A rate threshold mechanism regulates MAPK stress signaling and survival

Cells are exposed to changes in extracellular stimulus concentration that vary as a function of rate. However, how cells integrate information conveyed from stimulation rate along with concentration remains poorly understood. Here, we examined how varying the rate of stress application alters budding yeast mitogen-activated protein kinase (MAPK) signaling and cell behavior at the single-cell level. We show that signaling depends on a rate threshold that operates in conjunction with stimulus concentration to determine the timing of MAPK signaling during rate-varying stimulus treatments. We also discovered that the stimulation rate threshold and stimulation rate-dependent cell survival are sensitive to changes in the expression levels of the Ptp2 phosphatase, but not of another phosphatase that similarly regulates osmostress signaling during switch-like treatments. Our results demonstrate that stimulation rate is a regulated determinant of cell behavior and provide a paradigm to guide the dissection of major stimulation rate dependent mechanisms in other systems.

Perceptual learning of pitch provided by cochlear implant stimulation rate

Cochlear implant users hear pitch evoked by stimulation rate, but discrimination diminishes for rates above 300 Hz. This upper limit on rate pitch is surprising given the remarkable and specialized ability of the auditory nerve to respond synchronously to stimulation rates at least as high as 3 kHz and arguably as high as 10 kHz. Sensitivity to stimulation rate as a pitch cue varies widely across cochlear implant users and can be improved with training. The present study examines individual differences and perceptual learning of stimulation rate as a cue for pitch ranking. Adult cochlear implant users participated in electrode psychophysics that involved testing once per week for three weeks. Stimulation pulse rate discrimination was measured in bipolar and monopolar configurations for apical and basal electrodes. Base stimulation rates between 100 and 800 Hz were examined. Individual differences were quantified using psychophysically derived metrics of spatial tuning and temporal integration. This study examined distribution of measures across subjects, predictive power of psychophysically derived metrics of spatial tuning and temporal integration, and the effect of training on rate discrimination thresholds. Psychophysical metrics of spatial tuning and temporal integration were not predictive of stimulation rate discrimination, but discrimination thresholds improved at lower frequencies with training. Since most clinical devices do not use variable stimulation rates, it is unknown to what extent recipients may learn to use stimulation rate cues if provided in a clear and consistent manner.

Mathematical Modelling of the Inhibitory Role of Regulatory T Cells in Tumor Immune Response

The immune system against tumors acts through a complex dynamical process showing a dual role. On the one hand, the immune system can activate some immune cells to kill tumor cells (TCs), such as cytotoxic T lymphocytes (CTLs) and natural killer cells (NKs), but on the other hand, more evidence shows that some immune cells can help tumor escape, such as regulatory T cells (Tregs). In this paper, we propose a tumor immune interaction model based on Tregs-mediated tumor immune escape mechanism. When helper T cells’ (HTCs) stimulation rate by the presence of identified tumor antigens is below critical value, the coexistence (tumor and immune) equilibrium is always stable in its existence region. When HTCs stimulation rate is higher than the critical value, the inhibition rate of effector cells (ECs) by Tregs can destabilize the coexistence equilibrium and cause Hopf bifurcations and produce a limit cycle. This model shows that Tregs might play a crucial role in triggering the tumor immune escape. Furthermore, we introduce the adoptive cellular immunotherapy (ACI) and monoclonal antibody immunotherapy (MAI) as the treatment to boost the immune system to fight against tumors. The numerical results show that ACI can control TCs more, while MAI can delay the inhibitory effect of Tregs on ECs. The result also shows that the combination of both immunotherapies can control TCs and reduce the inhibitory effect of Tregs better than a single immunotherapy can control.

Neuromodulation Techniques in Phantom Limb Pain: A Systematic Review and Meta-analysis

Objective To evaluate the effects of neuromodulation techniques in adults with phantom limb pain (PLP). Methods A systematic search was performed, comprising randomized controlled trials (RCTs) and quasi-experimental (QE) studies that were published from database inception to February 2019 and that measured the effects of neuromodulation in adults with PLP. Hedge’s g effect size (ES) and 95% confidence intervals were calculated, and random-effects meta-analyses were performed. Results Fourteen studies (nine RCTs and five QE noncontrolled studies) were included. The meta-analysis of RCTs showed significant effects for i) excitatory primary motor cortex (M1) stimulation in reducing pain after stimulation (ES = −1.36, 95% confidence interval [CI] = −2.26 to −0.45); ii) anodal M1 transcranial direct current stimulation (tDCS) in lowering pain after stimulation (ES = −1.50, 95% CI = −2.05 to 0.95), and one-week follow-up (ES = −1.04, 95% CI = −1.64 to 0.45). The meta-analysis of noncontrolled QE studies demonstrated a high rate of pain reduction after stimulation with transcutaneous electrical nerve stimulation (rate = 67%, 95% CI = 60% to 73%) and at one-year follow-up with deep brain stimulation (rate = 73%, 95% CI = 63% to 82%). Conclusions The evidence from RCTs suggests that excitatory M1 stimulation—specifically, anodal M1 tDCS—has a significant short-term effect in reducing pain scale scores in PLP. Various neuromodulation techniques appear to have a significant and positive impact on PLP, but due to the limited amount of data, it is not possible to draw more definite conclusions.

A backward encoding approach to recover subcortical auditory activity

1.AbstractSeveral subcortical nuclei along the auditory pathway are involved in the processing of sounds. One of the most commonly used methods of measuring the activity of these nuclei is the auditory brainstem response (ABR). Due to its low signal-to-noise ratio, ABR’s have to be derived by averaging over thousands of artificial sounds such as clicks or tone bursts. This approach cannot be easily applied to natural listening situations (e.g. speech, music), which limits auditory cognitive neuroscientific studies to investigate mostly cortical processes.We propose that by training a backward encoding model to reconstruct evoked ABRs from high-density electrophysiological data, spatial filters can be tuned to auditory brainstem activity. Since these filters can be applied (i.e. generalized) to any other data set using the same spatial coverage, this could allow for the estimation of auditory brainstem activity from any continuous sensor level data. In this study, we established a proof-of-concept by using a backward encoding model generated using a click stimulation rate of 30 Hz to predict ABR activity recorded using EEG from an independent measurement using a stimulation rate of 9 Hz. We show that individually predicted and measured ABR’s are highly correlated (r ∼ 0.7). Importantly these predictions are stable even when applying the trained backward encoding model to a low number of trials, mimicking a situation with an unfavorable signal-to-noise ratio. Overall, this work lays the necessary foundation to use this approach in more interesting listening situations.