Representation of Spatiotemporal Information in Human Episodic Memory and Navigation

Neural diseases such as stroke can have distinct effects on the ability to navigate and orient compared to remembering daily events like when one last took medicine. This proposal seeks test rival hypotheses regarding the neural mechanisms underlying commonalities and differences in navigation and event-related memory, particularly as they relate to pre-existing knowledge. Such mechanistic insight could help inspire therapies that could be used to bolster intact brain function in a compensatory manner following strokes or other neural insults.

Study Overview

• Status: Enrolling by invitation
• Conditions: Scopolamine or Placebo; Schema to Organize Memory or no Schema
• Intervention / Treatment: Drug: Scopolamine

Detailed Description

Contemporary models of spatial navigation and episodic memory (memory for events) postulate that their underlying computations emerge primarily from shared neural mechanisms within the medial temporal lobes. As part of the last two rounds of funding for this competitive renewal, the investigators began delineation of important cognitive and neural differences between navigation and episodic memory. The emerging new framework argues for navigation as a sensory-driven cognitive motor skill involving extracting spatial regularities and episodic memory as primarily internally driven and involving ordinal placeholders. The investigators hypothesize that navigation and episodic memory therefore involve partially distinct brain regions and macroscale networks, although where and how these differences emerge in the brain remains an area of active exploration. Here, the investigators test novel aspects of this theoretical framework: how pre-existing knowledge differentially affects the acquisition of new episodic memories compared to navigation-related representations over both longer (days and weeks; Aim 1) and shorter (hours; Aim 2) intervals. Throughout, the investigators propose meaningful alternative models, including the idea that connectivity to the hippocampus and neocortex, and cortical macroscale networks outside of the hippocampus, play critical and unique roles in episodic memory compared to navigation. In Aim 1, using high-resolution fMRI, the investigators propose to employ three different experiments to compare how schema (pre-existing spatial knowledge) and scripts (pre-existing temporal knowledge) differentially interact with new learning in the context of episodic memory and navigation. Together, the outcomes from these experiments will provide mechanistic insight into how humans organize episodic memories and navigation-relevant knowledge over longer intervals that could be meaningful for cognitive rehabilitation. In Aim 2, the investigators focus on how episodic memory interacts with navigation and pre-existing knowledge over shorter-term intervals (hours) by studying mental simulation before and after navigation. Mental simulation involves actively remembering or planning experiences and has direct links with cognitive processes central to episodic memory, particularly in our three different proposed experiments. Here, the PI's team will employ time-resolved intracranial EEG in conjunction with Dr. Brad Lega at University of Texas Southwestern to better identify the mnemonic content of both navigation and mental simulation, including a causal manipulation involving the muscarinic acetylcholine antagonist scopolamine and single cell recordings. Together, the experiments in Aim 2 will provide novel insight into the mechanistic basis of episodic memory and navigation-related representations. Such mechanistic could be helpful in developing neurostimulation or pharmacological protocols (e.g., involving acetylcholine) that could be used to bolster either impaired memory or navigation function following stroke, seizure damage, or other brain injuries affecting hippocampal function.

• Study Type: Interventional
• Enrollment (Estimated): 15
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85721
      • University of Arizona Psychology Department and Evelyn McKnight Brain Institute
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center / O'Donnell Brain Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Inclusion Criteria (for healthy young adults in fMRI studies)

  1. Able to provide verbal and written informed consent
  2. Fluent English speaker
  3. At least 8th grade education
  4. Age between 18-40 years.
  5. Normal or corrected-to-normal eyesight

Exclusion Criteria (for healthy young adults in fMRI studies)

1. Magnetic resonance imaging contraindications (e.g., metallic objects in body, claustrophobia)
2. Current use of anticonvulsant, neuroleptic, sedatives, or other medications known to affect cognition
3. Neurologic conditions affecting the brain (e.g., stroke, epilepsy, traumatic brain injury with loss of consciousness)
4. Psychiatric conditions (e.g., major depression, schizophrenia)

Patient inclusion criteria for iEEG:

Inclusion Criteria:

1. Adult patients with medically refractory epilepsy who are scheduled to undergo or have previously undergone placement of sub-dural electrodes or depth electrodes or stereo-electroencephalography to localize the site of seizure onset.

Exclusion Criteria:

1. Patients with gross structural abnormalities (hematoma, tumors, large vascular malformations, diffuse malformations of cortical development) that may impact critical perceptual or memory areas needed to perform tasks.
2. Patients who are unable to participate in memory testing due to impaired cognition or mental retardation. All patients routinely undergo a detailed neuropsychological evaluation, and the neuropsychological report will be used to make this assessment.
3. Patients/volunteers with cardiac pacemakers, intracranial aneurysm clips, or other potentially mobile implanted metallic devices cannot be included in this study, because of possible effects of high power magnetic fields on them.
4. Patients with claustrophobia who cannot undergo an MRI scan without sedation.
5. Pregnant women

Patient inclusion criteria for scopolamine:

1. In good general health, aside from a history of epilepsy, as ascertained by medical history, physical examination (PE), clinical laboratory evaluations, and ECG.
2. Body mass index between 18-35 kg/m2.

Patient exclusion criteria:

1. History of renal insufficiency.
2. Patients with liver failure.
3. Patients with autoimmune neuropathy.
4. Patients with uncontrolled hyperthyroidism.
5. Patients with a history of dementia.
6. Patient with a history of delirium after using transdermal scopolamine.
7. History of narrow-angle glaucoma (due to increased eye pressure).
8. History of pyloric obstruction or paralytic ileus.
9. History of myasthenia gravis, obstructive uropathy, porphyria, or myasthenia gravis.

Exclusion Criteria:

-

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Patients undergoing surgical monitoring to plan resections for epilepsy; Patients will have electrodes implanted in their hippocampus for surgical monitoring allowing for direct recordings. Patients will receive scopolamine on one day and placebo on another.	Drug: Scopolamine; effects of scopolamine on brain oscillations, navigation, and memory

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
behavioral: navigational accuracy	accuracy (path error) of routes taken in virtual environment	from enrollment to end of study (3 days)
intracranial EEG low-frequency oscillatory power	approximate amplitude of signal recorded from the hippocampus of patients undergoing seizure monitoring	from enrollment to the end of study (3 days)
memory accuracy (as part of memory training component involving healthy controls)	how many words remembered	from enrollment to the end of study (3 weeks)
Route replay time	time (in seconds) it takes to remember a route that will or has been taken	from enrollment to the end of study (3 days)

Collaborators and Investigators

• Sponsor: University of Arizona
• Collaborators: University of Texas
• Investigators: Principal Investigator: Arne Ekstrom, Ph.D., University of Arizona McKnight Brain Institute; Study Director: Brad Lega, M.D., University of Texas, Southwestern Medican Center

Publications and helpful links

General Publications

• Seger SE, Kriegel JLS, Lega BC, Ekstrom AD. Memory-related processing is the primary driver of human hippocampal theta oscillations. Neuron. 2023 Oct 4;111(19):3119-3130.e4. doi: 10.1016/j.neuron.2023.06.015. Epub 2023 Jul 18.
• Zheng L, Boogaart Z, McAvan A, Garren J, Doner SG, Wilkes BJ, Groves W, Yuksel E, Cherep L, Ekstrom A, Weisberg SM. Newly trained navigation and verbal memory skills in humans elicit changes in task-related networks but not brain structure. Elife. 2025 Oct 28;14:RP106873. doi: 10.7554/eLife.106873.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2025
• Primary Completion (Estimated): March 29, 2030
• Study Completion (Estimated): March 29, 2030

Study Registration Dates

• First Submitted: February 6, 2026
• First Submitted That Met QC Criteria: February 13, 2026
• First Posted (Actual): February 20, 2026

Study Record Updates

• Last Update Posted (Actual): April 30, 2026
• Last Update Submitted That Met QC Criteria: April 28, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: scopolamine, memory training, hippocampus, brain oscillation
• Additional Relevant MeSH Terms: Organic Chemicals; Heterocyclic Compounds; Alkaloids; Aza Compounds; Heterocyclic Compounds, Bridged-Ring; Tropanes; Azabicyclo Compounds; Belladonna Alkaloids; Solanaceous Alkaloids; Bridged Bicyclo Compounds, Heterocyclic; Scopolamine Derivatives; Scopolamine
• Other Study ID Numbers: 2R01NS076856-11 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: All data will be anonymized and shared publicly upon publication.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No