Timed acoustic stimulation of sleep in relapsing-remitting multiple sclerosis

INTERVENTION: Permuted block randomisation is conducted by the Bristol Trials Centre (https://bristoltrialscentre.blogs.bristol.ac.uk/). Treatment arm: 2 weeks of consecutive nocturnal timed acoustic stimulation during sleep using SmartSleep®. Soft tones will be delivered through earphones during deep sleep (stage N3). The amplitude (stimulus intensity) and frequency (number of stimuli per unit time) of stimulation presentation will be systematically varied to identify optimal parameters for slow‐wave induction during sleep. Individually, the software will determine the range of stimulus intensity from minimum level sufficient for perceptual response (e.g. lowest audible volume setting for an auditory stimulus) to a stimulus level that the subject deems comfortable to still allow sleep. This is important, as sleep maintenance requires stimulus intensity low enough to avoid awakening. While maintaining stimulation intensity within optimal range, the stimulus frequency will be at 1Hz. The software uses the ongoing electroencephalogram (brain wave) recording to determine the appropriate sleep stage and deliver the acoustic stimulation. Together with a 1‐week period of getting used to the headband, a 2‐week 'sham' period when the soft tones are delivered but not phase‐locked to sleep stage N3 and a week between the active and placebo phases ('washout'), participants will be asked to wear the headband for 42 consecutive nights. All assessments will occur within this time period. CONDITION: Relapsing‐remitting multiple sclerosis (RRMS) ; Nervous System Diseases ; Multiple sclerosis PRIMARY OUTCOME: ; 1. Feasibility of timed acoustic stimulation of sleep in multiple sclerosis, determined by:; 1.1 Whether the pre‐defined progression target is met; 50% of participants show a =10% increase in slow‐wave activity (SWA, EEG power between 0.5‐4Hz) induced by timed acoustic stimulation of non‐rapid eye movement sleep. Measured at the end of 2 weeks timed acoustic stimulation (day 21 or day 42 depending on whether randomised to early or late stimulation); 1.2. Whether the target sample size of 12 is met within 6 months of the study opening to recruitment; 1.3. Adverse events reported on Days 0‐42; SECONDARY OUTCOME: ; 1. Neurophysiological parameters of sleep measured using electroencephalogram on days 0‐42; 2. Quality of sleep measured using a daily sleep evaluation questionnaire, sleep diary, Composite MotionWatch8 Sleep Quality Score and Pittsburgh Sleep Quality Index on days 0‐42; 3. Symptoms of multiple sclerosis measured using the MS Quality of Life‐29 questionnaire, MS Impact Score (MSIS‐29), Expanded Disability Status Scale (EDSS) and Brief International Cognitive Assessment for MS (BICAMS) on day 0, between days 21‐28 and day 42; 4. Quality of life measured using EQ‐5D and Depression, Anxiety and Stress Scale – 21 items (DASS‐21) on day 0, between days 21‐28 and day 42; INCLUSION CRITERIA: 1. Able to provide written, informed consent prior to entry 2. Age =18 years and =40 years 3. Estimated Expanded Disability Status Scale (EDSS) =6 (able to walk but may use some assistance if required) 4. Diagnosis of relapsing‐remitting multiple sclerosis (McDonald criteria) 5. Self‐report non‐restorative sleep, defined as sleep that is insufficiently refreshing