Representation of Spatiotemporal Information in Human Episodic Memory and Navigation

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.

• Scopolamine (Drug): effects of scopolamine on brain oscillations, navigation, and memory

Primary outcomes

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

Sex: All, ages: 18 Years to 40 Years, accepts healthy volunteers

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:

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• 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. PMID 37467749
• 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. PMID 41150161

• Arne Ekstrom, Ph.D., Principal investigator, University of Arizona McKnight Brain Institute
• Brad Lega, M.D., Study director, University of Texas, Southwestern Medican Center

NIH grants: R01NS076856