 and 56 days. Echocardiography was also performed in all rats after eight weeks, and blood samples were obtained for determination of plasma tHcy. Rats were then sacrificed for histopathological and biochemical assessment of cardiac structure. Results. The SBP in the methionine-treated rats was significantly higher compared with controls and significantly lower compared with the methionine-valsartan group at 28 and 56 days (p<0.001). In addition, left ventricular wall thickness (LVWT) in the methionine-valsartan group (4.36±0.11 mm) was significantly lower compared with the methionine group (5.0±0.23 mm, p=0.03). Furthermore, cardiac collagen to total protein ratio was significantly lower in the methionine-valsartan group (2.19±0.11%) compared with the methionine group (2.64±0.08%, p=0.026). Fractional shortening (FS) was not significantly different between groups. Conclusion. Results from this study suggest that hyperhomocysteinemia-induced hypertension and ventricular hypertrophy in rats are mediated, at least partly; by Ang II activation of AT1-receptors.

There is evidence that glutamate may participate as a transmitter at the junction between Merkel cells and the nerve terminals of slowly adapting type I (St I) units. We recorded extracellularly from the deep vibrissal nerve of an isolated rat vibrissa preparation in vitro. Five second trapezoid stimulus ramp deflections of the hair shaft were used to evoke responses. We bath‐applied two compounds, which we planned would interfere with glutamatergic transmission. (2S)‐2‐Amino‐2‐[(1S,2S)‐2‐carboxycycloprop‐1‐yl]‐3‐(xanth‐9‐yl) propanoic acid (LY341495) was used at concentrations up to 100 μM to block all known metabotropic glutamate (mGlu) receptors. The racemic mixture (RS)‐4‐carboxy‐3‐hydroxyphenylglycine ((RS)‐4C3HPG) was used up to 100 μM to block ionotropic and Group I metabotropic glutamate receptors, and as an agonist at Group II mGlu receptors. Unexpectedly, both compounds had rapid onset excitatory effects on mechanically‐evoked responses. (RS)‐4C3HPG increased responses, with a mean 146% of control (P< 0.05) in a concentration‐dependent manner. LY341495 increased responses, with a mean 128% of control (P< 0.05). With (RS)‐4C3HPG in particular, it was noted that the static component (the firing during the last 1 s plateau) was preferentially enhanced relative to the dynamic component (firing during the first 0.5 s). Rapid recovery was seen after wash. Slowly adapting type II units, which have no junctional transmission, were completely unaffected by these compounds up to 200 μM. These results suggest that mGlu receptors play a role in Merkel cell‐neurite complex mechanotransduction, although other explanations are considered. Synapse 59:235–242, 2006.