Salicylate Ototoxicity, Tinnitus, and Hyperacusis

Salicylate, the active ingredient in aspirin, is one of the most widely used drugs in the world. Extremely high doses of salicylate induce a temporary ototoxic condition that includes a transient hearing loss of approximately 25 dB, the phantom roaring sensation of tinnitus and hyperacusis, a condition in which everyday sounds are perceived as intolerably loud. Salicylate inhibits the formation of cyclooxygenase, which prevents the release of prostaglandins linked to pain and inflammation; however, high doses that are noxious also disrupt a host of other biological processes that contribute to their complex ototoxic effects. The hearing loss that emerges a few hours after salicylate ingestion primarily originates in the cochlea where the drug disrupts outer hair cells electromotile amplification and neural transmission from the inner hair cell to the auditory nerve. As the weak neural signals from the salicylate-impaired cochlea are relayed along the central auditory pathway, the suprathreshold neural responses are progressively amplified so that by the time the neural activity reaches the auditory cortex, suprathreshold soundevoked neural responses are much larger than normal. This sound-evoked hyperactivity is considered a putative neural correlate of loudness hyperacusis. Salicylate-induced increases in spontaneous brain activity and functional connectivity, assessed with functional magnetic resonance imaging, revealed increases in a distributed brain network that included central auditory structures, the reticular arousal system, the amygdala emotional center, cerebellar structures involved in motor control, and hippocampal regions linked to memory and spatial navigation. The salicylate-induced increases in spontaneous activity and functional connectivity within this distributed neural network can account for many of the symptoms associated with the phantom sound of tinnitus.