Vagus Nerve Stimulation Paired with Tones for the Treatment of Tinnitus: A Prospective Randomized Double-blind Controlled Pilot Study in Humans

Abstract

The aim of the pilot study was to evaluate the effect of Vagus Nerve Stimulation (VNS) paired with sounds in chronic tinnitus patients. All participants were implanted and randomized to a paired VNS (n = 16) or control (n = 14) group. After 6 weeks of home therapy, all participants received paired VNS. The device was used on 96% of days with good compliance. After 6 weeks, the paired VNS group improved on the Tinnitus Handicap Inventory (THI) (p = 0.0012) compared to controls (p = 0.1561). The between-group difference was 10.3% (p = 0.3393). Fifty percent of the participants in the paired VNS group showed clinically meaningful improvements compared to 28% in controls. At one year, 50% of participants had a clinically meaningful response. The therapy had greater benefits for participants with tonal and non-blast induced tinnitus at the end of 6 (24.3% vs. 2%, p = 0.05) and 12 weeks (34% vs. 2%, p = 0.004) compared to controls with 80% and 70% responding at 6 months and 1 year, respectively. Adverse effects were mild and well-tolerated and the therapy had a similar safety profile to VNS for epilepsy. VNS paired with tones may be effective for a subgroup of tinnitus patients and provides impetus for a larger pivotal study.

Figure 1

Individual changes in the Tinnitus Handicap Inventory (THI) score at baseline and 6 weeks for the paired VNS group (left; n = 16) and control (right; n = 14) group. Blue lines indicate participants with blast-induced and/or tonal tinnitus (n = 6 VNS; n = 5 controls).

Figure 2

The THI changes at baseline, 6 and 12 weeks of treatment based on the severity of tinnitus. The severity or THI grade is generally categorized as Slight (0–16), Mild (18–36), Moderate (38–56), Severe (58–76) and Catastrophic (78–100).

Figure 3

Study design. Participants were implanted with the device and randomized to either a paired VNS (n = 16) or control (n = 14) group. Participants performed the treatment at home for approximately 2.5 hours/day, 7 days/week. During the first 6-weeks, the implanted control group also received VNS but was unpaired from tones. After 6 weeks of blinded, controlled treatment, participants in the control group crossed over to receive paired VNS. After 6 weeks, participants in both groups received the paired VNS stimulation and were assessed until one year.

Figure 4

Setup using the Serenity® System that pairs Vagus Nerve Stimulation (VNS) with tones. The inset shows the electrode lead wrapped around the cervical vagus nerve. The device is the pulse generator that is implanted under the chest wall. The implant lead connects to the pulse generator. Image courtesy of MicroTransponder, Inc.

Figure 5

(a) Stimulation settings for paired VNS therapy. The lower panel shows the stimulation settings (0.8 mA, 30 Hz), which overlaps with the tone. Each VNS tone pairing was presented every 30 seconds, for approximately 2.5 hrs per session over a period of 24 hrs. (b) Stimulation settings for the Unpaired (Control) group. During each session, participants received 10 minutes of tones only, 5 minutes of silence and no VNS; 2 hours of VNS only; 5 minutes of silence and no VNS, and 10 minutes of tones only.

Figure 6

Pure Tone Audiometry for both the paired VNS and control group. Audiograms were obtained at baseline prior to implantation. Hearing thresholds were measured at 0.5 kHz, 1 kHz, 2 kHz, 3 kHz, 4 kHz, 6 kHz, 8 kHz, and 12.5 kHz.