Low-intensity TUS for Sleep Disturbances in Patients With Chronic Tinnitus

A Pilot Randomized Controlled Trial of MRI-guided Focused Low-intensity Transcranial Ultrasound Stimulation (TUS) for Sleep Disturbances in Patients With Chronic Tinnitus

Background: Tinnitus, as a common symptom, can jeopardize the sleep quality and brain function and even lead to hearing loss and cognitive decline in elderly patients. The co-occurring tinnitus and sleep disturbances can significantly affect the cognitive functions and quality of life, and even be implicated as a key contributing factor in the development of prodromal dementia. At present, very few non-pharmacological therapies are developed for managing these comorbidities in elderly patients. Focused low-intensity transcranial ultrasound stimulation (TUS) enables to stimulation the deep brain structures, such as hippocampus, with optimized focality and specific frequency.

Objectives: We aim to 1) investigate the safety, feasibility and efficacy of a 2-week focused low-intensity TUS on the severity of tinnitus and sleep disturbances in elderly patients; 2) determine the sample size of a full-scale randomized clinical trial of low-intensity TUS in patients with tinnitus; 3) evaluate the effects of low-intensity TUS on the severity of tinnitus, sleep quality and cognitive functions at 2, 4 and 6 weeks after the treatments.

Design: A 2-week randomized, double-blind, controlled clinical trial. Methods: Chinese right-handed tinnitus patients with sleep disturbances (aged from 60 to 90 years) will be randomly assigned to a 2-week intervention of either low intensity TUS or sham TUS, with 7 participants per arm. Before intervention, T1-weighted magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI) data is used to construct individual realistic head model. Comprehensive assessments, including sleep quality, cognitive performance and quality of life will be conducted at baseline, 2nd week, 4th week and 6th week. Program adherence and adverse effects will be monitored throughout intervention.

Significance: This study aims to investigate the feasibility, safety and efficacy of low intensity TUS for sleep disturbances in patients with tinnitus. It wills also test the program adherence, tolerability and adverse effects of this innovative neurotechnology. Information will be helpful for in-depth understanding the relationship of "tinnitus, sleep and cognition" and guiding the further studies of otology, sleep medicine and age-related neurodegenerative diseases.

Data analysis: The primary outcomes will be the changes in tinnitus symptoms and sleep quality, and the comparisons of group differences across different time points. Secondary outcomes will be the changes of cognitive functions and quality of life. Intention-to-treat analysis will be carried out. Changes of efficacy indicators from baseline to each follow up point will be tested with mixed effect model.

Inclusion Criteria:

• Chinese, right-handed, aged from 60 to 80 years.
• Chronic tinnitus is defined as tinnitus with a duration of at least 3 months. Depending on the justification, different time course definitions of chronic tinnitus are possible.
• Sleep disturbances are defined as a Pittsburgh Sleep Quality Index (PSQI) total score above 5.
• No interference with independence in everyday activities.

Exclusion Criteria:

• Diseases of ear canal and tympanic membrane checked by otoscopic examination.
• Previous diagnosis of Meniere's disease and acoustic neuromas.
• Past history of neurological or mental disorders.
• Physically frail affecting attendance to treatment sessions.
• Already attending regular treatments, such as cognitive behavioral therapy or music therapy.
• Taking a psychotropic or other medication known to affect hearing functions.
• Significant communicative impairments.