Bimodal Auditory Electrical Stimulation for the Treatment of Tinnitus: Preclinical and Clinical Studies.

Tinnitus, or the phantom perception of sound, arises from pathological neural activity. Neurophysiological research has shown increased spontaneous firing rates and synchronization along the auditory pathway correlate strongly with behavioral measures of tinnitus. Auditory neurons are plastic, enabling external stimuli to be utilized to elicit long-term changes to spontaneous firing and synchrony. Pathological plasticity can thus be reversed using bimodal auditory plus nonauditory stimulation to reduce tinnitus. This chapter discusses preclinical and clinical evidence for efficacy of bimodal stimulation treatments of tinnitus, with highlights on sham-controlled, double-blinded clinical trials. The results from these studies have shown some efficacy in reducing the severity of tinnitus, based on subjective and objective outcome measures including tinnitus questionnaires and psychophysical tinnitus measurements. While results of some studies have been positive, the degree of benefit and the populations that respond to treatment vary across the studies. Directions and implications of future studies are discussed.

Virtually Transparent TiO2/Polyelectrolyte Thin Multilayer Films as High-Efficiency Nanoporous Photocatalytic Coatings for Breaking Down Formic Acid and for Escherichia coli Removal.

Virtually transparent photocatalytic multilayer films composed of TiO2 nanoparticles and polyelectrolytes were built on model surfaces using layer-by-layer assembly and investigated as photocatalytic nanoporous coatings. Formic acid (HCOOH) and Escherichia coli were used as models for the degradation of gaseous pollutants and for studying antibacterial properties. Positively charged TiO2 nanoparticles were coassembled with negatively charged poly(sodium 4-styrenesulfonate) (NaPSS) which leads to highly transparent nanoscale coatings in which the content of TiO2 particles is controlled mainly by the number of deposition cycles and the enhanced translucency with respect to titania powders is likely due to the presence of the polyelectrolytes in the interstitial space between the particles. Build-up and structural properties of the films were determined by ellipsometry, quartz crystal microbalance (QCM-D, with dissipation monitoring), and UV-vis spectrophotometry in transmission and scanning electron microscopy. Complementary photophysical and activity tests of (PSS/TiO2)n multilayer films were performed in the gas-phase under UV-A light and revealed a peculiar dependence on the number of layer pairs (LPs), corresponding to a clear deviation from the usual observations in photocatalysis with increasing TiO2 amounts. Most notably, a single LP film showed a strongly enhanced HCOOH mineralization and outperformed films with a higher number of LPs, with respect to the quantity of TiO2 catalyst present in the films. It is believed that the high quantum yield (8.1%) of a coating consisting of a single TiO2 layer which is 6-7 times higher than that of a 6-10 LP film could be due to the optimum accessibility of the TiO2 crystallites toward both HCOOH and water molecules. In thicker films, while no detrimental light screening was observed with increasing the number of LPs, diffusion phenomena could cap the efficiency of the access of the pollutant and water to the catalytic surface. Unlike for HCOOH mineralization, three PSS/TiO2 LPs were required for observing a maximum antibacterial activity of the nanocomposite coatings. This is likely due to the fact that micrometer-sized E. coli bacteria do not enter into the interstitial space between the TiO2 particles and require a different surface morphology with respect to the number of active contact points for optimum degradation.

Remodeling of cholinergic input to the hippocampus after noise exposure and tinnitus induction in Guinea pigs.

Here, we investigate remodeling of hippocampal cholinergic inputs after noise exposure and determine the relevance of these changes to tinnitus. To assess the effects of noise exposure on the hippocampus, guinea pigs were exposed to unilateral noise for 2 hr and 2 weeks later, immunohistochemistry was performed on hippocampal sections to examine vesicular acetylcholine transporter (VAChT) expression. To evaluate whether the changes in VAChT were relevant to tinnitus, another group of animals was exposed to the same noise band twice to induce tinnitus, which was assessed using gap-prepulse Inhibition of the acoustic startle (GPIAS) 12 weeks after the first noise exposure, followed by immunohistochemistry. Acoustic Brainstem Response (ABR) thresholds were elevated immediately after noise exposure for all experimental animals but returned to baseline levels several days after noise exposure. ABR wave I amplitude-intensity functions did not show any changes after 2 or 12 weeks of recovery compared to baseline levels. In animals assessed 2-weeks following noise-exposure, hippocampal VAChT puncta density decreased on both sides of the brain by 20-60% in exposed animals. By 12 weeks following the initial noise exposure, changes in VAChT puncta density largely recovered to baseline levels in exposed animals that did not develop tinnitus, but remained diminished in animals that developed tinnitus. These tinnitus-specific changes were particularly prominent in hippocampal synapse-rich layers of the dentate gyrus and areas CA3 and CA1, and VAChT density in these regions negatively correlated with tinnitus severity. The robust changes in VAChT labeling in the hippocampus 2 weeks after noise exposure suggest involvement of this circuitry in auditory processing. After chronic tinnitus induction, tinnitus-specific changes occurred in synapse-rich layers of the hippocampus, suggesting that synaptic processing in the hippocampus may play an important role in the pathophysiology of tinnitus.

Auditory-somatosensory bimodal stimulation desynchronizes brain circuitry to reduce tinnitus in guinea pigs and humans.

The dorsal cochlear nucleus is the first site of multisensory convergence in mammalian auditory pathways. Principal output neurons, the fusiform cells, integrate auditory nerve inputs from the cochlea with somatosensory inputs from the head and neck. In previous work, we developed a guinea pig model of tinnitus induced by noise exposure and showed that the fusiform cells in these animals exhibited increased spontaneous activity and cross-unit synchrony, which are physiological correlates of tinnitus. We delivered repeated bimodal auditory-somatosensory stimulation to the dorsal cochlear nucleus of guinea pigs with tinnitus, choosing a stimulus interval known to induce long-term depression (LTD). Twenty minutes per day of LTD-inducing bimodal (but not unimodal) stimulation reduced physiological and behavioral evidence of tinnitus in the guinea pigs after 25 days. Next, we applied the same bimodal treatment to 20 human subjects with tinnitus using a double-blinded, sham-controlled, crossover study. Twenty-eight days of LTD-inducing bimodal stimulation reduced tinnitus loudness and intrusiveness. Unimodal auditory stimulation did not deliver either benefit. Bimodal auditory-somatosensory stimulation that induces LTD in the dorsal cochlear nucleus may hold promise for suppressing chronic tinnitus, which reduces quality of life for millions of tinnitus sufferers worldwide.