Integrating DNA methylation and gene expression data in a single gene network using the iNETgrate package.

Analyzing different omics data types independently is often too restrictive to allow for detection of subtle, but consistent, variations that are coherently supported based upon different assays. Integrating multi-omics data in one model can increase statistical power. However, designing such a model is challenging because different omics are measured at different levels. We developed the iNETgrate package ( https://bioconductor.org/packages/iNETgrate/ ) that efficiently integrates transcriptome and DNA methylation data in a single gene network. Applying iNETgrate on five independent datasets improved prognostication compared to common clinical gold standards and a patient similarity network approach.

"iNETgrate": integrating DNA methylation and gene expression data in a single gene network.

Integrating multi-omics data in one model can increase statistical power. However, designing such a model is challenging because different omics are measured at different levels. We developed the iNETgrate package (https://bioconductor.org/packages/iNETgrate/) that efficiently integrates transcriptome and DNA methylation data in a single gene network. Applying iNETgrate on five independent datasets improved prognostication compared to common clinical gold standards and a patient similarity network approach.

Block Phenomena During Electric Micro-Stimulation of Pyramidal Cells and Retinal Ganglion Cells.

Electric micro-stimulation of the nervous system is a means to restore various body functions. The stimulus amplitude necessary to generate action potentials, the lower threshold (LT), is well characterized for many neuronal populations. However, electric overstimulation above an upper threshold (UT) prevents action potential generation and therefore hinders optimal neuro-rehabilitation. Previous studies demonstrated the impact of the UT in micro-stimulation of retinal ganglion cells (RGCs). The observed phenomenon is mostly explained by (i) reversed sodium ion flow in the soma membrane, and (ii) anodal surround block that hinders spike conduction in strongly hyperpolarized regions of the axon at high stimulus intensities. However, up to now, no detailed study of the nature of these phenomena has been presented, particularly for different cell types. Here, we present computational analyses of LT and UT for layer 5 pyramidal cells (PCs) as well as alpha RGCs. Model neurons were stimulated in close vicinity to the cell body and LTs and UTs as well as the ratio UT/LT were compared. Aside from a simple point source electrode and monophasic stimuli also realistic electrode and pulse configurations were examined. The analysis showed: (i) in RGCs, the soma contributed to action potential initiation and block for small electrode distances, whereas in PCs the soma played no role in LTs or UTs. (ii) In both cell types, action potential always initiated within the axon initial segment at LT. (iii) In contrast to a complete block of spike conductance at UT that occurred in RGCs, an incomplete block of spiking appeared in PC axon collaterals. (iv) PC axon collateral arrangement influenced UTs but had small impact on LTs. (v) Population responses of RGCs change from circular regions of activation to ring-shaped patterns for increasing stimulus amplitude. A better understanding of the stimulation window that can reliably activate target neurons will benefit the future development of neuroprostheses.

Polarity Sensitivity of Human Auditory Nerve Fibers Based on Pulse Shape, Cochlear Implant Stimulation Strategy and Array.

Neural health is of great interest to determine individual degeneration patterns for improving speech perception in cochlear implant (CI) users. Therefore, in recent years, several studies tried to identify and quantify neural survival in CI users. Among all proposed techniques, polarity sensitivity is a promising way to evaluate the neural status of auditory nerve fibers (ANFs) in CI users. Nevertheless, investigating neural health based on polarity sensitivity is a challenging and complicated task that involves various parameters, and the outcomes of many studies show contradictory results of polarity sensitivity behavior. Our computational study benefits from an accurate three-dimensional finite element model of a human cochlea with realistic human ANFs and determined ANF degeneration pattern of peripheral part with a diminishing of axon diameter and myelination thickness based on degeneration levels. In order to see how different parameters may impact the polarity sensitivity behavior of ANFs, we investigated polarity behavior under the application of symmetric and asymmetric pulse shapes, monopolar and multipolar CI stimulation strategies, and a perimodiolar and lateral CI array system. Our main findings are as follows: (1) action potential (AP) initiation sites occurred mainly in the peripheral site in the lateral system regardless of stimulation strategies, pulse polarities, pulse shapes, cochlear turns, and ANF degeneration levels. However, in the perimodiolar system, AP initiation sites varied between peripheral and central processes, depending on stimulation strategies, pulse shapes, and pulse polarities. (2) In perimodiolar array, clusters formed in threshold values based on cochlear turns and degeneration levels for multipolar strategies only when asymmetric pulses were applied. (3) In the perimodiolar array, a declining trend in polarity (anodic threshold/cathodic threshold) with multipolar strategies was observed between intact or slight degenerated cases and more severe degenerated cases, whereas in the lateral array, cathodic sensitivity was noticed for intact and less degenerated cases and anodic sensitivity for cases with high degrees of degeneration. Our results suggest that a combination of asymmetric pulse shapes, focusing more on multipolar stimulation strategies, as well as considering the distances to the modiolus wall, allows us to distinguish the degeneration patterns of ANFs across the cochlea.

Dendritic Degeneration of Human Auditory Nerve Fibers and Its Impact on the Spiking Pattern Under Regular Conditions and During Cochlear Implant Stimulation.

Due to limitations of human in vivo studies, detailed computational models enable understanding the neural signaling in the degenerated auditory system and cochlear implants (CIs). Four human cochleae were used to quantify hearing levels depending on dendritic changes in diameter and myelination thickness from type I of the auditory nerve fibers (ANFs). Type I neurons transmit the auditory information as spiking pattern from the inner hair cells (IHCs) to the cochlear nucleus. The impact of dendrite diameter and degree of myelination on neural signal transmission was simulated for (1) synaptic excitation via IHCs and (2) stimulation from CI electrodes. An accurate three-dimensional human cochlear geometry, along with 30 auditory pathways, mimicked the CI environment. The excitation properties of electrical potential distribution induced by two CI were analyzed. Main findings: (1) The unimodal distribution of control dendrite diameters becomes multimodal for hearing loss cases; a group of thin dendrites with diameters between 0.3 and 1 µm with a peak at 0.5 µm appeared. (2) Postsynaptic currents from IHCs excite such thin dendrites easier and earlier than under control conditions. However, this advantage is lost as their conduction velocity decreases proportionally with the diameter and causes increased spike latency and jitter in soma and axon. Firing probability reduces through the soma passage due to the low intracellular current flow in thin dendrites during spiking. (3) Compared with dendrite diameter, variations in myelin thickness have a small impact on spiking performance. (4) Contrary to synaptic excitation, CIs cause several spike initiation sites in dendrite, soma region, and axon; moreover, fiber excitability reduces with fiber diameter. In a few cases, where weak stimuli elicit spikes of a target neuron (TN) in the axon, dendrite diameter reduction has no effect. However, in many cases, a spike in a TN is first initiated in the dendrite, and consequently, dendrite degeneration demands an increase in threshold currents. (5) Threshold currents of a TN and co-stimulation of degenerated ANFs in other frequency regions depend on the electrode position, including its distance to the outer wall, the cochlear turn, and the three-dimensional pathway of the TN.

Finite element analysis and three-dimensional reconstruction of tonotopically aligned human auditory fiber pathways: A computational environment for modeling electrical stimulation by a cochlear implant based on micro-CT.

The application of cochlear implants can be studied with computational models. The electrical potential distribution induced by an implanted device is evaluated with a volume conductor model, which is used as input for neuron models to simulate the reaction of cochlear neurons to micro-stimulation. In order to reliably predict the complex excitation profiles it is vital to consider an accurate representation of the human cochlea geometry including detailed three-dimensional pathways of auditory neurons reaching from the organ of Corti through the cochlea-volume. In this study, high-resolution micro-CT imaging (Δx = Δy = Δz = 3 µm) was used to reconstruct the pathways of 30 tonotopically organized nerve fiber bundles, distributed over eight octaves (11500-40 Hz). Results of the computational framework predict: (i) the peripheral process is most sensitive to cathodic stimulation (CAT), (ii) in many cases CAT elicits spikes in the peripheral terminal at threshold but with larger stimuli there is a second spike initiation site within the peripheral process, (iii) anodic stimuli (ANO) can excite the central process even at threshold, (iv) the recruitment of fibers by electrodes located in the narrowing middle- and apical turn is complex and impedes focal excitation of low frequency fibers, (v) degenerated cells which lost the peripheral process are more sensitive to CAT when their somata are totally covered with 2 membranes of a glial cell but they become ANO sensitive when the myelin covering is reduced.