The Sensitivity of the Electrically Stimulated Auditory Nerve to Amplitude Modulation Cues Declines With Advanced Age.

OBJECTIVES: This study aimed to investigate effects of aging and duration of deafness on sensitivity of the auditory nerve (AN) to amplitude modulation (AM) cues delivered using trains of biphasic pulses in adult cochlear implant (CI) users. DESIGN: There were 21 postlingually deaf adult CI users who participated in this study. All study participants used a Cochlear Nucleus device with a full electrode array insertion in the test ear. The stimulus was a 200-ms pulse train with a pulse rate of 2000 pulses per second. This carrier pulse train was sinusodially AM at four modulation rates (20, 40, 100, 200 Hz). The peak amplitude of the modulated pulse train was the maximum comfortable level (i.e., C level) measured for the carrier pulse train. The electrically evoked compound action potential (eCAP) to each of the 20 pulses selected over the last two AM cycles were measured. In addition, eCAPs to single pulses were measured with the probe levels corresponding to the levels of 20 selected pulses from each AM pulse train. There were seven electrodes across the array evaluated in 16 subjects (i.e., electrodes 3 or 4, 6, 9, 12, 15, 18, and 21). For the remaining five subjects, 4 to 5 electrodes were tested due to impedance issues or time constraints. The modulated response amplitude ratio (MRAR) was calculated as the ratio of the difference in the maximum and the minimum eCAP amplitude measured for the AM pulse train to that measured for the single pulse, and served as the dependent variable. Age at time of testing and duration of deafness measured/defined using three criteria served as the independent variables. Linear Mixed Models were used to assess the effects of age at testing and duration of deafness on the MRAR. RESULTS: Age at testing had a strong, negative effect on the MRAR. For each subject, the duration of deafness varied substantially depending on how it was defined/measured, which demonstrates the difficulty of accurately measuring the duration of deafness in adult CI users. There was no clear or reliable trend showing a relationship between the MRAR measured at any AM rate and duration of deafness defined by any criteria. After controlling for the effect of age at testing, MRARs measured at 200 Hz and basal electrode locations (i.e., electrodes 3 and 6) were larger than those measured at any other AM rate and apical electrode locations (i.e., electrodes 18 and 21). CONCLUSIONS: The AN sensitivity to AM cues implemented in the pulse-train stimulation significantly declines with advanced age. Accurately measuring duration of deafness in adult CI users is challenging, which, at least partially, might have accounted for the inconclusive findings in the relationship between the duration of deafness and the AN sensitivity to AM cues in this study.

Time-of-Day Dictates Transcriptional Inflammatory Responses to Cytotoxic Chemotherapy.

Many cytotoxic chemotherapeutics elicit a proinflammatory response which is often associated with chemotherapy-induced behavioral alterations. The immune system is under circadian influence; time-of-day may alter inflammatory responses to chemotherapeutics. We tested this hypothesis by administering cyclophosphamide and doxorubicin (Cyclo/Dox), a common treatment for breast cancer, to female BALB/c mice near the beginning of the light or dark phase. Mice were injected intravenously with Cyclo/Dox or the vehicle two hours after lights on (zeitgeber time (ZT2), or two hours after lights off (ZT14). Tissue was collected 1, 3, 9, and 24 hours later. Mice injected with Cyclo/Dox at ZT2 lost more body mass than mice injected at ZT14. Cyclo/Dox injected at ZT2 increased the expression of several pro-inflammatory genes within the spleen; this was not evident among mice treated at ZT14. Transcription of enzymes within the liver responsible for converting Cyclo/Dox into their toxic metabolites increased among mice injected at ZT2; furthermore, transcription of these enzymes correlated with splenic pro-inflammatory gene expression when treatment occurred at ZT2 but not ZT14. The pattern was reversed in the brain; pro-inflammatory gene expression increased among mice injected at ZT14. These data suggest that inflammatory responses to chemotherapy depend on time-of-day and are tissue specific.