Review: Neural Mechanisms of Tinnitus and Hyperacusis in Acute Drug-Induced Ototoxicity

Abstract

Purpose Tinnitus and hyperacusis are debilitating conditions often associated with age-, noise-, and drug-induced hearing loss. Because of their subjective nature, the neural mechanisms that give rise to tinnitus and hyperacusis are poorly understood. Over the past few decades, considerable progress has been made in deciphering the biological bases for these disorders using animal models. Method Important advances in understanding the biological bases of tinnitus and hyperacusis have come from studies in which tinnitus and hyperacusis are consistently induced with a high dose of salicylate, the active ingredient in aspirin. Results Salicylate induced a transient hearing loss characterized by a reduction in otoacoustic emissions, a moderate cochlear threshold shift, and a large reduction in the neural output of the cochlea. As the weak cochlear neural signals were relayed up the auditory pathway, they were progressively amplified so that the suprathreshold neural responses in the auditory cortex were much larger than normal. Excessive central gain (neural amplification), presumably resulting from diminished inhibition, is believed to contribute to hyperacusis and tinnitus. Salicylate also increased corticosterone stress hormone levels. Functional imaging studies indicated that salicylate increased spontaneous activity and enhanced functional connectivity between structures in the central auditory pathway and regions of the brain associated with arousal (reticular formation), emotion (amygdala), memory/spatial navigation (hippocampus), motor planning (cerebellum), and motor control (caudate/putamen). Conclusion These results suggest that tinnitus and hyperacusis arise from aberrant neural signaling in a complex neural network that includes both auditory and nonauditory structures.

Figure 1.

Salicylate dose dependently induces tinnitus-like behavior. Schedule-induced polydipsia avoidance conditioning (SIP-AC) was used to determine the dose of sodium salicylate that could induce tinnitus. Rats were trained to avoid foot shocks on trials in which sound was presented and only lick on trials with no sound (quiet). Here is a schematic illustrating lick suppression data obtained with SIP-AC as a function of salicylate dose. Rats seldom licked on trials when a sound was presented regardless of the salicylate dose or in the absence of salicylate (0 = control). On no-sound trials, rats licked robustly in the absence of salicylate (0 mg/kg, control); however, as the dose of salicylate exceeded 100 mg/kg, licks on no-sound trials largely ceased, which is behavioral evidence that the rats were perceiving the phantom sound of tinnitus in the absence of an external stimulus.

Figure 2.

Schematic of reaction time–intensity functions used to assess the growth of loudness during baseline testing and a few hours after salicylate treatment (200 mg/kg). During baseline testing, reaction times gradually decreased as intensity increased. Post-salicylate reaction times increased at low intensities (~30 dB SPL) because salicylate induced a hearing loss of approximately 20 dB, making low-intensity sound less audible. However, as intensity increased, reaction times rapidly increased, catching up to baseline reaction times at moderate intensities (~50 dB SPL) and then becoming shorter than normal at higher intensities. Intensities at which reaction times were shorter than baseline indicate that the sounds were perceived as louder than normal, which is behavioral evidence of hyperacusis. BBN = broadband noise.

Figure 3.

Salicylate depresses otoacoustic emissions. Distortion product otoacoustic emission (DPOAE) input/output functions measured pre-exposure and 2 h postexposure. Postexposure input/output functions shifted to the right (threshold shift), and suprathreshold amplitudes reduced. The largest rightward shifts and largest amplitude reductions occurred above and below 16 kHz.

Figure 4.

Salicylate suppresses the compound action potential (CAP). Here is a schematic of CAP input/output functions pre-salicylate and 2 hr post-salicylate. Salicylate right-shifted the input/output function by approximately 20 dB (threshold shift, blue line) and reduced the amplitude of the CAP by more than 60% at high intensities (green dashed line), greatly reducing the neural output of the cochlea delivered to the central auditory pathway.

Figure 5.

Salicylate depresses sound-evoked neural responses in the auditory periphery, but suprathreshold responses are enhanced in the central auditory pathway. Here are schematics illustrating the input/output functions obtained pre-salicylate (solid line) and post-salicylate (dashed line). Salicylate was administered systemically in Panels A–E but infused into the lateral amygdala (LA) while recordings were obtained from the auditory cortex (AC) in Panel F. Postexposure input/output functions in the cochlear nucleus (CN; Panel A), inferior colliculus (IC; Panel B), medial geniculate body (MGB; Panel C), and AC (Panel D) all shifted to the right of pre-exposure functions at low intensities, reflecting the salicylate-induced cochlear threshold shift. (A) Neural responses in the CN depressed at all intensities post-salicylate. (B) Post-salicylate neural responses in the IC depressed at low intensities but slightly larger than normal at high intensities. (C) Post-salicylate neural responses in the MGB and (D) AC depressed at low intensities but enhanced at high intensities. Salicylate-induced enhancement increases between the MGB and the AC. (E) Post-salicylate input/output function in the LA enhanced at high intensities. (F) Suprathreshold responses in the AC enhanced after salicylate was infused into the LA; however, threshold was unaffected when salicylate was applied to the LA (compare Panel F with Panel D).

Figure 6.

Suprathreshold sound-evoked activity is progressively amplified post-salicylate as neural activity is relayed along the auditory pathway from the auditory nerve (AN), cochlear nucleus (CN), inferior colliculus (IC), medial geniculate body (MGB), and auditory cortex (AC). Here is a schematic depicting percent reduction (depressed, down arrow on the right) or enhancement (enhanced, up arrow on the right) following high-dose salicylate treatment observed in the AN, CN, IC, MGB, or AC as a function of stimulus frequency. Note the massive reduction in neural response from the cochlea. The greatest enhancement of suprathreshold neural activity occurs in the midbrain and cortical areas (IC, MGB, and AC), particularly near 16 kHz.

Figure 7.

Salicylate enhances functional connectivity. With the seed region in the auditory cortex (AC), functional connectivity was enhanced with the medial geniculate body (MGB), lobule IV and the parafloccular lobe of the cerebellum (CB), inferior colliculus (IC), and portions of the reticular formation (RF). With the seed region in the MGB, functional connectivity was increased with the AC and hippocampus (HIP). With the seed region in the IC, functional connectivity was enhanced with the AC and HIP.