The investigators aim to evaluate the effect of closed-loop auditory stimulation during sleep
in healthy children, adolescents and adults, as well children, adolescents and adults with
epilepsy. During closed-loop auditory stimulation, a brief, quiet, non-arousing auditory
stimuli, e.g. brief bursts of pink noise (50ms), are presented at specific moments during
sleep. This procedure allows to noninvasively interact with endogenous brain activity and to
influence sleep-dependent neuroplasticity.
Sleep slow waves (SSW) and the pathophysiological mechanisms of spike generation in patients
with epilepsy are tightly linked. SSW are cortically generated oscillations (~1 Hz)
alternating between a hyperpolarized down-state (neuronal silence) and a depolarized up-state
(neuronal firing). It has been shown experimentally that with increasing synchrony of slow
neuronal oscillations, spike wave occurrence is facilitated. Auditory stimulation applied in
correspondence to the SSW "up-phase" may increase the amplitude of the following SSW.
Contrarywise, tones applied at the SSW "down-phase" may have a disruptive effect on SSW.
In a control week participants' usual sleeping behavior will be assessed using activity
meters and sleep diaries. During the lab visits, sleep and wake brain activity will be
measured using EEG at the sleep laboratory. For sleep recordings, other standard
polysomnographic (PSG) measures will be recorded as well. Within the study, further measures
include a structural MRI, IQ, as well as motor, cognitive, and vigilance tests. Participants'
well-being and tolerance to the intervention will be assessed with questionnaires.
Thus, the investigators will have the following source data: PSG data, computer based test
results (cognitive functioning, vigilance, memory and motor tests), IQ and questionnaire
data, actigraphy data, and, depending on the participant and the availability of the MRI
scanner, structural MRI data.
The sample size of the study is based on previous publications showing a significant effect
of closed-loop auditory stimulation on NREM sleep EEG markers and declarative memory
consolidation (Ngo et al., 2013). By including 11 participants they could demonstrate
significant results both for the behavioral and electrophysiological data. Therefore, the
investigators assume that it would be statistically meaningful to recruit at least 20
subjects per age group.
As the goal is to record 160 complete datasets, all these datasets will be used for the
analysis. Incomplete datasets due to early withdrawal can be included partially for analyses
in which only the available measures are included.
For any given analysis, datasets missing the relevant data will be excluded. The
investigators will ensure that no analysis is based on less than 90% of the pursued sample
size, meaning that at least 18 datasets per age and health group will enter all analyses
(healthy participants or patients with epilepsy of a particular age group). In other words,
no more than two participants would be excluded between outliers and missing data. Should
this be exceeded, the investigators will compensate by recruiting additional participants
The data quality will be checked immediately after each experimental session to confirm the
correct timing of presented sounds, as well as to assess the effect of closed-loop auditory
stimulation on sleep EEG markers. The experiment will be continued if there will be a
significant change in slow-wave activity in the first 10 participants (p < 0.05,
paired-samples t-test) associated with closed-loop auditory stimulation application. The
final analysis described in the section below will be performed after all the data is
collected.
All study data will be archived at University Children's Hospital for a minimum of 10 years
after study termination or premature termination of the clinical trial. The anonymized EEGs
are stored on the server of the EEG division of the University Children's Hospital.
Data generation, transmission, archiving and analysis strictly follows the current Swiss
legal requirements for data protection. Personal identifiable information will be handled
with complete confidentiality and will only be accessible to authorized personnel who require
such information to fulfill their duties within the scope of the research project. The
documents of the telephone interview are kept enclosed. On the project specific documents,
participants are only identified by a unique participant number. Participant IDs and
corresponding names will be saved in an encrypted participant identification list, accessible
only to the Principal Investigator and authorized members of the team.
The Sponsor-Investigator is implementing and maintaining quality assurance and quality
control systems with written SOPs and Working Instructions to ensure that trials are
conducted and data are generated, documented (record), and reported in compliance with the
protocol, GCP, and applicable regulatory requirement(s). Monitoring and audits will be
conducted during the course of the study for quality assurance purposes. The day-to-day
management of the study will be coordinated through the selected PhD student supervised by
the postdoctoral researcher.
The investigator will allow the persons being responsible for the audit or the inspection to
have access to the source data/documents and to answer any questions arising. All involved
parties will keep the patient data strictly confidential.
