Animal Models of Hyperacusis: Neural Hyperactivity in Auditory, Emotional, Arousal, Memory, and Motor Networks

High doses of salicylate, the active ingredient in aspirin, are ototoxic resulting in behavioral evidence of tinnitus and hyperacusis and electrophysiological increases in auditory thresholds of 20-25 dB at the auditory nerve (AN), cochlear nucleus (CN), inferior colliculus (IC), medial geniculate body (MGB), and auditory cortex (AC). High doses of salicylate reduce suprathreshold neural response by more than 60% at the AN (hypoactivity). However, suprathreshold responses are progressively amplified as neural responses are relayed from CN, to IC, MGB, and AC so that suprathreshold neural responses are enhanced nearly 100% at the AC (hyperactivity). Remarkably, high-dose salicylate also enhances suprathreshold sound-evoked responses in brain regions outside the classical auditory pathway in brain regions involved with emotion (amygdala), memory and spatial navigation (hippocampus), arousal (reticular formation), and motor coordination and tinnitus gating (parafloccular lobe of cerebellum). Functional magnetic resonance imaging and connectome network analysis revealed increased functional connectivity of AC, MGB, and IC with the amygdala, hippocampus, reticular formation and parafloccular lobe of the cerebellum, structures that link and embellish auditory perceptual activity to other brain regions involved with memory, spatial navigation, emotion, arousal, motor coordination, and tinnitus. Tinnitus and hyperacusis likely have their origins in a complex neural network involving both auditory and non-auditory brain regions.