Stimulation of Sleep in Patients With Epilepsy

January 18, 2021 updated by: University Children's Hospital, Zurich

Investigating the Effect of Closed-loop Auditory Stimulation on Sleep and Behavior in Patients With Epilepsy and Healthy Controls: a Developmental Study

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Anticipated)

120

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Switzerland
      • Zurich, Switzerland, 8032
        • Recruiting
        • University Children's Hospital Zurich
        • Contact:
        • Principal Investigator:
          • Reto Huber, Prof. Dr.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

4 years to 30 years (ADULT, CHILD)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: BASIC_SCIENCE
  • Allocation: RANDOMIZED
  • Interventional Model: CROSSOVER
  • Masking: TRIPLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Children (4-11y) with epilepsy
Down-phase-targeted closed-loop auditory stimulation is administered in each arm.
Other: Down-phase targeted auditory stimulation
The presentation of a soft, brief tone (50 ms of pink noise). The volume will be held low enough to avoid provoking arousals or awakenings. In case of a waking-up-reaction, the volume will be lowered in steps of 5 dB.
EXPERIMENTAL: Teenagers (12-17y) with epilepsy
Other: Down-phase targeted auditory stimulation
The presentation of a soft, brief tone (50 ms of pink noise). The volume will be held low enough to avoid provoking arousals or awakenings. In case of a waking-up-reaction, the volume will be lowered in steps of 5 dB.
EXPERIMENTAL: Young adults (18-30y) with epilepsy
Other: Down-phase targeted auditory stimulation
The presentation of a soft, brief tone (50 ms of pink noise). The volume will be held low enough to avoid provoking arousals or awakenings. In case of a waking-up-reaction, the volume will be lowered in steps of 5 dB.
EXPERIMENTAL: Healthy children (4-11y)
Other: Down-phase targeted auditory stimulation
The presentation of a soft, brief tone (50 ms of pink noise). The volume will be held low enough to avoid provoking arousals or awakenings. In case of a waking-up-reaction, the volume will be lowered in steps of 5 dB.
EXPERIMENTAL: Healthy teenagers (12-17y)
Other: Down-phase targeted auditory stimulation
The presentation of a soft, brief tone (50 ms of pink noise). The volume will be held low enough to avoid provoking arousals or awakenings. In case of a waking-up-reaction, the volume will be lowered in steps of 5 dB.
EXPERIMENTAL: Healthy young adults (18-30y)
Other: Down-phase targeted auditory stimulation
The presentation of a soft, brief tone (50 ms of pink noise). The volume will be held low enough to avoid provoking arousals or awakenings. In case of a waking-up-reaction, the volume will be lowered in steps of 5 dB.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
CLAS on EEG characteristics & behavior
Time Frame: Up to 4 years
CLAS changes sleep EEG characteristics (slow-wave and spindle activity) and the measured behavior (e.g. cognitive, memory and motor performance).
Up to 4 years
EEG characteristics on behavior & wake EEG characteristics
Time Frame: Up to 4 years
The changes in sleep EEG characteristics (slow-wave and spindle activity) correlate with the changes in measured behavior (attention [TAP battery], reaction time [TAP battery], and declarative [word-pair memory task] & spatial memory [object-location task]) and wake EEG characteristics (frequencies up to 40 Hz).
Up to 4 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Performance in attention in epilepsy patients
Time Frame: Up to 4 years
Attention (measured with TAP battery) of patients with epilepsy is restored to the level of healthy participants of the same age.
Up to 4 years
Performance in reaction times in epilepsy patients
Time Frame: Up to 4 years
Reaction times (measured with TAP battery) of patients with epilepsy is restored to the level of healthy participants of the same age.
Up to 4 years
Performance in spatial memory in epilepsy patients
Time Frame: Up to 4 years
Spatial memory (measured with object-location task) of patients with epilepsy is restored to the level of healthy participants of the same age.
Up to 4 years
Performance in declarative memory in epilepsy patients
Time Frame: Up to 4 years
Declarative memory (measured with word-pair memory task) of patients with epilepsy is restored to the level of healthy participants of the same age.
Up to 4 years
CLAS on sleep slow waves
Time Frame: Up to 4 years
Qualitative exploration of CLAS effect on the sleep slow waves across different age groups.
Up to 4 years
CLAS on other sleep EEG characteristics, such as sleep spindles
Time Frame: Up to 4 years
Qualitative exploration of CLAS effect on other sleep EEG characteristics, such as sleep spindles across different age groups.
Up to 4 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Children's Hospital, Zurich

Collaborators

University of Zurich
ETH Zurich

Investigators

  • Principal Investigator: Reto Huber, Prof. Dr., University Children's Hospital, Zurich

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

July 29, 2020

Primary Completion (ANTICIPATED)

October 1, 2022

Study Completion (ANTICIPATED)

December 1, 2025

Study Registration Dates

First Submitted

December 14, 2020

First Submitted That Met QC Criteria

January 18, 2021

First Posted (ACTUAL)

January 20, 2021

Study Record Updates

Last Update Posted (ACTUAL)

January 20, 2021

Last Update Submitted That Met QC Criteria

January 18, 2021

Last Verified

January 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2019-02134

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Voluntary approval of the participant or legal guardian of the participant is given by signed informed consent. Personal data will be collected and immediately coded to provide strict confidentiality. The participant code will only be available to the principal investigator and research coordinators. The EEG data, completely anonymized, will be made publicly available to be used in other studies, for which the participant must provide separate consent. The investigators comply with all legal provisions of the Data Protection Act.

The data, fully anonymized, will be published in a dedicated online repository. The data includes

  • PSG data + CLAS triggers
  • Basic demographic information: gender, age, socioeconomic status, handedness
  • Chronotype score
  • Responses to behavioral tests
  • Actigraphy
  • Sleep quality and sleepiness scores

IPD Sharing Time Frame

Start: December 2019 End: December 2025

IPD Sharing Access Criteria

Ideally, the investigators would like to publish the data through the University of Zurich, which is currently in the process of developing and contributing to the SWISSUbase. Unfortunately, at this time, the repository for neural, biological or psychology data has not yet been created. If, by the time of publication, this is still unavailable, the investigators will choose a repository that is compliant with the FAIR principles such as OpenNeuro. At the end of the project the investigators will evaluate the infrastructures available; it is conceivable that a Swiss university resource, or more suitable repository, will be established by then.

Study Data/Documents

  1. Individual Participant Data Set

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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