Human Cognition During Surgery: Stimulation-based and Cholinergic Modulation

NCT07721272 | Not Yet Recruiting Early Phase 1 FDA Drug

• 1 other identifier: STU20251732
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

This is a research study to determine how COBENFY KarXT (FDA approved), a drug which has been approved for treatment of certain disorders, affects brain activity and cognitive tasks which may be regulated by the cholinergic system. This study aims to answer: 1) how cholinergic circuitries act during task performance in humans, and 2) develop a better understanding of how cognitive control interacts with learning, memory and decision making in the setting of cholinergic manipulation. Participants will complete a single treatment arm, regardless of which surgical procedure they are to receive. An anesthesiologist or other clinical staff will administer either the drug or the saline at a critical point which addresses the research questions, prior to patient surgery. This will be either with the drug, or the placebo pill. Half of the participants will be randomized to receive the drug, and the other half of these the placebo. Participants will be unaware whether the actual drug has been received. Essential tremor patients who participate will complete a cognitive task during an awake surgery. Epilepsy patients who participate will have a resting state recording during the procedure from the deep cortical layers of the brain. A probe will be used during the surgery to measure the effects of this drug and other procedures of the study on the cholinergic system. This probe is the clinical probe known as the AlphaOmega, which is FDA approved for standard of care procedures. Researchers will compare the brain activity between treatment arms to determine what brain activity changes based on the cholinergic manipulation.

Conditions

Epilepsy; Essential Tremor; Seizures; Memory Consolidation; Motor Abilities; Cognitive Control; Memory Disorders; Memory Replay; Memory Encoding

Keywords

interoperative; oscillatory changes; neuronal spiking; time cell; place cell; cholinergic agonist; cholinergic modulation

Outcome Measures

Primary Outcomes (10)

• Cognitive control task-related changes in brain electrical activity in participants from baseline at cholinergic modulation post-intervention (approx. within 2-5 hrs)

  Cognitive control task-related changes in brain electrical activity in participants from baseline at cholinergic modulation post-intervention (approx. within 2-5 hrs) is measured by comparing the cognitive control task with the electrical readings collected across all bandwidths, but focusing on primarily slow theta and spike changes.

  Baseline, at cholinergic modulation post-intervention (approx. within 2-5 hrs)

• Cognitive control task-related changes in brain electrical activity in participants from baseline at placebo post-intervention (approx. within 2-5 hrs)

  Cognitive control task-related changes in brain electrical activity in participants from baseline at placebo post-intervention (approx. within 2-5 hrs) is measured by comparing the cognitive control task with the electrical readings collected across all bandwidths, but focusing on primarily slow theta and spike changes.

  Baseline, at placebo post-intervention (approx. within 2-5 hrs)

• Memory task-related changes in brain electrical activity in participants from baseline at cholinergic modulation post-intervention (approx. within 2-5 hrs)

  Memory task-related changes in brain electrical activity in participants from baseline at cholinergic modulation post-intervention (approx. within 2-5 hrs) is measured by comparing the associative memory or recognition task with the electrical readings collected across all bandwidths, but focusing on primarily slow theta and spike changes.

  Baseline, at cholinergic modulation post-intervention (approx. within 2-5 hrs)

• Memory task-related changes in brain electrical activity in participants from baseline at placebo post-intervention (approx. within 2-5 hrs)

  Memory task-related changes in brain electrical activity in participants from baseline at placebo post-intervention (approx. within 2-5 hrs) is measured by comparing the associative memory or recognition task with the electrical readings collected across all bandwidths, but focusing on primarily slow theta and spike changes.

  Baseline, at placebo post-intervention (approx. within 2-5 hrs)

• Working-memory task-related changes in brain electrical activity in participants from baseline at cholinergic modulation post-intervention (approx. within 2-5 hrs)

  Working-memory task-related changes in brain electrical activity in participants from baseline at cholinergic modulation post-intervention (approx. within 2-5 hrs) is measured by comparing the spatial or verbal working memory task with the electrical readings collected across all bandwidths, but focusing on primarily slow theta and spike changes.

  Baseline, at cholinergic modulation post-intervention (approx. within 2-5 hrs)

• Working-memory task-related changes in brain electrical activity in participants from baseline at placebo post-intervention (approx. within 2-5 hrs)

  Working-memory task-related changes in brain electrical activity in participants from baseline at placebo post-intervention (approx. within 2-5 hrs) is measured by comparing the spatial or verbal working memory task with the electrical readings collected across all bandwidths, but focusing on primarily slow theta and spike changes.

  Baseline, at placebo post-intervention (approx. within 2-5 hrs)

• Navigation and memory task-related changes in brain electrical activity in participants from baseline at cholinergic modulation post-intervention (approx. within 2-5 hrs)

  Navigation and memory task-related changes in brain electrical activity in participants from baseline at cholinergic modulation post-intervention (approx. within 2-5 hrs) is measured by comparing the spatial navigation and memory task with the electrical readings collected across all bandwidths, but focusing on primarily slow theta and spike changes.

  Baseline, at cholinergic modulation post-intervention (approx. within 2-5 hrs)

• Navigation and memory task-related changes in brain electrical activity in participants from baseline at placebo post-intervention (approx. within 2-5 hrs)

  Navigation and memory task-related changes in brain electrical activity in participants from baseline at placebo post-intervention (approx. within 2-5 hrs) is measured by comparing the spatial navigation and memory task with the electrical readings collected across all bandwidths, but focusing on primarily slow theta and spike changes.

  Baseline, at placebo post-intervention (approx. within 2-5 hrs)

• Changes in brain electrical activity in participants from baseline at cholinergic modulation post-intervention (approx. within 2-5 hrs)

  Changes in brain electrical activity in participants from baseline at cholinergic modulation post-intervention (approx. within 2-5 hrs) by comparing the passive recording of the patient under anesthesia during cholinergic manipulation with the baseline activity electrical readings collected across all bandwidths, focusing on primarily slow theta and spike changes.

  Baseline, at cholinergic modulation post-intervention (approx. within 2-5 hrs)

• Changes in brain electrical activity in participants from baseline at placebo post-intervention (approx. within 2-5 hrs)

  Changes in brain electrical activity in participants from baseline at placebo post-intervention (approx. within 2-5 hrs) by comparing the passive recording of the patient under anesthesia during placebo with the baseline activity electrical readings collected across all bandwidths, focusing on primarily slow theta and spike changes.

  Baseline, at placebo post-intervention (approx. within 2-5 hrs)

Study Arms (4)

Essential Tremor w/Placebo

PLACEBO COMPARATOR

Subjects will receive placebo pill (equivalent of 50/20mg) 2 hours prior to surgery. During awake surgery, the participant will complete either an episodic memory, a spatial memory, a working memory, or a cognitive control task session.

Drug: Placebo

Essential Tremor w/Cobenfy KarXT (xanomeline and trospium chloride)

EXPERIMENTAL

Subjects will receive Cobenfy KarXT pill (50/20 mg) 2 hours prior to surgery. During awake surgery, the participant will complete either an episodic memory, a spatial memory, a working memory, or a cognitive control task session.

Drug: Cobenfy KarXT pill (50/20 mg)

Epilepsy w/Placebo

PLACEBO COMPARATOR

Subjects will receive placebo pill (equivalent of 50/20mg) 2 hours prior to surgery. A passive recording with the patient under anesthesia during placebo state will be conducted in order to observe layer-specific baseline firing rate that can be linked with extraoperative ex vivo and in vivo recordings in other contexts.

Drug: Placebo

Epilepsy w/Cobenfy KarXT (xanomeline and trospium chloride)

EXPERIMENTAL

Subjects will receive Cobenfy KarXT pill (50/20 mg) 2 hours prior to surgery. A passive recording with the patient under anesthesia during cholinergic manipulation will be conducted in order to observe layer-specific changes in firing rate that can be linked with extraoperative ex vivo and in vivo recordings in other contexts.

Drug: Cobenfy KarXT pill (50/20 mg)

Interventions

Placebo DRUG

Subjects will receive placebo pill (equivalent of 50/20mg) 2 hours prior to surgery.

Epilepsy w/Placebo; Essential Tremor w/Placebo

Cobenfy KarXT pill (50/20 mg) DRUG

Subjects will receive Cobenfy KarXT pill (50/20 mg) 2 hours prior to surgery.

Epilepsy w/Cobenfy KarXT (xanomeline and trospium chloride); Essential Tremor w/Cobenfy KarXT (xanomeline and trospium chloride)

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of Essential Tremor
• Recommended to undergo deep brain stimulation implantation surgery for surgical management of medication-resistant tremor based on clinical indications

You may not qualify if:

• Patients with recent use (within one week) of anticoagulant or antiplatelet agent
• Contraindication to use of cholinergic modulation
• Diagnosis of intractable epilepsy
• Undergoing neuromodulation procedure that utilizes insertion of electrodes into subcortical structures, including the thalamus or hippocampus
• Undergoing neuromodulation procedure that utilizes frame-based insertion of electrodes into the thalamus (ANT or CM)
• Patients with recent use (within one week) of anticoagulant or antiplatelet agent
• Contraindication to use of cholinergic modulation
• Contraindication for cholinergic modulation in both patient sets will be assessed by members of the treatment team (e.g. epileptologist), as well as a neuroanesthesiologist. Multiple medications and conditions are singular disqualifiers; however some medications are eliminated only in combination following neuroanesthesiologist evaluation. Patients at risk of reaction to the treatment arm based on concurrent or recent medications or other health conditions will be excluded from participation.
• Is patient between 18-70?
• In general good health, aside from history of epilepsy or essential tremor, as ascertained by medical history, physical exam, clinical labs, and ECG?
• Candidate for surgery as determined independently by the patient's treating physician/clinical team as part of the patient's routine medical care?
• Able to read, understand, and provide written, dated informed consent, and participate in cognitive tasks?
• Female that is pregnant, breastfeeding, or has a positive pregnancy test?
• Under 18, over 70, or currently a prisoner on medical release?
• Hepatic impairment (moderate or severe)?

Sponsors & Collaborators

• University of Texas Southwestern Medical Center: lead
• Peter O'Donnell Jr. Brain Institute: collaborator

Study Sites (1)

University of Texas Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

MeSH Terms

Conditions

Epilepsy; Essential Tremor; Seizures; Memory Disorders

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Neurobehavioral Manifestations

Study Officials

• Bradley C Lega, MC

  University of Texas Southwestern Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Bradley C Lega, MD

CONTACT

214-648-7816; Bradley.Lega@UTSouthwestern.edu

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: BASIC SCIENCE
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: July 17, 2026
• First Posted: July 23, 2026
• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): September 1, 2030
• Study Completion (Estimated): September 1, 2030
• Last Updated: July 23, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)