- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04021797
Autonomic Mechanisms of Sleep-dependent Memory Consolidation (MemS)
Study Overview
Status
Intervention / Treatment
Detailed Description
Poor sleep is associated with significant cognitive health decline. Recently, sleep disturbances have emerged as notable predictive and exacerbating factors in the onset and development of neurodegenerative disease. Decades of research have implicated that sleep plays a critical role in memory consolidation (i.e. the transformation of recent experiences into stable, long-term memories), the decline of which is critical in the early stages of dementia. This literature affords that sleep, a period of reduced external interference, provides an optimal window for memory consolidation and that electrophysiological features that emerge during sleep are integrally involved in the consolidation process. Most of this literature has focused on the central nervous system and technologies like electroencephalography (EEG) to unpack neural correlates involved in memory processing. However, little impact from this work has translated into practical treatments and recent reviews of the literature question these sleep - memory associations. This lack of clarity suggests that there may be other factors critical to our understanding of sleep-dependent memory consolidation that have not been given due consideration. This proposal suggests that the autonomic nervous system (ANS) during sleep may reflect a critical, though understudied, pathway linking sleep and memory.
An expansive body of research has supported the role of the ANS for memory formation. Rodent studies have found that the storage of new information in memory is either enriched or impaired following learning acquisition by directly modifying peripheral activity through the vagus nerve. The vagus nerve is responsible for communicating information about peripheral excitation and arousal via projections to the brainstem, which then projects to memory-related areas including the amygdala complex, hippocampus, and prefrontal cortex. Indeed, in humans, researchers have demonstrated that direct stimulation of the vagus nerve, via surgical implants, can enhance declarative memory in epileptic patients and in patients with Alzheimer's Disease. Recently, in a sample of healthy older adults, non-invasive (transcutaneous) vagal nerve stimulation during wake boosted memory for face-name associations. Importantly, previous research has demonstrated the predominance of parasympathetic/vagal activity during sleep, particularly during slow wave sleep, which has received critical attention for its causal role in declarative memory consolidation. More so, the PI's work has shown that sleep acts as a regulatory influence over vagal activity and that vagally-mediated activity during sleep can predict post-sleep memory improvement. Yet, few investigations have examined the causal impact of vagal activity during sleep for memory outcomes, which is the central aim of this application.
In this project, the investigators will utilize a within-subject, sham-controlled, counterbalanced design to determine the impact of active (inside of left ear) vs. sham (left earlobe) transcutaneous vagal nerve stimulation (tVNS) on: 1) sleep architecture, 2) autonomic activity during sleep, and 3) memory performance post-sleep. To this end, the investigators will utilize a daytime nap protocol, a common methodological tool used to assess the role of sleep for cognition. A nap approach allows for strict circadian-control of cognition and provides for an examination of tVNS's impact on a full cycle of sleep that includes both NREM and REM stages. The researchers will assess declarative memory performance, using a word-pair associates task, before and after the nap period for both the active and sham stimulation conditions. Autonomic physiology, including electrocardiography and impedance cardiography, will be gathered at baseline before the word-pairs task and continuously during sleep to examine vagal tone (i.e. heart rate variability) and sympathetic activation (i.e. pre-ejection period) in response to both the active and sham stimulation conditions. Polysomnography will also be gathered during the nap to examine sleep architecture.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
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California
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San Francisco, California, United States, 94143
- Langley Porter Psychiatric Institute
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Healthy, adult volunteers between the ages of 18-64.
- English speaking
- Self-reported napping
Exclusion Criteria:
- Aged greater than 64 years
- Lack of adherence to sleep/wake schedule of at least 7 hours a night for 5-days prior to study and during study timeline.
- Body mass index of 35 or above
- Presence of any clinical sleep disorder, including insomnia and obstructive sleep apnea (OSA)
- Presence of medical or psychiatric condition that is likely to affect sleep/wake function or cardiovascular functioning, including doctor diagnosed arrhythmia, bradycardia, hypertension, congestive heart failure, major depression, bipolar disorder, post-traumatic stress disorder.
- Medication use that is likely to affect sleep/wake function or cardiovascular functioning, including antidepressants, anxiolytic or soporific medication, and beta-blockers.
- Pregnancy
- Epilepsy
- head trauma
- alcoholism
- migraines
- metal pieces in the body (may confound tVNS delivery)
- history of substance abuse
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: Randomized
- Interventional Model: Crossover Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Sham Comparator: Sham
For the sham condition, the electrodes will be attached to an ear location that has not been shown to engage the vagus nerve.
The stimulation frequency, intensity and duration will be aligned with the same parameters presented for the active tVNS condition (8Hz frequency, 5.0 mA electrical current and 200 ms pulse width).
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The transcutaneous stimulator engages the cymba conchae in the left inner ear, compared to the left earlobe in the sham stimulation condition.
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Experimental: Active
For the active condition, the electrodes will be attached to the ear at a place previously demonstrated to stimulate the vagus nerve.
The stimulation frequency, intensity and duration will be aligned with the same parameters presented for the sham condition (8Hz frequency, 5.0 mA electrical current and 200 ms pulse width).
|
The transcutaneous stimulator engages the cymba conchae in the left inner ear, compared to the left earlobe in the sham stimulation condition.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in memory between sham and active stimulation
Time Frame: active stimulation - sham stimulation (visits are counterbalanced); measured on day 6 and on day 12
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word-pair associates
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active stimulation - sham stimulation (visits are counterbalanced); measured on day 6 and on day 12
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in amount of time in sleep stages between sham and active stimulation
Time Frame: active stimulation - sham stimulation (visits are counterbalanced); measured on day 6 and on day 12
|
polysomnographically-recorded nap
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active stimulation - sham stimulation (visits are counterbalanced); measured on day 6 and on day 12
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Change in sleep spectral features between sham and active stimulation
Time Frame: active stimulation - sham stimulation (visits are counterbalanced); measured on day 6 and on day 12
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polysomnographically-recorded nap
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active stimulation - sham stimulation (visits are counterbalanced); measured on day 6 and on day 12
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Change in vagal activity between sham and active stimulation
Time Frame: active stimulation - sham stimulation (visits are counterbalanced); measured on day 6 and on day 12
|
continuous heart rate variability during nap
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active stimulation - sham stimulation (visits are counterbalanced); measured on day 6 and on day 12
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Change in sympathetic activity between sham and active stimulation
Time Frame: active stimulation - sham stimulation (visits are counterbalanced); measured on day 6 and on day 12
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continuous impedance cardiography during nap
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active stimulation - sham stimulation (visits are counterbalanced); measured on day 6 and on day 12
|
Collaborators and Investigators
Investigators
- Principal Investigator: Lauren N Whitehurst, PhD, University of California, San Francisco
Publications and helpful links
General Publications
- Diekelmann S, Born J. The memory function of sleep. Nat Rev Neurosci. 2010 Feb;11(2):114-26. doi: 10.1038/nrn2762. Epub 2010 Jan 4.
- Clark KB, Naritoku DK, Smith DC, Browning RA, Jensen RA. Enhanced recognition memory following vagus nerve stimulation in human subjects. Nat Neurosci. 1999 Jan;2(1):94-8. doi: 10.1038/4600.
- Kreuzer PM, Landgrebe M, Husser O, Resch M, Schecklmann M, Geisreiter F, Poeppl TB, Prasser SJ, Hajak G, Langguth B. Transcutaneous vagus nerve stimulation: retrospective assessment of cardiac safety in a pilot study. Front Psychiatry. 2012 Aug 7;3:70. doi: 10.3389/fpsyt.2012.00070. eCollection 2012.
- Clancy JA, Mary DA, Witte KK, Greenwood JP, Deuchars SA, Deuchars J. Non-invasive vagus nerve stimulation in healthy humans reduces sympathetic nerve activity. Brain Stimul. 2014 Nov-Dec;7(6):871-7. doi: 10.1016/j.brs.2014.07.031. Epub 2014 Jul 16.
- Whitehurst LN, Cellini N, McDevitt EA, Duggan KA, Mednick SC. Autonomic activity during sleep predicts memory consolidation in humans. Proc Natl Acad Sci U S A. 2016 Jun 28;113(26):7272-7. doi: 10.1073/pnas.1518202113. Epub 2016 Jun 13.
- Whitehurst LN, Naji M, Mednick SC. Comparing the cardiac autonomic activity profile of daytime naps and nighttime sleep. Neurobiol Sleep Circadian Rhythms. 2018 Mar 15;5:52-57. doi: 10.1016/j.nbscr.2018.03.001. eCollection 2018 Jun.
- Ghacibeh GA, Shenker JI, Shenal B, Uthman BM, Heilman KM. The influence of vagus nerve stimulation on memory. Cogn Behav Neurol. 2006 Sep;19(3):119-22. doi: 10.1097/01.wnn.0000213908.34278.7d.
- Cellini N, Whitehurst LN, McDevitt EA, Mednick SC. Heart rate variability during daytime naps in healthy adults: Autonomic profile and short-term reliability. Psychophysiology. 2016 Apr;53(4):473-81. doi: 10.1111/psyp.12595. Epub 2015 Dec 16.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Other Study ID Numbers
- Memory+Stimulation
- A127552 (Other Grant/Funding Number: National Center for Advancing Translational Science)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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