Clinical trial NCT04716673: Stimulation of Sleep in Patients With Epilepsy
Official title: Investigating the Effect of Closed-loop Auditory Stimulation on Sleep and Behavior in Patients With Epilepsy and Healthy Controls: a Developmental Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Epilepsy
Keywords: epilepsy
sleep
closed-loop auditory stimulation
epileptic discharges
spikes
Lead sponsor: University Children's Hospital, Zurich
Sponsor class: OTHER
Collaborators: name: ETH Zurich
name: University of Zurich
First posted: 2021-01-20
Enrollment: 120
Sex: ALL
Minimum age (years): 4
Maximum age (years): 30
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: 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 (STIM condition). This procedure allows to noninvasively interact with endogenous brain activity and to influence sleep-dependent neuroplasticity. During one experimental night, closed-loop auditory stimulation will be applied (STIM night). In the SHAM night, the experimental set-up is the same as in the experimental night, but no sounds will be presented.
Primary purpose: BASIC_SCIENCE

Brief summary: 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.

Participants: Patients with epilepsy with epileptic discharges in their sleep EEG, as well as healthy controls

Objective: Characterizing the effects of down-phase-targeted auditory stimulation on behavior and sleep EEG characteristics and determine whether the changes in sleep EEG characteristics are associated with the changes in behavior and wake EEG characteristics.

Detailed description: 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.

Eligibility criteria: Inclusion criteria

* Participants of any gender
* Children, adolescents and young adults (4-30 years old)
* Right-handed
* Written informed consent by the participant or, if applicable, by their legal guardian after receiving information about the study For healthy participants:
* Good general health status

For patients with epilepsy:

* Diagnosed with epilepsy
* Wake or sleep EEG within the last 12 months showing epileptic discharges.
* Attending a regular school.

Exclusion criteria

* Irregular sleep-wake rhythm
* Shift work
* Daytime sleep
* Excessive sweating
* Obesity
* Sleep, psychiatric, neurological or physical disorders or illnesses other than epilepsy
* Hearing disorder
* Travelling across 2 or more time zones within the last month
* Pregnancy
* Skin allergy or very sensitive skin
* Drug and medication use or abuse other than for the treatment of epilepsy
* Daily nicotine use
* High caffeine consumption, including coffee, black and green tea, mate, cola, energy drinks, and iced tea

  * \<16 years: \>1 servings/day = \>80 mg caffeine
  * \>=16 years: \>2 servings/day = \>160 mg caffeine
* Alcohol consumption

  * \<16 years: any alcohol
  * 16-17 years: \>3-4 standard servings per week
  * \>=18 years: \>1 standard serving per day (\>14 mg)
* Inability to follow the procedures of the study For patients with epilepsy:
* Epilepsy syndromes with a high risk of seizure occurrence during the study night
* Generalized motor and/or focal motor seizure frequency \>1/week
* Generalized motor and/or focal motor seizure within 24h before the study night
* History of convulsive status epilepticus
* History of seizures provoked by sleep deprivation
* Treatment with corticosteroids, immunosuppressants or vagus nerve stimulation

Primary outcomes:
measure: CLAS on EEG characteristics & behavior
timeFrame: Up to 4 years
measure: EEG characteristics on behavior & wake EEG characteristics
timeFrame: Up to 4 years
Secondary outcomes:
measure: Performance in attention in epilepsy patients
timeFrame: Up to 4 years
measure: Performance in reaction times in epilepsy patients
timeFrame: Up to 4 years
measure: Performance in spatial memory in epilepsy patients
timeFrame: Up to 4 years
measure: Performance in declarative memory in epilepsy patients
timeFrame: Up to 4 years
measure: CLAS on sleep slow waves
timeFrame: Up to 4 years
measure: CLAS on other sleep EEG characteristics, such as sleep spindles
timeFrame: Up to 4 years
Other outcomes:
Locations:
city: Zurich
country: Switzerland
facility: University Children's Hospital Zurich
Study officials:
affiliation: University Children's Hospital, Zurich
name: Reto Huber, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References:
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