Researchers headed by a team at Cedars-Sinai have discovered two types of brain cells that play a key role in dividing continuous human experience into distinct segments that can be recalled later. Memory is foundational to us as human beings, noted Ueli Rutishauser, PhD, professor of neurosurgery, neurology, and biomedical sciences at Cedars-Sinai. “One of the reasons we can’t offer significant help for somebody who suffers from a memory disorder is that we don’t know enough about how the memory system works.” The newly reported discovery provides insights that could help direct the future development of treatments for memory disorders such as dementia and Alzheimer’s disease.

Rutishauser is senior author of the team’s published study in Nature Neuroscience, which is titled, “Neurons detect cognitive boundaries to structure episodic memories in humans.” The research team included postdoctoral fellow Jie Zheng, PhD, and neuroscientist Gabriel Kreiman, PhD, from Boston Children’s Hospital; neurosurgeon Taufik A. Valiante, MD, PhD, of the University of Toronto; and Adam Mamelak, MD, professor of neurosurgery and director of the Functional Neurosurgery Program at Cedars-Sinai.

Human experience is continuous, but psychologists believe—based on observations of people’s behavior—that memories are divided by the brain into distinct events, a concept known as event segmentation. “ … we remember discrete episodes (‘events’), which serve as anchors to bind together the myriad different aspects (where, when, and what) of a given autobiographical memory, much like objects do in perception,” the team noted. The transformation from ongoing experience to distinct events is thought to rely on the identification of boundaries that separate events. “A fundamental unresolved question in human memory is, therefore, what marks the beginning and the end of an episode?”

As part of ongoing research into how memory works, Rutishauser and co-investigators looked at how brain cells react as memories are formed. Working with 19 patients with drug-resistant epilepsy, the scientists were able to study how individual neurons in the medial temporal lobe (MTL) of the brain perform during this process, and their activity during the formation and retrieval of memories with complex narratives.

Patients participating in the study had electrodes surgically inserted into their brains to help locate the focus of their epileptic seizures, allowing investigators to record the activity of individual neurons while the patients viewed film clips that included cognitive boundaries. While these boundaries in daily life are nuanced, for research purposes, the investigators focused on “hard” boundaries (HBs) and “soft” boundaries (SBs). “SBs are episodic transitions between related events within the same movie, while HBs are episodic transitions between two unrelated movies,” the authors noted. “An example of a soft boundary would be a scene with two people walking down a hallway and talking, and in the next scene, a third person joins them, but it is still part of the same overall narrative,” said Rutishauser, interim director of the Center for Neural Science and Medicine and the Board of Governors chair in neurosciences at Cedars-Sinai.

In the case of a hard boundary, the second scene might involve a completely different set of people riding in a car. “The difference between hard and soft boundaries is in the size of the deviation from the ongoing narrative,” Rutishauser added. “Is it a totally different story, or like a new scene from the same story?”

When study participants watched film clips, investigators noted that certain neurons in the brain, which they labeled “boundary cells,” increased their activity after both hard and soft boundaries. Another group of neurons, designated “event cells,” increased their activity only in response to hard boundaries, but not to soft boundaries. “Boundary cells respond to both SBs and HBs, whereas event cells respond only to HB,” the team wrote.

Rutishauser and his co-investigators theorize that peaks in the activity of boundary and event cells—which are highest after hard boundaries, when both types of cells fire—send the brain into the proper state for initiating a new memory. “A boundary response is kind of like creating a new folder on your computer,” said Rutishauser. “You can then deposit files in there. And when another boundary comes around, you close the first folder and create another one.”

To retrieve memories, the brain uses boundary peaks as what Rutishauser calls “anchors for mental time travel.” He explained further, “When you try to remember something, it causes brain cells to fire. The memory system then compares this pattern of activity to all the previous firing peaks that happened shortly after boundaries. If it finds one that is similar, it opens that folder. You go back for a few seconds to that point in time, and things that happened then come into focus.”

To test their theory, investigators gave study participants two memory tests. They first showed participants a series of still images and asked them whether or not they had seen them in the film clips they had viewed. Study participants were more likely to remember images that closely followed a hard or soft boundary, when a new “memory folder” would have been created.

The investigators also showed participants pairs of images from film clips they had viewed and asked which of the images appeared first. Participants had difficulty remembering the correct order of images that appeared on opposite sides of a hard boundary, possibly because the brain had segmented those images into separate memory folders.

“When participants are reexposed to familiar target frames during the later recognition test, the neural state reinstates if the item is successfully recognized,” the authors noted. “Similar to place field reinstatement, the reinstated neural state is most similar to the one following boundaries even before when the tested frame is shown.”

Rutishauser said that therapies that improve event segmentation could help patients with memory disorders. Even something as simple as a change in atmosphere can amplify event boundaries, he explained. “The effect of context is actually quite strong. If you study in a new place, where you have never been before, instead of on your couch where everything is familiar, you will create a much stronger memory of the material.”

The team also noted during the newly reported study that when event cells fired in time with one of the brain’s internal rhythms, the theta rhythm—a repetitive pattern of activity linked to learning, memory and navigation—subjects were better able to remember the order of images they had seen. This is an important new insight because it shows that deep brain stimulation that adjusts theta rhythms could prove therapeutic for memory disorders.

“Theta rhythms are thought to be the ‘temporal glue’ for episodic memory,” said Zheng, first author of the study. “We think that firing of event cells in synchrony with the theta rhythm builds time-based links across different memory folders.”

Summarizing their research, the investigators stated, “These findings reveal a neuronal substrate for detecting cognitive boundaries that transform experience into mnemonic episodes and structure mental time travel during retrieval … Behaviorally, both SBs and HBs enhanced recognition of video clip content that followed a boundary, whereas HBs impaired memory of the temporal order of events.

We found neurons in the MTL that signaled the timing of both types of boundaries. The activity of these boundary-responsive neurons predicted memory strength as assessed by scene recognition and temporal order discrimination accuracy.”

In follow-up studies, the team plans to test the theory that boundary and event cells activate dopamine neurons when they fire, and that dopamine, a chemical that sends messages between cells, might be used as a therapy to strengthen memory formation.

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