Interaural Time-Delay Sensitivity in Bilateral Cochlear Implant Users: Effects of Pulse Rate, Modulation Rate, and Place of Stimulation

Electrical interaural time delay (ITD) discrimination was measured using 300-ms bursts applied to binaural pitch matched electrodes at basal, mid, and apical locations in each ear. Six bilateral implant users, who had previously shown good ITD sensitivity at a pulse rate of 100 pulses per second (pps), were assessed. Thresholds were measured as a function of pulse rate between 100 and 1,000 Hz, as well as modulation rate over that same range for high-rate pulse trains at 6,000 pps. Results were similar for all three places of stimulation and showed decreasing ITD sensitivity as either pulse rate or modulation rate increased, although the extent of that effect varied across subjects. The results support a model comprising a common ITD mechanism for high- and low-frequency places of stimulation, which, for electrical stimulation, is rate-limited in the same way across electrodes because peripheral temporal responses are largely place invariant. Overall, ITD sensitivity was somewhat better with unmodulated pulse trains than with high-rate pulse trains modulated at matched rates, although comparisons at individual rates showed that difference to be significant only at 300 Hz. Electrodes presenting with the lowest thresholds at 600 Hz were further assessed using bursts with a ramped onset of 10 ms. The slower rise time resulted in decreased performance in four of the listeners, but not in the two best performers, indicating that those two could use ongoing cues at 600 Hz. Performance at each place was also measured using single-pulse stimuli. Comparison of those data with the unmodulated 300-ms burst thresholds showed that on average, the addition of ongoing cues beyond the onset enhanced overall ITD sensitivity at 100 and 300 Hz, but not at 600 Hz. At 1,000 Hz, the added ongoing cues actually decreased performance. That result is attributed to the introduction of ambiguous cues within the physiologically relevant range and increased dichotic firing

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes

OBJECTIVE - Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired b-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS - We have conducted a meta-analysis of genome-wide association tests of ;2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS - Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10-8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/ C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 3 10-4), improved b-cell function (P = 1.1 × 10-5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10-6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS - We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis