Cholinergic Enhancement of Theta

Overview

The goal of this study is to learn about the effects of Cobenfy KarXT (xanomeline and trospium chloride) on episodic memory processing, including specific effects on areas of the brain involved in memory and changes it may have on brain activity. The investigators will do this by testing epileptic patients who are already undergoing intracranial surgery for seizure monitoring, and measuring the activity from the brain areas being assessed. The main questions it aims to answer are 1) whether Cobenfy KarXT changes memory activity based on its agonist effect on muscarinic receptors and acetylcholine, and 2) what the nature of these brain activity changes are. This work builds on previous experiments evaluating cholinergic antagonists. Participants will complete two treatment arms. One of these will be with the drug, and the other will be with a placebo pill, so that the participants are unaware which session the actual drug has been received. Patients will complete a verbal serial recall and/or associative recognition task each of the two days. An anesthesiologist or patient nurse will administer either the drug or the placebo at a critical point which addresses both of the research questions. Researchers will compare the brain activity between the two treatment arms to determine what brain activity changes, and whether there is an additional behavioral effect on memory.

Patient Identification: The study team plans to recruit adult patients who are undergoing invasive electroencephalographic (EEG) monitoring as part of standard clinical procedure for the treatment of pharmacologically resistant epilepsy at UT Southwestern. Patients are identified from the pool of patients presented at the epilepsy management conference and approached when they present to the clinic for evaluation for seizure surgery. Patients are screened by a coordinator as well as anesthesiologist on the study team for contraindications which make them ineligible for receiving the drug. Study procedures: Participation takes place only during the time that the electrodes are surgically in place. Active participation will end when the electrodes are removed. Tasks described below will be administered by key personnel on the study. The data will be de-identified and converted to signal data for processing and analysis. Study personnel, excluding the PI (aka 'experimenters') will perform analysis. Once patients are in the epilepsy monitoring unit (EMU), subjects will be randomized to receive either a dose of 50 mg/20 mg orally BID of xanomeline and trospium chloride (COBENFY) or placebo pill. Approximately 2 hours after administration, the participant will complete an episodic memory task session. At least 24 hours following the first session (at least four half-lives after the first session), the participant will receive the alternative agent not given the first day. For example, if the patient received COBENFY the first day, they would receive the placebo the second day, and vice versa. They will then complete an additional episodic memory task session 2 hours after administration. Day 1: Randomized to receive either COBENFY or placebo (sham); Complete episodic memory task session Day 2: Receives alternate agent from day 1; Completes episodic memory task session Participant will not know whether Cobenfy KarXT is being administered, or if he/she receives the placebo. Researchers will be blind to this until after patient has completed both sessions. The randomization will be generated by the pharmacy using a psuedorandomizer. The participant's attending nurse will administer Cobenfy KarXT and/or placebo 2 hours prior to the test. Physiologic Monitoring: Patients in the epilepsy monitoring undergo EKG and pulse oxygen monitoring in addition to seizure monitoring electrodes at all times as part of routine care and this will not be interrupted during the study period. There is a certified epilepsy monitoring team available should the cholinergic effects enhance seizures. A board-certified anesthesiologist with specialist practice in neuroanesthesia will be immediately available within the hospital to respond with any other concerns. In our previous experiments using cholinergic modulation (antagonism), there have not been any adverse events. Specifically, there has not been an impact on seizure activity. While we do not anticipate an effect of Cobenfy KarXT on seizure activity, we note that all patients are located in the EMU environment with 2:1 nursing ratios and immediately available protocols for interventions if seizures occur. Overview of Memory Testing: Episodic memory tasks in our lab typically last 30-75 minutes provided patient does not request a break during the task. There is no physical risk to participants from cognitive tasks. Participants may stop and resume each task whenever they need a break. Participants for this protocol would need to wait at least 24 hours/six half-lives following completion of one of the testing sessions prior to completing the second, regardless of whether administration of either placebo or Cobenfy KarXT occurred. The cognitive tasks will cause patients to incur no additional medical or surgical risk; rather patients often report the game-like testing protocols provide relief from the boredom of awaiting seizures. Within each session, patients may request breaks to avoid fatigue. Testing may also be paused or interrupted for any health-care-related needs. The research team will attend to the comfort of all participants, who may discontinue the testing at any time, without repercussions. Episodic Memory Tasks: Patients will participate in verbal memory tasks, such as lists of specific words to be recalled freely or in a serial order. such lists are comprised of words or nameable pictures. A computer controls stimulus presentation and records participants' response of words or word order. Each list is followed by a brief distractor task consisting of a simple addition or subtraction problem prior to recall. This end-of-list distracter task serves to reduce the large advantage accorded to end-of-list items during recall, or recency effect. There are approximately 10-12 words or items in one list. Participants are then given the opportunity to place these words in the order they recall them. Their responses are digitally recorded by the computer and anonymously stored for later analysis. This paradigm cannot specifically address questions regarding differences on encoding versus retrieval, so patients may be also be given other types of verbal memory tasks, such as recognition paradigms of associative recognition, or other verbal tasks that will be able to parse out such aspects of episodic memory. Collection of iEEG data: Patients included in the study undergo the acquisition of EEG data for clinical purposes by clinicians, using a computerized EEG collection system. In this study, we will copy these data, strip them of any confidential information, and analyze the raw traces of EEG. Synchronization of the experimental computer with the iEEG signals is accomplished by sending an optically isolated pulse to an input on the EEG recording system. This train of pulses enables the iEEG record to synchronize itself with the testing computer, in standard fashion for this work.