Focused low-intensity hippocampal transcranial ultrasound stimulation (TUS) for sleep disturbances in patients with chronic tinnitus: A study protocol for a pilot randomized controlled trial

Abstract

Background: Sleep disturbances are very common in tinnitus sufferers with a high prevalence ranging from 50% to 77%. Untreated sleep disturbances and tinnitus can cause brain shrinkage and lead to cognitive impairments in late adulthood. Until now, non-pharmacological treatments are very few for older patients suffering from sleep disturbances and chronic tinnitus. Even though clinical trials of transcranial magnetic stimulation (TMS) have shown positive results in the treatment of either sleep disturbances or chronic tinnitus, the results are highly varied due to the superficial cortical target. Compared to TMS, focused low-intensity transcranial ultrasound stimulation (TUS) is a newly developed modality of non-invasive brain stimulation that offers promising therapeutic effects by transmitting acoustic energy into deep brain structures with a high spatial resolution (i.e., sub-millimeter), which sparks interest in managing the comorbidities in ageing populations.

Methods and design: Chinese individuals between the ages of 60 and 90 years, who are right-handed and have sleep disturbances and chronic tinnitus, will participate in this pilot randomized clinical trial (RCT). Eligible participants will be randomly assigned to two treatment groups (1:1 ratio): low-intensity TUS or sham TUS (i.e., placebo-controlled group). Each group will consist of 15 participants. Before the treatment, high-resolution T1-weighted magnetic resonance imaging (MRI) data will be used to create a computational head model for each participant. The head model will help identify the treatment target of the left hippocampus. The treatments schedule contains six sessions of low-intensity TUS, three times per week, lasting two weeks. Each session of treatment lasts for 80 seconds. Throughout the study, outcome measurements will be conducted at four time points, including baseline, 2nd week, 6th week, and 12th week. The primary outcomes include subjective sleep quality and severity of tinnitus. The secondary measurements include actigraphy, tinnitus handicap inventory and glymphatic function. Participants' adherence to the program and any adverse event will be closely monitored throughout the duration of the clinical trial.

Conclusions: It is expected that a 2-week treatment of low-intensity TUS will show significant enhancement in sleep quality and the severity of tinnitus symptoms compared to sham TUS. This proposed clinical trial will provide high-level and valuable clinical evidence that could inform the effect size and personalized modeling of focused low-intensity TUS for different types of brain diseases.

Trial registration: ClinicalTrials.gov Identifier: NCT06776705.

Fig 1. Schedule of the pilot randomized clinical trial according to the standard protocol items: Recommendations for interventional trials checklist (SPIRIT).

Abbreviations: TUS = Transcranial ultrasound stimulation.

Fig 2. The Consolidated Standards of Reporting Trials (CONSORT) flow diagram for the clinical trial of focused low-intensity hippocampal transcranial ultrasound stimulation (TUS).