Autonomic Mechanisms of Sleep-dependent Memory Consolidation

Study Overview
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Brief Summary
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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
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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.

Official Title
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Autonomic Mechanisms of Sleep-dependent Memory Consolidation

Conditions
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Memory, Sleep

Intervention / Treatment
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* Device: transcutaneous vagal nerve stimulation


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional 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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: Sham<br>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<br>* The transcutaneous stimulator engages the cymba conchae in the left inner ear, compared to the left earlobe in the sham stimulation condition.<br>|
| Experimental: Active<br>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<br>* The transcutaneous stimulator engages the cymba conchae in the left inner ear, compared to the left earlobe in the sham stimulation condition.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in memory between sham and active stimulation | word-pair associates | active stimulation - sham stimulation (visits are counterbalanced); measured on day 6 and on day 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in amount of time in sleep stages between sham and active stimulation | polysomnographically-recorded nap | active stimulation - sham stimulation (visits are counterbalanced); measured on day 6 and on day 12 | 
| Change in sleep spectral features between sham and active stimulation | polysomnographically-recorded nap | active stimulation - sham stimulation (visits are counterbalanced); measured on day 6 and on day 12 | 
| Change in vagal activity between sham and active stimulation | continuous heart rate variability during nap | active stimulation - sham stimulation (visits are counterbalanced); measured on day 6 and on day 12 | 
| Change in sympathetic activity between sham and active stimulation | continuous impedance cardiography during nap | active stimulation - sham stimulation (visits are counterbalanced); measured on day 6 and on day 12 |