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Prospective within-subject study of dexmedetomidine sedation paired with CLAS conditions in repeated blocks. Intervention will consist of CLAS in-phase with EEG slow waves. Anti-phase stimulation will serve as an active control while sham stimulation will serve as a passive control.
Both nonpharmacologic and pharmacologic interventions augment expression of EEG slow waves that mimic those of natural sleep. Closed loop auditory stimulation (CLAS) is a noninvasive inexpensive approach to augment the spectral power and duration of these slow waves. Whether in-phase CLAS may address this need is unknown, since acoustic potentiation of pharmacologically-induced slow waves has not been investigated. This prospective within-subject study of dexmedetomidine sedation paired with CLAS will assess the feasibility of augmenting EEG slow waves during sedation.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| CLASS-D Cohort - In-phase | Experimental | Within-subject crossover cohort with intervention, acoustic stimulation delivered in phase with the anticipated peak of EEG slow wave oscillation |
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| CLASS-D Cohort - Anti-phase | Active Comparator | Within-subject crossover cohort with intervention, acoustic stimulation delivered in phase with the anticipated trough of EEG slow wave oscillation |
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| CLASS-D Cohort - Sham | Sham Comparator | Within-subject crossover cohort with intervention, acoustic stimulation anticipated in phase with the anticipated peak of EEG slow wave oscillation but no acoustic stimulation delivered. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| MRI | Radiation | A non-contrast brain MRI will be acquired for localizing EEG slow waves |
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| Measure | Description | Time Frame |
|---|---|---|
| Difference in EEG Slow Wave Activity From Sham to In-phase Stimulation | EEG slow waves activity (power) relative to the timing of the stimulation. Values are log-transformed All participants serve in the same arm but experience both sham and in-phase blocks. | Sham stimulation and in-phase stimulation blocks during the intervention |
| Difference in EEG Slow Wave Activity From Anti-phase to In-phase Stimulation | EEG slow waves activity (power) relative to the timing of the stimulation. Values are log-transformed All participants serve in the same arm but experience both anti-phase and in-phase blocks. | Anti-phase and in-phase blocks during the intervention |
| Difference in EEG Slow Wave Density From Anti-phase to In-phase Stimulation | Difference in EEG slow wave density from anti-phase to in-phase stimulation by looking at EEG slow waves duration relative to the timing of the stimulation All participants serve in the same arm but experience both anti-phase and in-phase blocks. | anti-phase and in-phase blocks during the intervention |
| Difference in EEG Slow Wave Density From Sham to In-phase Stimulation | Difference in EEG slow wave density from sham to in-phase stimulation by looking at EEG slow waves relative to the timing of the stimulation All participants serve in the same arm but experience both sham and in-phase blocks. | Sham stimulation and in-phase stimulation blocks during the intervention |
| Measure | Description | Time Frame |
|---|---|---|
| Difference of Reactivity to Thermal Stimulation From Anti-phase to In-phase Stimulation | Difference of reactivity to thermal stimulation from anti-phase to in-phase stimulation by measuring the threshold for responsiveness to thermal stimulation All participants serve in the same arm but experience both anti-phase and in-phase blocks. | Anti-phase and in-phase blocks of the intervention |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Ben J Palanca, MD PhD | Washington University School of Medicine | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Washington University School of Medicine/Barnes-Jewish Hospital | St Louis | Missouri | 63110 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 27927806 | Background | Prerau MJ, Brown RE, Bianchi MT, Ellenbogen JM, Purdon PL. Sleep Neurophysiological Dynamics Through the Lens of Multitaper Spectral Analysis. Physiology (Bethesda). 2017 Jan;32(1):60-92. doi: 10.1152/physiol.00062.2015. | |
| 29490885 | Background | Leger D, Debellemaniere E, Rabat A, Bayon V, Benchenane K, Chennaoui M. Slow-wave sleep: From the cell to the clinic. Sleep Med Rev. 2018 Oct;41:113-132. doi: 10.1016/j.smrv.2018.01.008. Epub 2018 Feb 5. |
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2 participants were withdrawn after consent.
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| ID | Title | Description |
|---|---|---|
| FG000 | CLASS-D Cohort | Dexmedetomidine: All participants will receive dexmedetomidine with sedation titrated stepwise to 2, 3 or 4 ng/ml. Breathe-Squeeze Task: All participants will be asked to perform the breathe-squeeze task throughout the experiment. This will allow us to determine loss and return of responsiveness. Subjects will receive multiple 5-minute blocks of acoustic stimulation during two states: 1. while performing the task; and 2. after becoming unresponsive to the task. Quantitative Sensory Testing (QST): Quantitative sensory testing (QST) using increasing ramp thermal stimulation (32-52 ºC) will be delivered to compare arousal thresholds between conditions. While performing task and after being unresponsive to the task: acoustic stimulation (65db) with up-slope of EEG with QST: 65 db acoustic stimulation synchronized with the up-slope of EEG slow waves (in-phase) While performing task and after being unresponsive to the task: acoustic stimulation (65db) with down-slope of EEG with QST: 65 dB acoustic stimulation synchronized with the down-slope of the EEG slow waves (anti-phase) While performing task and after being unresponsive to the task: sham stimulation (0 db stimulation) with QST MRI: A non-contrast brain MRI will be acquired for localizing EEG slow waves Home sleep study: All subjects will prove unattended home sleep studies to be conducted on the night preceding and following the sedation to assess slow wave homeostasis changes. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Pre-sedation Sleep |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jul 30, 2021 |
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| Quantitative Sensory Testing (QST) | Diagnostic Test | Quantitative sensory testing (QST) using increasing ramp thermal stimulation (32-52 ºC) will be delivered to compare arousal thresholds between conditions. |
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| Home sleep study | Diagnostic Test | Unattended home sleep studies will be conducted on the night preceding sedation and on the night following sedation to assess changes in slow wave homeostasis. |
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| Acoustic stimulation (65 decibels or db) up-slope of EEG with QST | Other | Acoustic stimulation (65 db) synchronized in-phase with the up-slope of EEG slow waves |
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| Acoustic stimulation (65db) down-slope of EEG with QST | Other | 65 dB acoustic stimulation synchronized with the down-slope of the EEG slow waves (anti-phase) |
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| 0 db with QST | Other | sham stimulation (0 dB volume) |
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| Dexmedetomidine | Drug | All participants will receive dexmedetomidine with sedation titrated step-wise to 2, 3 or 4 ng/ml |
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| Breathe-Squeeze Task | Other | All participants will be asked to perform the breathe-squeeze task throughout the experiment. This will allow us to determine loss and return of responsiveness. |
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| Difference of Reactivity to Thermal Stimulation From Sham to In-phase Stimulation | Difference of reactivity to thermal stimulation from sham to in-phase stimulation by measuring the threshold for responsiveness to thermal stimulation All participants serve in the same arm but experience both sham and in-phase blocks. | Sham and in-phase blocks during intervention |
| Slow Wave Activity Calculated During N3 Sleep | Change in slow wave activity on the night of the intervention will be compared to that on the night prior to the study session. Calculated as power | on the nights before and the night of the intervention |
| 26834569 | Background | Neske GT. The Slow Oscillation in Cortical and Thalamic Networks: Mechanisms and Functions. Front Neural Circuits. 2016 Jan 14;9:88. doi: 10.3389/fncir.2015.00088. eCollection 2015. |
| 38571816 | Derived | Smith SK, Kafashan M, Rios RL, Brown EN, Landsness EC, Guay CS, Palanca BJA. Daytime dexmedetomidine sedation with closed-loop acoustic stimulation alters slow wave sleep homeostasis in healthy adults. BJA Open. 2024 Mar 28;10:100276. doi: 10.1016/j.bjao.2024.100276. eCollection 2024 Jun. |
| 36967282 | Derived | Guay CS, Hight D, Gupta G, Kafashan M, Luong AH, Avidan MS, Brown EN, Palanca BJA. Breathe-squeeze: pharmacodynamics of a stimulus-free behavioural paradigm to track conscious states during sedation☆. Br J Anaesth. 2023 May;130(5):557-566. doi: 10.1016/j.bja.2023.01.021. Epub 2023 Mar 24. |
| COMPLETED |
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| NOT COMPLETED |
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| Sedation |
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| Post-sedation Sleep |
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| HD-EEG |
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| MRI |
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| ID | Title | Description |
|---|---|---|
| BG000 | CLASS-D Cohort | Dexmedetomidine: All participants will receive dexmedetomidine with sedation titrated stepwise to 2, 3 or 4 ng/ml. Breathe-Squeeze Task: All participants will be asked to perform the breathe-squeeze task throughout the experiment. This will allow us to determine loss and return of responsiveness. Subjects will receive multiple 5-minute blocks of acoustic stimulation during two states: 1. while performing the task; and 2. after becoming unresponsive to the task Quantitative Sensory Testing (QST): Quantitative sensory testing (QST) using increasing ramp thermal stimulation (32-52 ºC) will be delivered to compare arousal thresholds between conditions While performing task: acoustic stimulation (65db) with up-slope of EEG with QST: 65 db acoustic stimulation synchronized with the up-slope of EEG slow waves (in-phase) While performing task: acoustic stimulation (65db) with down-slope of EEG with QST: 65 dB acoustic stimulation synchronized with the down-slope of the EEG slow waves (anti-phase) While performing task: sham stimulation (0 db stimulation) with QST MRI: A non-contrast brain MRI will be acquired for localizing EEG slow waves Home sleep study: All subjects are to prove unattended home sleep studies to be conducted on the night preceding sedation and the night following sedation to assess changes in slow-wave homeostasis. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| ASA Physical Status | Participants were graded based on either the absence or presence of mild systemic disease (ASA). Mild systemic disease refers to a general medical condition that affects multiple body systems but is not severe enough to cause significant functional impairment or life-threatening complications. The ASA classification uses a grading system of I (one) through V (five), with I identifying a person in good health and V identifying a person with a severe, life-threatening condition. | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Difference in EEG Slow Wave Activity From Sham to In-phase Stimulation | EEG slow waves activity (power) relative to the timing of the stimulation. Values are log-transformed All participants serve in the same arm but experience both sham and in-phase blocks. | Posted | Median | Full Range | Log(μV squared) | Sham stimulation and in-phase stimulation blocks during the intervention |
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| Primary | Difference in EEG Slow Wave Activity From Anti-phase to In-phase Stimulation | EEG slow waves activity (power) relative to the timing of the stimulation. Values are log-transformed All participants serve in the same arm but experience both anti-phase and in-phase blocks. | Posted | Median | Full Range | log(μV squared) | Anti-phase and in-phase blocks during the intervention |
|
| ||||||||||||||||||||||||||||||
| Primary | Difference in EEG Slow Wave Density From Anti-phase to In-phase Stimulation | Difference in EEG slow wave density from anti-phase to in-phase stimulation by looking at EEG slow waves duration relative to the timing of the stimulation All participants serve in the same arm but experience both anti-phase and in-phase blocks. | Posted | Median | Full Range | waves/minute | anti-phase and in-phase blocks during the intervention |
| |||||||||||||||||||||||||||||||
| Primary | Difference in EEG Slow Wave Density From Sham to In-phase Stimulation | Difference in EEG slow wave density from sham to in-phase stimulation by looking at EEG slow waves relative to the timing of the stimulation All participants serve in the same arm but experience both sham and in-phase blocks. | Posted | Median | Full Range | waves/minute | Sham stimulation and in-phase stimulation blocks during the intervention |
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| Secondary | Difference of Reactivity to Thermal Stimulation From Anti-phase to In-phase Stimulation | Difference of reactivity to thermal stimulation from anti-phase to in-phase stimulation by measuring the threshold for responsiveness to thermal stimulation All participants serve in the same arm but experience both anti-phase and in-phase blocks. | Posted | Median | Full Range | degrees celsius | Anti-phase and in-phase blocks of the intervention |
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| Secondary | Difference of Reactivity to Thermal Stimulation From Sham to In-phase Stimulation | Difference of reactivity to thermal stimulation from sham to in-phase stimulation by measuring the threshold for responsiveness to thermal stimulation All participants serve in the same arm but experience both sham and in-phase blocks. | Posted | Median | Full Range | degrees celsius | Sham and in-phase blocks during intervention |
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| Secondary | Slow Wave Activity Calculated During N3 Sleep | Change in slow wave activity on the night of the intervention will be compared to that on the night prior to the study session. Calculated as power | Only one cohort as measures taken after all cross over conditions | Posted | Median | Inter-Quartile Range | μV squared/Hz | on the nights before and the night of the intervention |
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1 week
Within subject trial. Participant performs task while responsive. Dexmedetomidine infusion initiated while participant performs task. After unresponsive and no longer performing task due to sedation with dexmedetomidine, cross-over with concomitant dexmedetomidine sedation: in-phase CLAS, anti-phase CLAS, and sham. Participant then recovers from the sedation while unresponsive. After awakening, participant performs task while recovering from dexmedetomidine.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | CLASS-D Cohort While Performing Task Without Sedation | Participants awake and performing task without sedation and before In-phase/anti-phase/sham CLAS administered. Task can only be performed when responsive. | 0 | 16 | 0 | 16 | 0 | 16 |
| EG001 | CLASS-D Cohort While Performing Task With Sedation | Participants under sedation and performing task during dexmedetomidine sedation and before In-phase/anti-phase/sham CLAS administered. Task can only be performed when responsive. | 0 | 16 | 0 | 16 | 0 | 16 |
| EG002 | CLASS-D Cohort Unresponsive During Sedation But Before CLAS | Participants no longer performing task during dexmedetomidine sedation and before In-phase/anti-phase/sham CLAS administered. Participant unresponsive | 0 | 16 | 0 | 16 | 4 | 16 |
| EG003 | CLASS-D Cohort - In-phase After Becoming Unresponsive to Task | After participant unresponsive and no longer performing task since sedated with dexmedetomidine. Within-subject crossover cohort with intervention, acoustic stimulation delivered in phase with the anticipated peak of EEG slow wave oscillation | 0 | 16 | 0 | 16 | 0 | 16 |
| EG004 | CLASS-D Cohort - Anti-phase After Becoming Unresponsive to Task | After participant unresponsive and no longer performing task since sedated with dexmedetomidine. Within-subject crossover cohort with intervention, acoustic stimulation delivered in phase with the anticipated trough of EEG slow wave oscillation | 0 | 16 | 0 | 16 | 0 | 16 |
| EG005 | Sham Comparator: CLASS-D Cohort - Sham After Becoming Unresponsive to Task | After participant unresponsive and no longer performing task since sedated with dexmedetomidine. Within-subject crossover cohort with intervention, acoustic stimulation anticipated in phase with the anticipated peak of EEG slow wave oscillation but no acoustic stimulation delivered. | 0 | 16 | 0 | 16 | 0 | 16 |
| EG006 | CLASS-D Cohort Unresponsive During Sedation and After CLAS | Participants sedated no during dexmedetomidine sedation and after In-phase/anti-phase/sham CLAS administered. Participant unresponsive and not performing task. | 0 | 16 | 0 | 16 | 0 | 16 |
| EG007 | CLASS-D Cohort Awake Performing Task While Recovering From Sedation | Participants recovering from sedation and performing task during dexmedetomidine sedation and after In-phase/anti-phase/sham CLAS administered. | 0 | 16 | 0 | 16 | 0 | 16 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Restlessness | Nervous system disorders | Non-systematic Assessment |
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| bradycardia | Cardiac disorders | Systematic Assessment | bradycardia requiring glycopyrrolate |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Ben Palanca | Washington University School of Medicine | 314-273-9076 | palancab@wustl.edu |
| May 31, 2023 |
| Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | May 24, 2023 | May 31, 2023 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D000161 | Acoustic Stimulation |
| D020927 | Dexmedetomidine |
| ID | Term |
|---|---|
| D013812 | Therapeutics |
| D026421 | Sensory Art Therapies |
| D000529 | Complementary Therapies |
| D010812 | Physical Stimulation |
| D008919 | Investigative Techniques |
| D007093 | Imidazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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| Unknown or Not Reported |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| ASA 3 |
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| ASA 4 |
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| ASA 5 |
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Within-subject crossover cohort with intervention, acoustic stimulation delivered in phase with the anticipated trough of EEG slow wave oscillation
MRI: A non-contrast brain MRI will be acquired for localizing EEG slow waves
Quantitative Sensory Testing (QST): Quantitative sensory testing (QST) using increasing ramp thermal stimulation (32-52 ºC) will be delivered to compare arousal thresholds between conditions.
Home sleep study: Unattended home sleep studies will be conducted on the night preceding sedation and on the night following sedation to assess changes in slow wave homeostasis.
Acoustic stimulation (65db) down-slope of EEG with QST: 65 dB acoustic stimulation synchronized with the down-slope of the EEG slow waves (anti-phase)
Dexmedetomidine: All participants will receive dexmedetomidine with sedation titrated step-wise to 2, 3 or 4 ng/ml
Breathe-Squeeze Task: All participants will be asked to perform the breathe-squeeze task throughout the experiment. This will allow us to determine loss and return of responsiveness.
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|
Within-subject crossover cohort with intervention, acoustic stimulation anticipated in phase with the anticipated peak of EEG slow wave oscillation but no acoustic stimulation delivered.
MRI: A non-contrast brain MRI will be acquired for localizing EEG slow waves
Quantitative Sensory Testing (QST): Quantitative sensory testing (QST) using increasing ramp thermal stimulation (32-52 ºC) will be delivered to compare arousal thresholds between conditions.
Home sleep study: Unattended home sleep studies will be conducted on the night preceding sedation and on the night following sedation to assess changes in slow wave homeostasis.
0 db with QST: sham stimulation (0 dB volume)
Dexmedetomidine: All participants will receive dexmedetomidine with sedation titrated step-wise to 2, 3 or 4 ng/ml
Breathe-Squeeze Task: All participants will be asked to perform the breathe-squeeze task throughout the experiment. This will allow us to determine loss and return of responsiveness.
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