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出境医 / 临床实验 / Autonomic Mechanisms of Sleep-dependent Memory Consolidation (MemS)

Autonomic Mechanisms of Sleep-dependent Memory Consolidation (MemS)

Study Description
Brief Summary:
The goal of the proposed project is to identify the impact vagal activity during sleep for memory formation. Nearly 100 years of research contends that sleep plays a critical role in memory consolidation (i.e. the transformation of recent experiences into stable, long-term memories), yet much of this literature has focused on the central nervous system and technologies like electroencephalography (EEG) to unpack neural correlates involved in memory processing. Sleep is also a unique period of autonomic variation and an expansive literature has indicated the critical importance of the autonomic nervous system for memory formation. This project would be amongst the first to examine the autonomic nervous system during sleep as a critical, causal pathway linking sleep to memory processing. The investigators will assess the impact of non-invasive, transcutaneous vagal nerve stimulation on sleep and post-sleep memory performance. Autonomic physiology, including electrocardiography and impedance cardiography, will be gathered at baseline, before the memory 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 active and sham stimulation conditions. Polysomnography will also be gathered during the nap to examine sleep architecture. The proposed research will address a critical gap in the literature by: 1) examining the causal role of the ANS for memory functioning in humans, 2) extending the current understanding of sleep's impact on memory processing, and 3) set the groundwork for novel, sleep-based interventions with the goal of improving cognitive health.

Condition or disease Intervention/treatment Phase
Memory Sleep Device: transcutaneous vagal nerve stimulation Not Applicable

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 Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 12 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: We will employ a within-subjects, crossover, sham-controlled design. Each participant will be exposed to both active and sham conditions over two visits (5-days apart).
Masking: Double (Participant, Outcomes Assessor)
Masking Description: Participant's will not be aware which configuration represents the sham vs active stimulation condition. Data analyses will be conducted blind to sham or active stimulation.
Primary Purpose: Basic Science
Official Title: Autonomic Mechanisms of Sleep-dependent Memory Consolidation
Actual Study Start Date : October 15, 2019
Actual Primary Completion Date : March 15, 2020
Actual Study Completion Date : March 15, 2020
Arms and Interventions
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).
 Device: transcutaneous vagal nerve stimulation
The transcutaneous stimulator engages the cymba conchae in the left inner ear, compared to the left earlobe in the sham stimulation condition.
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).
 Device: transcutaneous vagal nerve stimulation
The transcutaneous stimulator engages the cymba conchae in the left inner ear, compared to the left earlobe in the sham stimulation condition.
Outcome Measures
Primary Outcome Measures :
  1. 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 ]
    word-pair associates


Secondary Outcome Measures :
  1. 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

  2. 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 ]
    polysomnographically-recorded nap

  3. 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

  4. 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 ]
    continuous impedance cardiography during nap


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years to 64 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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
Contacts and Locations

Locations
Layout table for location information
United States, California
Langley Porter Psychiatric Institute
San Francisco, California, United States, 94143
Sponsors and Collaborators
University of California, San Francisco
National Center for Advancing Translational Science (NCATS)
Investigators
Layout table for investigator information
Principal Investigator: Lauren N Whitehurst, PhD University of California, San Francisco
Tracking Information
First Submitted Date  ICMJE July 9, 2019
First Posted Date  ICMJE July 16, 2019
Last Update Posted Date May 28, 2021
Actual Study Start Date  ICMJE October 15, 2019
Actual Primary Completion Date March 15, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 15, 2019) 		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 ]
word-pair associates
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 15, 2019)
  • 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
  • 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 ]
    polysomnographically-recorded nap
  • 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
  • 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 ]
    continuous impedance cardiography during nap
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Autonomic Mechanisms of Sleep-dependent Memory Consolidation
Official Title  ICMJE Autonomic Mechanisms of Sleep-dependent Memory Consolidation
Brief Summary The goal of the proposed project is to identify the impact vagal activity during sleep for memory formation. Nearly 100 years of research contends that sleep plays a critical role in memory consolidation (i.e. the transformation of recent experiences into stable, long-term memories), yet much of this literature has focused on the central nervous system and technologies like electroencephalography (EEG) to unpack neural correlates involved in memory processing. Sleep is also a unique period of autonomic variation and an expansive literature has indicated the critical importance of the autonomic nervous system for memory formation. This project would be amongst the first to examine the autonomic nervous system during sleep as a critical, causal pathway linking sleep to memory processing. The investigators will assess the impact of non-invasive, transcutaneous vagal nerve stimulation on sleep and post-sleep memory performance. Autonomic physiology, including electrocardiography and impedance cardiography, will be gathered at baseline, before the memory 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 active and sham stimulation conditions. Polysomnography will also be gathered during the nap to examine sleep architecture. The proposed research will address a critical gap in the literature by: 1) examining the causal role of the ANS for memory functioning in humans, 2) extending the current understanding of sleep's impact on memory processing, and 3) set the groundwork for novel, sleep-based interventions with the goal of improving cognitive health.
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  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:
We will employ a within-subjects, crossover, sham-controlled design. Each participant will be exposed to both active and sham conditions over two visits (5-days apart).
Masking: Double (Participant, Outcomes Assessor)
Masking Description:
Participant's will not be aware which configuration represents the sham vs active stimulation condition. Data analyses will be conducted blind to sham or active stimulation.
Primary Purpose: Basic Science
Condition  ICMJE
  • Memory
  • Sleep
Intervention  ICMJE Device: transcutaneous vagal nerve stimulation
The transcutaneous stimulator engages the cymba conchae in the left inner ear, compared to the left earlobe in the sham stimulation condition.
Study Arms  ICMJE
  • 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).
    Intervention: Device: transcutaneous vagal nerve stimulation
  • 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).
    Intervention: Device: transcutaneous vagal nerve stimulation
Publications *
  • 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.
  • 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.
  • 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.
  • 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. Review.
  • 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.
  • 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.
  • 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: July 28, 2020) 		12
Original Estimated Enrollment  ICMJE
 (submitted: July 15, 2019) 		60
Actual Study Completion Date  ICMJE March 15, 2020
Actual Primary Completion Date March 15, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 64 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04021797
Other Study ID Numbers  ICMJE Memory+Stimulation
A127552 ( Other Grant/Funding Number: National Center for Advancing Translational Science )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party University of California, San Francisco
Study Sponsor  ICMJE University of California, San Francisco
Collaborators  ICMJE National Center for Advancing Translational Science (NCATS)
Investigators  ICMJE
Principal Investigator: Lauren N Whitehurst, PhD University of California, San Francisco
PRS Account University of California, San Francisco
Verification Date May 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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