Abstract
Introduction
Tinnitus is the presence of sound in the absence of an external sound source, which is associated with suffering in tinnitus disorder and affects quality of life worldwide. Vagus nerve stimula- tion (VNS) paired with non-tinnitus sounds has shown promise in reverting the tonotopic map changes seen in tinnitus. An alternative approach is to pair a replica of the tinnitus sound with VNS in order to associate it with the parasympathetic rest-and-digest response via Pavlovian conditioning. As the parasympathetic response may occur 5 seconds after VNS, the auditory stimulation (AS) could also be presented 5 seconds after VNS. This study aimed to evaluate the safety and feasibility of a novel paired non-invasive VNS and tinnitus-matched sound bimodal stimulation, and to explore whether activity and functional connectivity would be altered within tinnitus networks and the associated effects on clinical outcomes.
Materials and Methods
A double-blinded randomised trial was conducted with three parallel participant groups. Partic- ipants (N = 30, n = 10 in each group) with chronic, pure-tone tinnitus were equally randomised into three groups: a simultaneous VNS and AS group, a group for which AS was presented with a 5 second delay after VNS onset, and a placebo group for which VNS and AS were randomly placed. Participants received nine sessions of treatment over three weeks. Primary outcomes included safety and feasibility measures and tinnitus loudness ratings, and secondary outcomes included clinical measures for tinnitus, psychological distress, and sleep as well as electroencephalographic measures. These outcomes were collected after treatment and at 1- month follow-up. Mann-Whitney U tests were used to compare between-group differences from baseline for each outcome measure.
Results
Descriptive measures indicated that paired VNS and AS treatment for tinnitus is safe (no se- rious adverse effects reported) and feasible (recruitment rate 7.5 participants per month, mean adherence 94%, dropout rate 10%). No significant differences were found between groups for changes in tinnitus loudness rating or Tinnitus Functional Index. The delayed AS group dif- fered from one other group for tinnitus unpleasantness rating change at 1-month follow-up (U = 22.50, z = -2.14, p = .032), Pittsburgh Sleep Quality Index change post-treatment (U = 22.00, Z = -2.15, p = .031), and the anxiety subscale change for the Depression Anxiety Stress Scale 21 post-treatment (U = 21.00, z = -2.23, p = .026). These differences are not significant following Bonferroni correction. Small changes in resting-state electroencephalography source power and functional connectivity were seen in the auditory cortices and in other tinnitus network regions, none of which were significant following Bonferroni correction.
A future fully-powered clinical trial is warranted to investigate longer-term effects of VNS,
to verify that non-invasive VNS is activating a sufficient parasympathetic response, and to com-
pare bimodal stimulation with non-invasive VNS alone.
Clinical Trial Registration
The ANZCTR registration number for this study is ACTRN12625000152426.