Small molecule modulation of the large-conductance calcium-activated potassium channel suppresses salicylate-induced tinnitus in mice.

Tinnitus is the phantom perception of sound that has no external source. A neurological signature of tinnitus, and the frequently associated hyperacusis, is an imbalance between excitatory and inhibitory activity in the central auditory system (CAS), leading to dysregulated network excitability. The large conductance, calcium-activated potassium (BK) channel is a key player in pre- and post-synaptic excitability through its mediation of K+ currents. Changes in BK channel activity are associated with aberrant network activity in sensory regions of the CNS, raising the possibility that BK channel modulation could regulate activity associated with tinnitus and hyperacusis. To test whether BK channel openers are able to suppress biomarkers of drug-induced tinnitus and hyperacusis, the 1,3,4 oxadiazole BMS-191011 was given to young adult CBA mice that had been administered 250 mg/kg sodium salicylate (SS). Systemic treatment with BMS-191011 reduced behavioral manifestations of SS-induced tinnitus, but not hyperacusis, probed via the gap-in-noise startle response method. Systemic BMS-191011 treatment did not influence SS-induced increases in auditory brainstem response functions, but local application at the inferior colliculus did reverse SS-suppressed spontaneous activity, particularly in the frequency region of the tinnitus percept. Thus, action of BMS-191011 in the inferior colliculus may contribute to the reduction in behaviorally measured tinnitus. Together, these findings support the utility of BK channel openers in reducing central auditory processing changes associated with the formation of the tinnitus percept.

Sodium salicylate alters temporal integration measured through increasing stimulus presentation rates.

OBJECTIVE: High doses of sodium salicylate (SS) are known to induce tinnitus, general hyperexcitability in the central auditory system, and to cause mild hearing loss. We used the auditory brainstem response (ABR) to assess the effects of SS on auditory sensitivity and temporal processing in the auditory nerve and brainstem. ABRs were evoked using tone burst stimuli varying in frequency and intensity with presentation rates from 11/s to 81/s. DESIGN: ABRs were recorded and analysed prior to and after SS treatment in each animal, and peak 1 and peak 4 amplitudes and latencies were determined along with minimal response threshold. STUDY SAMPLE: Nine young adult CBA/CaJ mice were used in a longitudinal within-subject design. RESULTS: No measurable effects of presentation rate were found on ABR threshold prior to SS; however, following SS administration increasing stimulus rates lowered ABR thresholds by as much as 10 dB and compressed the peak amplitude by intensity level functions. CONCLUSIONS: These results suggest that SS alters temporal integration and compressive nonlinearity, and that varying the stimulus rate of the ABR may prove to be a useful diagnostic tool in the study of hearing disorders that involve hyperexcitability.

Construction and Evaluation of Rodent-Specific rTMS Coils.

Rodent models of transcranial magnetic stimulation (TMS) play a crucial role in aiding the understanding of the cellular and molecular mechanisms underlying TMS induced plasticity. Rodent-specific TMS have previously been used to deliver focal stimulation at the cost of stimulus intensity (12 mT). Here we describe two novel TMS coils designed to deliver repetitive TMS (rTMS) at greater stimulation intensities whilst maintaining spatial resolution. Two circular coils (8 mm outer diameter) were constructed with either an air or pure iron-core. Peak magnetic field strength for the air and iron-cores were 90 and 120 mT, respectively, with the iron-core coil exhibiting less focality. Coil temperature and magnetic field stability for the two coils undergoing rTMS, were similar at 1 Hz but varied at 10 Hz. Finite element modeling of 10 Hz rTMS with the iron-core in a simplified rat brain model suggests a peak electric field of 85 and 12.7 V/m, within the skull and the brain, respectively. Delivering 10 Hz rTMS to the motor cortex of anaesthetized rats with the iron-core coil significantly increased motor evoked potential amplitudes immediately after stimulation (n = 4). Our results suggest these novel coils generate modest magnetic and electric fields, capable of altering cortical excitability and provide an alternative method to investigate the mechanisms underlying rTMS-induced plasticity in an experimental setting.

Alterations in peripheral and central components of the auditory brainstem response: a neural assay of tinnitus.

Chronic tinnitus, or "ringing of the ears", affects upwards of 15% of the adult population. Identifying a cost-effective and objective measure of tinnitus is needed due to legal concerns and disability issues, as well as for facilitating the effort to assess neural biomarkers. We developed a modified gap-in-noise (GIN) paradigm to assess tinnitus in mice using the auditory brainstem response (ABR). We then compared the commonly used acoustic startle reflex gap-prepulse inhibition (gap-PPI) and the ABR GIN paradigm in young adult CBA/CaJ mice before and after administrating sodium salicylate (SS), which is known to reliably induce a 16 kHz tinnitus percept in rodents. Post-SS, gap-PPI was significantly reduced at 12 and 16 kHz, consistent with previous studies demonstrating a tinnitus-induced gap-PPI reduction in this frequency range. ABR audiograms indicated thresholds were significantly elevated post-SS, also consistent with previous studies. There was a significant increase in the peak 2 (P2) to peak 1 (P1) and peak 4 (P4) to P1 amplitude ratios in the mid-frequency range, along with decreased latency of P4 at higher intensities. For the ABR GIN, peak amplitudes of the response to the second noise burst were calculated as a percentage of the first noise burst response amplitudes to quantify neural gap processing. A significant decrease in this ratio (i.e. recovery) was seen only at 16 kHz for P1, indicating the presence of tinnitus near this frequency. Thus, this study demonstrates that GIN ABRs can be used as an efficient, non-invasive, and objective method of identifying the approximate pitch and presence of tinnitus in a mouse model. This technique has the potential for application in human subjects and also indicates significant, albeit different, deficits in temporal processing in peripheral and brainstem circuits following drug induced tinnitus.

Transcutaneous electric nerve stimulation: the effect of intensity on local and distal cutaneous blood flow and skin temperature in healthy subjects.

OBJECTIVE: To determine what effect transcutaneous electric nerve stimulation (TENS) intensity has on local and distal cutaneous blood flow and skin temperature. DESIGN: Double-blind conditions. SETTING: University research laboratory. PARTICIPANTS: Forty subjects (20 men, 20 women) randomly assigned to 1 of 4 groups (10 per group): control, above-motor-threshold TENS, below-motor-threshold TENS, or perception-threshold TENS. INTERVENTION: TENS (4Hz, 200micros) was applied over the median nerve of the right forearm for 15 minutes. MAIN OUTCOME MEASURES: Blood flow measured by laser Doppler flowmeter and skin temperature measured by skin thermistor were recorded during TENS and for 15 minutes after it. RESULTS: Significant differences occurred between groups for forearm (P <.0001; repeated-measures analysis of variance) but not fingertip cutaneous blood flow. Post hoc Fisher tests showed a significant increase in forearm blood flow during TENS application in the above-motor-threshold TENS group compared with the other 3 groups. No significant differences between groups for skin temperature data were observed. CONCLUSIONS: The effect of TENS on cutaneous blood flow depends on whether muscle activity is induced. Low-frequency TENS applied above the motor threshold significantly increases local cutaneous blood flow. There were no significant differences between groups for skin temperature.

The lack of hypoalgesic efficacy of H-wave therapy on experimental ischaemic pain.

The hypoalgesic effect of H-wave therapy (HWT) at various frequencies (2-60 Hz) was assessed using a standardised form of the submaximal effort tourniquet technique (SETT). Healthy human volunteers (n = 112; 56 men, 56 women) were required to attend on two occasions; on the first, baseline pain scores were obtained and on the second, 48 h later, subjects were randomly assigned to control, placebo or 1 of 5 H-wave treatment conditions. In the treatment groups 2 self-adhesive electrodes were attached to the ipsilateral Erb's point and just lateral to the spinous processes of C6/C7. H-wave stimulation commenced 10 min prior to pain induction and continued throughout the 12-min duration of the technique. In the placebo group electrodes were attached as normal but leads were connected to a dummy power output. Analysis of variance of the differences in visual analogue scale and McGill Pain Questionnaire scores showed no significant differences in the treatment groups compared to placebo or controls. These results do not provide convincing evidence for any hypoalgesic effects of HWT at the frequency parameters stated on the experimental model of pain used.