SENS: Sevoflurane's Effect on Neurocognition Study

Sponsor

Keith M. Vogt, MD, PhD (Other)

Overall Status

Recruiting

CT.gov ID

NCT06044740

Collaborator

National Institute of General Medical Sciences (NIGMS) (NIH)

Enrollment

Location

Arm

Anticipated Duration (Months)

3.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the effects of acute pain on long-term memory and conditioned physiologic responses in the presence and absence of low dose sevoflurane. Functional magnetic resonance imaging will be used to identify the neural correlates of these phenomena. The study will occur over 2 visits and involves no long-term follow up.

Condition or Disease	Intervention/Treatment	Phase
Anesthesia Pain Amnesia	Drug: Sevoflurane Device: Peripheral Nerve Stimulation	Phase 1

Detailed Description

This is a non-randomized, clinical trial study of healthy volunteer subjects, which will employ neuroimaging and behavioral measures to characterize the effects of inhalational sevoflurane on pain processing and cognitive function. Sedative doses of sevoflurane will be targeted, and steady-state end-tidal (expired) concentrations achieved, while subjects perform a pain and memory cognitive task. At both no-drug baseline and the targeted doses, task and resting-state functional magnetic resonance imaging (MRI) scans will be acquired, and this data will be analyzed subsequently for task-related brain activity(from pain processing and memory formation) and functional connectivity. This work will use a systems neuroscience approach to fill an important knowledge gap about the central effects of inhalational sevoflurane in the context of painful stimulation.

The investigators propose to complete the following 3 Aims, at 2 targeted sedative doses of

Sevoflurane, compared to no-drug baseline, using functional MRI:

Aim 1: Determine how the brain response to acute pain stimulation is modulated by sevoflurane. It is anticipated that sevoflurane will correlate to decreased activation in both somatosensory (thalamus, insula, primary somatosensory/motor) and affective (anterior cingulate) components of the pain processing brain areas.

Aim 2: Determine how memory encoding is modulated by sevoflurane, in the context of periodic painful stimulation. It is anticipated that sevoflurane will correlate to decreased activation in both the explicit memory (hippocampus, parahippocampus) and associative learning (amygdala, anterior cingulate) brain systems.

Aim 3: Determine the neural effects of inhalational sevoflurane on brain connectivity both at rest and during the combined pain and memory task performance. It is anticipated that hypothesize that sevoflurane will cause widespread dose-dependent decreases in long-range functional connectivity between brain areas known to be involved in pain processing and to the default mode network, and that this connectivity will differ between the resting (task-free) and periodic pain states.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

60 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Basic Science

Official Title:

Sevoflurane's Effect on Neurocognition Study

Anticipated Study Start Date :

Dec 1, 2023

Anticipated Primary Completion Date :

Jul 1, 2025

Anticipated Study Completion Date :

Jul 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sevoflurane+Pain Single-arm study. All subjects receive sevoflurane and painful electric nerve stimulation, as described in the interventions.	Drug: Sevoflurane After a no-drug control period, subjects will inhale sevoflurane, administered via a breathing circuit and face mask, until a steady-state target end-tidal expired concentration is reached. During the two drug conditions, subjects will first receive low-dose sevoflurane (0.4% corresponding to 0.2 Minimum Alveolar Concentration) and then a higher dose sevoflurane condition (0.8% corresponding to 0.4 Minimum Alveolar Concentration). Other Names: Ultane Device: Peripheral Nerve Stimulation Experimental acute pain stimulus will be delivered using a nerve stimulator. These painful shocks will be paired with a fixed number of the experimental cues, in a pattern that appears random to participants. Other Names: Electric Nerve Stimulation

Arm

Intervention/Treatment

Experimental: Sevoflurane+Pain

Single-arm study. All subjects receive sevoflurane and painful electric nerve stimulation, as described in the interventions.

Drug: Sevoflurane

After a no-drug control period, subjects will inhale sevoflurane, administered via a breathing circuit and face mask, until a steady-state target end-tidal expired concentration is reached. During the two drug conditions, subjects will first receive low-dose sevoflurane (0.4% corresponding to 0.2 Minimum Alveolar Concentration) and then a higher dose sevoflurane condition (0.8% corresponding to 0.4 Minimum Alveolar Concentration).

Other Names:

Ultane

Device: Peripheral Nerve Stimulation

Experimental acute pain stimulus will be delivered using a nerve stimulator. These painful shocks will be paired with a fixed number of the experimental cues, in a pattern that appears random to participants.

Other Names:

Electric Nerve Stimulation

Outcome Measures

Primary Outcome Measures

functional magnetic resonance imaging activation in response to experimental tasks [Visit 1: Immediate; average activity, calculated from each task scan]
Event-related blood-oxygen level dependent (BOLD) Magnetic Resonance Imaging (MRI) responses will be determined for each experimental item presented, revealing localized changes in blood flow, which correlate to increased neuronal activity. These will be averaged across the multiple repetitions of each type of experimental item (memory only, pain only, and memory+pain), creating an anatomical map of Z-scores. Cross-condition comparisons will be the main effect of interest, comparing saline to low concentration sevoflurane AND comparing saline to high concentration sevoflurane.
Functional connectivity [Visit 1: Immediate; brain activity captured in data acquired across entire 6-8 minute scan.]
Whole-brain functional connectivity will be determined in each condition (no-sevoflurane, low-dose, and high-dose). This generates a matrix of cross-correlation values. Cross-condition comparisons will be the main effect of interest, comparing no sevoflurane to low concentration sevoflurane AND comparing no-sevoflurane to high concentration sevoflurane.

Secondary Outcome Measures

Explicit memory performance [Visit 2: 24-hrs post-learning experiment]
Recognition memory testing, using the Remember-Know procedure, in which subjects indicate whether they recognize previously experienced experimental items among novel items (not previously in the experiment). This allows calculation of interdependent measures of recollection & familiarity using the signal detection statistic, d'. d' is calculated as the cumulative Gaussian distribution of false positive responses subtracted from the cumulative Gaussian distribution of correctly identified previously-experienced items. d' is on a (theoretically infinite) scale of standard deviation units, with negative values representing performance worse than chance guessing and positive values representing stand deviations of performance above chance.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 59 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Adults, age 18-59, who are native English speakers with at least a high school education
have normal hearing and memory
be of normal body-weight
be generally healthy (free from significant chronic disease)
have none of the specific exclusion criteria
have a valid email address and valid phone number throughout the study
anticipate ability to participate in all visits required for the phase of the study in which they are enrolled

Exclusion Criteria:

being pregnant or attempting to conceive
having a body mass index (BMI) > 35
having significant memory impairment or hearing loss
having sleep apnea
having chronic pain or frequently taking pain medication (including tramadol)
having any severe or poorly-controlled medical problem (hypertension, diabetes)
having neurologic or psychiatric disease, including anxiety, and depression
having significant cardiac valvular disease or cardiomyopathy
having a history of abnormal heartbeats (cardiac conduction abnormality or arrhythmia)
having a history of seizures or convulsions
having a history of liver disease
having a history of asthma or other significant pulmonary disease
having a history of malignant hyperthermia, muscular dystrophy, central core disease, or hyperkalemia
being claustrophobic
have metal implants or non-removable metal piercings
having a history of adverse reaction to anesthetics
daily alcohol or heavy alcohol use; history of alcohol abuse
current daily smoker
regular or recent marijuana use (including prescribed/medical marijuana)
illicit drug use
regularly taking: antiepileptics, antidepressants, anti-psychotics, antihistamines, anti-anxiety medication, stimulants, or sleep-aids
current use of selective serotonin reuptake inhibitors (SSRIs), noradrenaline reuptake inhibitors (SNRIs), or monoamine oxidase inhibitors (MAOIs) and some other specific drugs phenytoin, carbamazepine, and rifampin
history of QT prolongation
hypersensitivity or allergic reaction to ondansetron (Zofran)