Cisplatin is a widely used chemotherapeutic agent effective against various cancers; however, a significant side effect is hearing loss, particularly affecting high-frequency sounds. This study explores the alterations in auditory brainstem response (ABR) thresholds in a controlled mouse model subjected to cisplatin treatment, specifically assessing responses to bone-conducted ultrasonic stimulation. Results indicate a discrepancy in response shifts between conventional ABR thresholds and those elicited by ultrasonic stimulation, which may reflect varying degrees of cochlear damage.
Cisplatin, a chemotherapy drug first introduced in the 1970s, has remained a cornerstone in the treatment of several malignancies, including those of the lung, stomach, and head and neck. Despite its efficacy in prolonging survival, cisplatin is notorious for its dose-dependent toxicities, prominently nephrotoxicity and ototoxicity, leading to permanent hearing loss in a significant portion of patients.
Hearing loss connected with cisplatin typically presents as bilateral, progressive impairment primarily in high frequencies. Current methodologies for monitoring this adverse effect, such as serial audiometry and electrophysiology, primarily assess threshold changes after the onset of hearing loss, and effective restoration of hearing post-loss remains elusive.
The phenomenon of ultrasonic hearing, detected through bone-conducted ultrasonic stimulation, may serve as a non-invasive marker of cochlear integrity. Previous studies suggest that responses to such stimulation are related to cochlear hair cell activity and depend on specific acoustic properties. However, the effects of cochlear damage, specifically from cisplatin, on ABR responses evoked by ultrasonic stimulation have not been extensively investigated, creating a gap in the current understanding of cochlear function post-therapy. This study aims to elucidate the differential impacts of cisplatin on ABR thresholds across varied stimulus conditions in a mouse model.
All animal experiments adhered to ethical guidelines mandated by the Physiological Society of Japan and were approved by the Institutional Animal Research Committee of Gifu University. Standard care protocols were followed to ensure animal welfare throughout the study.
A total of 32 healthy female C57BL/6JmsSlc mice, aged 6-12 weeks, were used. The specific combination of anaesthetics was administered to ensure consistent conditions during ABR measurements. Animals with a baseline threshold exceeding 70 dB at 40 kHz were excluded to establish a reliable testing pool. The remaining subjects then received either saline or cisplatin over a calculated regimen aimed at inducing meaningful high-frequency hearing loss.
A piezoelectric actuator drove the bone-conducted ultrasonic stimulation during the tests, with a high-sensitivity hydrophone utilized for calibration to ensure consistency and reliability of the stimulation parameters. Measurements across various frequencies were standardized to facilitate comparative analysis.
The ABR recordings followed established protocols with stainless-steel electrodes placed appropriately to capture brainstem responses. Various tone bursts were generated, with consistent settings used to evaluate auditory thresholds before and after treatment across conventional and ultrasonic frequencies.
Threshold shifts were statistically analyzed, with paired t-tests employed to explore differences within conventional and ultrasonic ranges. A significance level of p < 0.05 was established, and statistical software was utilized for data processing.
Following administration, ABR thresholds within the conventional hearing range showed significant elevation, while bone-conducted ultrasonic stimulation thresholds remained less affected or unchanged across many frequencies. Notably, shifts in ABR thresholds displayed different characteristics when comparing conventional auditory measures to those beyond the typical ranges
Test results demonstrated that the threshold shifts observed at higher frequencies (typical hearing range) markedly exceeded those seen in responses to ultrasonic stimulation. This outcome suggests a distinct response mechanism affected by cochlear status initially elicited by cisplatin treatment, highlighting that impairments affecting hair cell functions do not correspond directly with ABR responses derived from bone-conducted stimuli.
The findings of this study reveal that while cisplatin elicits predictable shifts in thresholds for conventional hearing assessment, the responses obtained through bone-conducted ultrasonic stimulation do not show the same degree of change. This dissociation indicates that cochlear mechanisms involved in processing ultrasonic signals may remain relatively intact despite significant losses in the conventional hearing spectrum. Consequently, understanding this divergence in auditory processing under cisplatin damage may assist in refining monitoring strategies for hearing impaired individuals and develop future therapeutic avenues.