Temporal Pitch Sensitivity in an Animal Model: Psychophysics and Scalp Recordings: Temporal Pitch Sensitivity in Cat

Cochlear implant (CI) users show limited sensitivity to the temporal pitch conveyed by electric stimulation, contributing to impaired perception of music and of speech in noise. Neurophysiological studies in cats suggest that this limitation is due, in part, to poor transmission of the temporal fine structure (TFS) by the brainstem pathways that are activated by electrical cochlear stimulation. It remains unknown, however, how that neural limit might influence perception in the same animal model. For that reason, we developed non-invasive psychophysical and electrophysiological measures of temporal (i.e., non-spectral) pitch processing in the cat. Normal-hearing (NH) cats were presented with acoustic pulse trains consisting of band-limited harmonic complexes that simulated CI stimulation of the basal cochlea while removing cochlear place-of-excitation cues. In the psychophysical procedure, trained cats detected changes from a base pulse rate to a higher pulse rate. In the scalp-recording procedure, the cortical-evoked acoustic change complex (ACC) and brainstem-generated frequency following response (FFR) were recorded simultaneously in sedated cats for pulse trains that alternated between the base and higher rates. The range of perceptual sensitivity to temporal pitch broadly resembled that of humans but was shifted to somewhat higher rates. The ACC largely paralleled these perceptual patterns, validating its use as an objective measure of temporal pitch sensitivity. The phase-locked FFR, in contrast, showed strong brainstem encoding for all tested pulse rates. These measures demonstrate the cat’s perceptual sensitivity to pitch in the absence of cochlear-place cues and may be valuable for evaluating neural mechanisms of temporal pitch perception in the feline animal model of stimulation by a CI or novel auditory prostheses.     

Comparison of Signal and Gap-Detection Thresholds for Focused and Broad Cochlear Implant Electrode Configurations

Cochlear implant (CI) users usually exhibit marked across-electrode differences in detection thresholds with “focused” modes of stimulation, such as partial-tripolar (pTP) mode. This may reflect differences either in local neural survival or in the distance of the electrodes from the modiolus. To shed light on these two explanations, we compared stimulus-detection thresholds and gap-detection thresholds (GDTs) at comfortably loud levels for at least four electrodes in each of ten Advanced Bionics CI users, using 1031-pps pulse trains. The electrodes selected for each user had a wide range of stimulus-detection thresholds in pTP mode. We also measured across-electrode variations in both stimulus-detection and gap-detection tasks in monopolar (MP) mode. Both stimulus-detection and gap-detection thresholds correlated across modes. However, there was no significant correlation between stimulus-detection and gap-detection thresholds in either mode. Hence, gap-detection thresholds likely tap a source of across-electrode variation additional to, or different from, that revealed by stimulus-detection thresholds. Stimulus-detection thresholds were significantly lower for apical than for basal electrodes in both modes; this was only true for gap detection in pTP mode. Finally, although the across-electrode standard deviation in stimulus-detection thresholds was greater in pTP than in MP mode, the reliability of these differences—assessed by dividing the across-electrode standard deviation by the standard deviation across adaptive runs for each electrode—was similar for the two modes; this metric was also similar across modes for gap detection. Hence across-electrode differences can be revealed using clinically available MP stimulation, with a reliability comparable to that observed with focused stimulation.     

The Frequency Following Response (FFR) May Reflect Pitch-Bearing Information But is Not a Direct Representation of Pitch

The frequency following response (FFR), a scalp-recorded measure of phase-locked brainstem activity, is often assumed to reflect the pitch of sounds as perceived by humans. In two experiments, we investigated the characteristics of the FFR evoked by complex tones. FFR waveforms to alternating-polarity stimuli were averaged for each polarity and added, to enhance envelope, or subtracted, to enhance temporal fine structure information. In experiment 1, frequency-shifted complex tones, with all harmonics shifted by the same amount in Hertz, were presented diotically. Only the autocorrelation functions (ACFs) of the subtraction-FFR waveforms showed a peak at a delay shifted in the direction of the expected pitch shifts. This expected pitch shift was also present in the ACFs of the output of an auditory nerve model. In experiment 2, the components of a harmonic complex with harmonic numbers 2, 3, and 4 were presented either to the same ear (“mono”) or the third harmonic was presented contralaterally to the ear receiving the even harmonics (“dichotic”). In the latter case, a pitch corresponding to the missing fundamental was still perceived. Monaural control conditions presenting only the even harmonics (“2 + 4”) or only the third harmonic (“3”) were also tested. Both the subtraction and the addition waveforms showed that (1) the FFR magnitude spectra for “dichotic” were similar to the sum of the spectra for the two monaural control conditions and lacked peaks at the fundamental frequency and other distortion products visible for “mono” and (2) ACFs for “dichotic” were similar to those for “2 + 4” and dissimilar to those for “mono.” The results indicate that the neural responses reflected in the FFR preserve monaural temporal information that may be important for pitch, but provide no evidence for any additional processing over and above that already present in the auditory periphery, and do not directly represent the pitch of dichotic stimuli.     

Skinfold thickness varies directly with spring coefficient and inversely with jaw pressure

PURPOSE: The main aims of this study were to: 1) determine whether heavy use of Harpenden calipers caused deterioration of the spring coefficient (force per unit length), 2) to quantify the change in skinfold thickness per unit change in jaw closing (downscale) pressure, and 3) to develop a calibration range for these calipers. METHODS: Part a) The change in spring force per unit length after at least 100,000 cycles of opening and closing five different springs was measured on a load cell. Part b) The dynamic downscale jaw pressure exerted by six pairs of Harpenden springs was measured on one caliper. Two were new pairs of springs (N1 and N2), two were 25-yr-old springs (O1 and O2), and two pairs (S1 and S2) had been used for less 1 yr. The six spring pairs were used to measure skinfold thicknesses at nine sites, in triplicate, on 20 subjects with the order of springs randomized and counterbalanced. Part c) The downscale jaw pressure of 78 Harpenden calipers was measured at eight jaw gaps. RESULTS: Part a) The springs did not change their characteristics after >100,000 cycles. Part b) At each skinfold site, the lowest thickness was recorded for S2 which exerted the highest jaw pressure (9.04 g x mm(-2)) and conversely the highest thickness was for N1 which exerted the lowest jaw pressure (8.02 g x mm(-2)). Increasing the downscale jaw closing pressure from 8.0 to 9.0 g x mm(-2) reduced a skinfold thickness by approximately 10%. Part c) The mean downscale jaw pressure was 7.82 +/- 0.25 g x mm(-2). CONCLUSIONS: In summary, it is suggested that if accurate skinfold measures between different Harpenden calipers are required, the downscale jaw pressure should be in the range of 7.40-7.82 and 7.85-8.21 g x mm(-2), at jaw gaps of 5 and 40 mm, respectively. These jaw pressures can be achieved by servicing the caliper pivot and indicator gauge to minimize frictional losses, adjusting the caliper jaw alignment, and by selecting springs that have a spring coefficient in the range 1.10-1.15 N x mm(-1).     

Optimizing the clinical fit of auditory brain stem implants

OBJECTIVE: To develop and implement a new audiological fitting procedure for auditory brain stem implants (ABIs), based on an efficient algorithm, and to compare it with two procedures presently used in clinical practice. DESIGN: First, the different procedures were compared by using computer models and simulations with normal-hearing subjects (N = 4). This allows for an analysis of the accuracy of the procedures in a way that is not possible when testing ABI users. The root-mean-square error between the order estimated by the procedure and the true order was calculated. In addition, ABI users (N = 2) were tested with the new procedure to see if it could be successfully applied in clinic. The degree of variability of their results across runs and sessions was analyzed. RESULTS: The tests of the normal-hearing subjects showed that our proposed procedure required significantly fewer trials (22 on average) than procedures presently used in clinic (with 76 and 234 trials on average for the two other procedures tested) to produce the same degree of accuracy. Computer modeling also demonstrated this advantage. Additional testing showed this advantage was maintained under a variety of conditions relevant to the clinic. The two patients tested were able to use this procedure with success, even though they were poor at discriminating the pitch of electrodes. The patients showed results consistent with having about 4 to 5 discriminable groups of electrodes with the 12 to 14 electrodes tested. CONCLUSIONS: The proposed procedure requires fewer trials to produce a clinically useful result and is well tolerated in the clinic. An additional advantage is that it allows testing to be broken down into several "blocks," each containing a small number of trials. If the variability between blocks is small, information can be combined across blocks to increase the accuracy of the result. If the variability is large, perhaps between blocks on different days, this may reflect a significant change in the percepts generated by the implant, and signal to the clinician that a significant alteration in the fitting is required. We recommend its use in ABI user fitting and in cochlear implant fitting when pitch ranking is problematic.     

A Site-Selection Strategy Based on Polarity Sensitivity for Cochlear Implants: Effects on Spectro-Temporal Resolution and Speech Perception

Thresholds of asymmetric pulses presented to cochlear implant (CI) listeners depend on polarity in a way that differs across subjects and electrodes. It has been suggested that lower thresholds for cathodic-dominant compared to anodic-dominant pulses reflect good local neural health. We evaluated the hypothesis that this polarity effect (PE) can be used in a site-selection strategy to improve speech perception and spectro-temporal resolution. Detection thresholds were measured in eight users of Advanced Bionics CIs for 80-pps, triphasic, monopolar pulse trains where the central high-amplitude phase was either anodic or cathodic. Two experimental MAPs were then generated for each subject by deactivating the five electrodes with either the highest or the lowest PE magnitudes (cathodic minus anodic threshold). Performance with the two experimental MAPs was evaluated using two spectro-temporal tests (Spectro-Temporal Ripple for Investigating Processor EffectivenesS (STRIPES; Archer-Boyd et al. in J Acoust Soc Am 144:2983–2997, 2018) and Spectral-Temporally Modulated Ripple Test (SMRT; Aronoff and Landsberger in J Acoust Soc Am 134:EL217–EL222, 2013)) and with speech recognition in quiet and in noise. Performance was also measured with an experimental MAP that used all electrodes, similar to the subjects’ clinical MAP. The PE varied strongly across subjects and electrodes, with substantial magnitudes relative to the electrical dynamic range. There were no significant differences in performance between the three MAPs at group level, but there were significant effects at subject level—not all of which were in the hypothesized direction—consistent with previous reports of a large variability in CI users’ performance and in the potential benefit of site-selection strategies. The STRIPES but not the SMRT test successfully predicted which strategy produced the best speech-in-noise performance on a subject-by-subject basis. The average PE across electrodes correlated significantly with subject age, duration of deafness, and speech perception scores, consistent with a relationship between PE and neural health. These findings motivate further investigations into site-specific measures of neural health and their application to CI processing strategies.

     

Persistent effects of a serotonin depletor (p-chlorophenylalanine) in regenerated planaria (Dugesia dorotocephala)

p-Chlorophenylalanine (pCPA) caused an increase in looping and locomotion speed in planaria (Dugesia dorotocephala). These effects dissipated quickly after treatment, except in animals that regenerated from worms surgically sectioned after treatment. Planaria that regenerated from head sections showed more looping 6 and 11 days later than tail regenerates, regenerates from untreated worms, and uncut worms. After the initial acceleration, pCPA animals, especially regenerates from tail sections, slowed down compared with untreated controls. Tail regenerates showed reduced speed 6 and 11 days later in comparison with head regenerates, regenerates from untreated animals, and uncut animals. The speed effect may have been due to pathogenesis in the eye spots in pCPA animals. The looping effect, however, may have been due to persisting serotonin depletion in the head regenerates. It is suggested that research on this problem might profitably be pursued with sexually reproducing planaria, to examine the possibility of genetic recoding due to serotonin depletion.     

Anaplasma phagocytophilum Dense-Cored Organisms Mediate Cellular Adherence through Recognition of Human P-Selectin Glycoprotein Ligand 1

Anaplasma phagocytophilum is an obligate intracellular bacterium that infects granulocytes to cause human granulocytic anaplasmosis. The susceptibilities of human neutrophils and promyelocytic HL-60 cells to A. phagocytophilum are linked to bacterial usage of P-selectin glycoprotein ligand 1 (PSGL-1) as a receptor for adhesion and entry. A. phagocytophilum undergoes a biphasic developmental cycle, transitioning between a smaller electron dense-cored cell (DC), which has a dense nucleoid, and a larger, pleomorphic electron lucent reticulate cell (RC), which has a dispersed nucleoid. The pathobiological roles of each form have not been elucidated. To ascertain the role of each form, we used electron microscopy to monitor bacterial binding, entry, and intracellular development within HL-60 cells. Only DCs were observed binding to and inducing uptake by HL-60 cells. By 12 h, internalized DCs had transitioned to RCs, which had initiated replication. By 24 h, large RC numbers were observed within individual inclusions. Reinfection had occurred by 36 h, as individual, vacuole-enclosed DCs and RCs were again observed. The abilities of DC- and RC-enriched A. phagocytophilum populations to bind and/or infect HL-60 cells or Chinese hamster ovary cells transfected to express PSGL-1 (PSGL-1 CHO) were compared. Only DCs bound PSGL-1 CHO cells and did so in a PSGL-1-blocking antibody-inhibitable manner. These results demonstrate that the respective roles of A. phagocytophilum DCs and RCs are consistent with analogous forms of other obligate intracellular pathogens that undergo biphasic development and hint that the PSGL-1-targeting adhesin(s) may be upregulated or optimally posttranslationally modified on DCs.Anaplasma phagocytophilum is a member of the family Anaplasmataceae and an obligate intracellular bacterium that infects peripherally circulating neutrophils and bone marrow progenitors to cause the emerging and potentially fatal tick-transmitted disease human granulocytic anaplasmosis (HGA) (4, 11). Clinical manifestations of HGA range from subclinical or mild infection to severe or even fatal disease. Common symptoms include fever, malaise, myalgia, and headache. Laboratory findings consist of leukopenia, thrombocytopenia, and elevated levels of hepatic transaminases (4). The hallmark of HGA is the presence of intravacuolar colonies of A. phagocytophilum, termed morulae, within the cytosol of peripheral granulocytes.Sialyl Lewis x (sLe^x)-modified P-selectin glycoprotein ligand 1 (PSGL-1) is the confirmed receptor utilized by A. phagocytophilum to bind and invade human neutrophils, bone marrow progenitors, and myeloid cell lines (12, 16). A. phagocytophilum binding to PSGL-1 requires cooperative recognition of the N-terminal primary amino acid sequence and the α2,3-linked sialic acid and α1,3-linked fucose of sLe^x (9, 44). This complex interaction is mediated either by multiple A. phagocytophilum adhesins or by a single adhesin having multiple binding domains (9, 44). The A. phagocytophilum adhesin(s) that mediates attachment to human sLe^x-modified PSGL-1 has yet to be identified.A. phagocytophilum undergoes a biphasic developmental cycle, transitioning between a smaller electron dense-cored cell (DC), which has a dense nucleoid, and a larger, pleomorphic electron lucent reticulate cell (RC), which has a dispersed nucleoid (14, 27-29, 31, 35, 41). The respective pathobiological role that each form plays has not been elucidated, but indirect insights into their potential roles are presented when the biphasic developmental cycles of other intravacuolar pathogens are considered. Biphasic development was first identified and is most well studied for Chlamydia spp., but it has also been observed for two Anaplasmataceae pathogens, Anaplasma marginale (26, 28) and Ehrlichia chaffeensis (31, 46), as well as Coxiella burnetii, the causative agent of Q fever (15, 25). Chlamydial elementary bodies (EB), which are analogous to DCs, are metabolically inert, environmentally resistant, and mediate attachment to and entry of eukaryotic host cells (2). Following attachment, EB are internalized via induced phagocytosis into a host cell-derived vacuole. EB remain within the pathogen-occupied vacuole, where they differentiate into noninfectious, metabolically active reticulate bodies (RB) and subsequently begin to divide by binary fission. Next, the progeny RB condense into EB and are released to reinitiate infection. Zhang and colleagues recently demonstrated that the E. chaffeensis DCs and RCs play analogous pathobiological roles to chlamydial EB and RB, respectively (46).Obligate intracellular pathogen binding to host cells precedes entry and is therefore requisite for survival. An important observation that has been made for both the chlamydial EB and E. chaffeensis DC is that they specifically express outer membrane proteins that have been identified as adhesin candidates (32, 37, 42, 46), while the RC forms of each bacterium do not. Because A. phagocytophilum also transitions between the DC and RC, we hypothesized that adhesins targeting PSGL-1 are expressed on the DC. In this study, we monitored A. phagocytophilum development in human promyelocytic HL-60 cells over a 72-h time course following synchronous infection and tested bacterial populations enriched for DCs or RCs for their abilities to adhere to human PSGL-1 expressed on transfected Chinese hamster ovary (CHO) cell surfaces and to bind and infect HL-60 cells. Our results demonstrate that the A. phagocytophilum DC is the infectious form and that it mediates cellular adherence and specifically recognizes PSGL-1. These observations enhance our understanding of A. phagocytophilum-host cell interactions and represent a key step toward elucidating the PSGL-1-targeting adhesin(s).