Auditory cortex electrical stimulation suppresses tinnitus in rats

Abstract

Recent clinical studies have demonstrated that auditory cortex electrical stimulation (ACES) has yielded promising results in the suppression of patients' tinnitus. However, the large variability in the efficacy of ACES-induced suppression across individuals has hindered its development into a reliable therapy. Due to ethical reasons, many issues cannot be comprehensively addressed in patients. In order to search for effective stimulation targets and identify optimal stimulation strategies, we have developed the first rat model to test for the suppression of behavioral evidence of tone-induced tinnitus through ACES. Our behavioral results demonstrated that electrical stimulation of all channels (frequency bands) in the auditory cortex significantly suppressed behavioral evidence of tinnitus and enhanced hearing detection at the central level. Such suppression of tinnitus and enhancement of hearing detection were respectively demonstrated by a reversal of tone exposure compromised gap detection at 10-12, 14-16, and 26-28 kHz and compromised prepulse inhibition at 10-12 and 26-28 kHz. On the contrary, ACES did not induce behavioral changes in animals that did not manifest any behavioral evidence of tinnitus and compromised hearing detection following the same tone exposure. The results point out that tinnitus may be more related to compromised central auditory processing than hearing loss at the peripheral level. The ACES-induced suppression of behavioral evidence of tinnitus may involve restoration of abnormal central auditory processing.

FIG. 1

Diagrams (left column) and screen shots from experiments (right column) showing: Startle stimulus alone (A) yielded robust startle-only responses (A′); startle stimulus preceded by a 40-ms silent gap (B) suppressed startle responses, indicating detection of gap (B′); startle stimulus preceded by a gap that is filled with tinnitus signals (C) yielded increased startle response, indicating gap detection was compromised (C′); decreased/suppressed tinnitus signals by ACES (D) diminished startle responses, suggesting restoration of compromised gap detection (D′). Background noise was narrow band noise at 60 dB SPL and startle stimulus was broadband noise at 115 dB SPL. Startle responses were reflected in Newtons.

FIG. 2

An example showing chronic implantation of a 4 × 4 microwire electrode array in the rat AC and electrophysiological responses to acoustic stimulation. A AC areas before implantation. B Placement of a chronic microwire electrode array. C Frequency tuning curves were recorded and used to determine the frequency representations of the implanted electrodes in the AC. Responses in channels such as 1, 2, 3, 4, 5, 9, 11, 12, 13, 14, 15, and 16 were well or sharply tuned to tones, suggesting that these neurons are located in the core area of the AC. Responses in channels such as 6, 7, 8, and 10 were less sensitive or broadly tuned to tones, suggesting that these neurons are probably near or located in the belt region. Scale bar for activity rate is on CH8.

FIG. 3

Data showing tone-induced behavioral evidence of tinnitus and ACES-induced suppression of behavioral evidence of tinnitus. A–E Robust gap detection (PreStim condition) occurred at 6–8, 10–12, 14–16, and 26–28 kHz and BBN prior to tone exposure, indicating no tinnitus development. B–D Comparison among PreExp, PreStim, and DurStim conditions demonstrated that following tone exposure, gap detection was significantly attenuated at 10–12, 14–16, and 26–28 kHz, indicating that tinnitus was developed at these frequencies. Comparison between PreExp and DurStim conditions demonstrated that ACES reversed the affected gap detection at these frequencies back to the normal state (PreExp condition). PreExp before tone exposure, PreStim after tone exposure but before ACES, DurStim during ACES to suppress tinnitus. Error bars represent the standard error of the mean.

FIG. 4

Data showing tone-induced PPI deficit and ACES-induced reversal of the PPI deficit. Robust PPI responses (PreStim condition) were seen at all frequencies prior to tone exposure, indicating normal PPI responses (A–E). Comparison among PreExp, PreStim, and DurStim conditions demonstrated that following tone exposure, PPI was significantly attenuated at 26–28 kHz and BBN. The data showed a tendency of tone-induced PPI attenuation at 10–12 kHz, although the statistics did not reach the significance (p = 0.07). In addition, although the statistics reached a significant level for PPI responses at BBN, the fact that PPI response was robust compared to startle-only response demonstrated that PPI responses were not significantly attenuated at BBN, indicating a hearing detection. Following ACES, the attenuated PPI responses were significantly reversed at 26–28 kHz and marginally reversed at 10–12 kHz (p = 0.05) (B, D). Comparison between PreExp and DurStim conditions demonstrated that ACES reversed the affected PPI to the normal state (PreExp condition) (B, D). PreExp before tone exposure, PreStim after tone exposure but before ACES, DurStim during ACES to suppress tinnitus. Error bars represent the standard error of the mean.

FIG. 5

Data from tinnitus⁽⁻⁾ animals showing that tone exposure did not induce behavioral evidence of tinnitus (compromised gap detection) and ACES did not significantly affect the gap detection responses in tinnitus⁽⁻⁾ animals. Note that significant gap detection responses to 6–8, 10–12, 14–16, and 26–28 kHz and BBN sounds were found before and after tone exposure as well as during ACES (A–E). Error bars represent the standard error of the mean.

FIG. 6

Data from tinnitus⁽⁻⁾ animals showing that both tone exposure and ACES did not affect PPI responses. Note that significant PPI responses (compared to startle-only responses) were seen before and after tone exposure as well as after ACES (A–E). Error bars represent the standard error of the mean.

FIG. 7

Data from tinnitus⁽⁺⁾ animals showing that ACES did not decrease the amplitudes of startle-only responses (background sounds without silent gaps) at lower frequency bands (6–8 and 10–12 kHz) and BBN. Instead, ACES tended to restore/enhance tone exposure-attenuated amplitudes of startle-only responses, especially for high-frequency bands at which gap detection was compromised and behavioral evidence of tinnitus was robust (compare gray and black bars). The restoration of the amplitudes of startle-only responses was significant at 26–28 kHz and marginal at 14–16 kHz.

FIG. 8

Click- and tone-evoked ABR thresholds collected before and 4 months after tone exposure. The data showed that no significant difference in tone-induced ABR threshold shifts in the left ears (LEs) was found between tinnitus⁽⁺⁾ and tinnitus⁽⁻⁾ animals. A ABR data from tinnitus⁽⁺⁾ animals showing that tone exposure induced significant hearing loss in the LE compared to pre-exposure data from the LE and compared to post-exposure data from the right ear (RE). B Similar ABR data from tinnitus⁽⁻⁾ animals showing that tone exposure induced significant hearing loss in the LE compared to pre-exposure data from the LE. One difference was that the hearing thresholds in tinnitus⁽⁻⁾ animals were not significantly affected using clicks and less affected at 8 kHz compared to those in tinnitus⁽⁺⁾ animals. In both tinnitus⁽⁺⁾ and tinnitus⁽⁻⁾ animals, their intact right ears maintained relatively normal hearing. Error bars represent the standard error of the mean.