Simulated auditory fiber myelination heterogeneity desynchronizes population responses to electrical stimulation limiting inter-aural timing difference representation.

Auditory nerve responses to electrical stimulation exhibit aberrantly synchronous response latencies to low-rate pulse trains, nevertheless, cochlear implant users generally have elevated inter-aural timing difference detection thresholds. These findings present an apparent paradox in which single units are unusually precise but downstream within the auditory pathway access to this precision is lost. Auditory nerves innervating a region of cochlea exhibit natural heterogeneity in their diameter, myelination, and other structural properties; a key question is whether this diversity may contribute to the loss of temporal fidelity. In this work, responses of simulated auditory neuron populations with realistic intrinsic diameter and myelination heterogeneity to low-rate pulse trains were produced. By performing a receiver operating characteristic analysis on response latency distributions, ideal-observer interaural timing difference (ITD) detection limits were produced for each population. Fiber heterogeneity produced dispersion of inter-fiber latencies that produced ITD thresholds like that observed in the best performing cochlear implant users. Incorporation of myelin loss into these populations further increased inter-fiber latency variance and elevated ITD detection limits. These findings suggest that the interaction of applied currents with fibers' specific intrinsic properties may introduce fundamental limits on presentation of fine temporal structure in electrical stimulation.

Anatomic resolution of neurotransmitter-specific projections to the VTA reveals diversity of GABAergic inputs.

The ventral tegmental area (VTA) is important for reward processing and motivation. The anatomic organization of neurotransmitter-specific inputs to the VTA remains poorly resolved. In the present study, we mapped the major neurotransmitter projections to the VTA through cell-type-specific retrograde and anterograde tracing. We found that glutamatergic inputs arose from a variety of sources and displayed some connectivity biases toward specific VTA cell types. The sources of GABAergic projections were more widespread, displayed a high degree of differential innervation of subregions in the VTA and were largely biased toward synaptic contact with local GABA neurons. Inactivation of GABA release from the two major sources, locally derived versus distally derived, revealed distinct roles for these projections in behavioral regulation. Optogenetic manipulation of individual distal GABAergic inputs also revealed differential behavioral effects. These results demonstrate that GABAergic projections to the VTA are a major contributor to the regulation and diversification of the structure.

Spectral aliasing in an acoustic spectral ripple discrimination task.

Spectral ripple discrimination tasks are commonly used to probe spectral resolution in cochlear implant (CI), normal-hearing (NH), and hearing-impaired individuals. In addition, these tasks have also been used to examine spectral resolution development in NH and CI children. In this work, stimulus sine-wave carrier density was identified as a critical variable in an example spectral ripple-based task, the Spectro-Temporally Modulated Ripple (SMR) Test, and it was demonstrated that previous uses of it in NH listeners sometimes used values insufficient to represent relevant ripple densities. Insufficient carry densities produced spectral under-sampling that both eliminated ripple cues at high ripple densities and introduced unintended structured interference between the carriers and intended ripples at particular ripple densities. It was found that this effect produced non-monotonic psychometric functions for NH listeners that would cause systematic underestimation of thresholds with adaptive techniques. Studies of spectral ripple detection in CI users probe a density regime below where this source of aliasing occurs, as CI signal processing limits dense ripple representation. While these analyses and experiments focused on the SMR Test, any task in which discrete pure-tone carriers spanning frequency space are modulated to approximate a desired pattern must be designed with the consideration of the described spectral aliasing effect.

Simulated auditory nerve axon demyelination alters sensitivity and response timing to extracellular stimulation.

Since cochlear implant function involves direct depolarization of spiral ganglion neurons (SGNs) by applied current, SGN physiological health must be an important factor in cochlear implant (CI) outcomes. This expected relationship has, however, been difficult to confirm in implant recipients. Suggestively, animal studies have demonstrated both acute and progressive SGN ultrastructural changes (notably axon demyelination), even in the absence of soma death, and corresponding altered physiology following sensorineural deafening. Whether such demyelination occurs in humans and how such changes might impact CI function remains unknown. To approach this problem, we incorporated SGN demyelination into a biophysical model of extracellular stimulation of SGN fibers. Our approach enabled exploration of the entire parameter space corresponding to simulated myelin diameter and extent of fiber affected. All simulated fibers were stimulated distally with anodic monophasic, cathodic monophasic, anode-phase-first (AF) biphasic, and cathode-phase-first (CF) biphasic pulses from an extracellular disc electrode and monitored for spikes centrally. Not surprisingly, axon sensitivity generally decreased with demyelination, resulting in elevated thresholds, however, this effect was strongly non-uniform. Fibers with severe demyelination affecting only the most peripheral nodes responded nearly identically to normally myelinated fibers. Additionally, partial demyelination (<50%) yielded only minimal increases in threshold even when the entire fiber was impacted. The temporal effects of demyelination were more unexpected. Both latency and jitter of responses demonstrated resilience to modest changes but exhibited strongly non-monotonic and stimulus-dependent relationships to more profound demyelination. Normal, and modestly demyelinated fibers, were more sensitive to cathodic than anodic monophasic pulses and to CF than AF biphasic pulses, however, when demyelination was more severe these relative sensitivities were reversed. Comparison of threshold crossing between nodal segments demonstrated stimulus-dependent shifts in action potential initiation with different fiber demyelination states. For some demyelination scenarios, both phases of biphasic pulses could initiate action potentials at threshold resulting in bimodal latency and initiation site distributions and dramatically increased jitter. In summary, simulated demyelination leads to complex changes in fiber sensitivity and spike timing, mediated by alterations in action potential initiation site and slowed action potential conduction due to non-uniformities in the electrical properties of axons. Such demyelination-induced changes, if present in implantees, would have profound implications for the detection of fine temporal cues but not disrupt cues on the time scale of speech envelopes. These simulation results highlight the importance of exploring the SGN ultrastructural changes caused by a given etiology of hearing loss to more accurately predict cochlear implantation outcomes.

Rapid detection of Mycobacterium tuberculosis biomarkers in a sandwich immunoassay format using a waveguide-based optical biosensor.

Early diagnosis of active tuberculosis (TB) remains an elusive challenge, especially in individuals with disseminated TB and HIV co-infection. Recent studies have shown a promise for the direct detection of pathogen-specific biomarkers such as lipoarabinomannan (LAM) for the diagnosis of TB in HIV-positive individuals. Currently, traditional immunoassay platforms that suffer from poor sensitivity and high non-specific interactions are used for the detection of such biomarkers. In this manuscript, we demonstrate the development of sandwich immunoassays for the direct detection of three TB-specific biomarkers, namely LAM, early secretory antigenic target 6 (ESAT6) and antigen 85 complex (Ag85), using a waveguide-based optical biosensor platform. Combining detection within the evanescent field of a planar optical waveguide with functional surfaces that reduce non-specific interactions allows for the ultra-sensitive and quantitative detection of biomarkers (an order of magnitude enhanced sensitivity, as compared to plate-based ELISA) in complex patient samples (urine, serum) within a short time. We also demonstrate the detection of LAM in urine from a small sample of subjects being treated for TB using this approach with excellent sensitivity and 100% corroboration with disease status. These results suggest that pathogen-specific biomarkers can be applied for the rapid and effective diagnosis of disease. It is likely that detection of a combination of biomarkers offers greater reliability of diagnosis, rather than detection of any single pathogen biomarker. NCT00341601.