What comes next? It can mean any number of things – what the next step in your life will be after a major triumph – or even a major setback and you’re wondering how you’ll land on your feet next time, if there will be a next time. Either way – all of our stories have beginnings and endings – and so do the tasks that we learn to do over time. The question is – how do our brains make sense of chronology – deciding what comes first and what comes later? The key to understanding it lies in the brain’s hemispheres – within a structure known as the hippocampi – which consists of actual time-sensitive neurons – a fairly recent discovery that could hold some vital clues to the formation of our episodic memories.
A team of researchers led by Leila Reddy, who is a neuroscience researcher at the French National Center for Scientific Research, looked to understand how human neurons within the hippocampus encode temporal information when learning new information. In their study, published over the summer by the Journal of Neuroscience, Reddy and her colleagues discovered that in order to shepherd specific moments of our own experience into the necessary context, human time cells release signals at climactic moments while carrying out every task.
The study provided further confirmation that time cells reside in the hippocampus, a key memory processing center. They switch on as events unfold, providing a record of the flow of time in an experience. “These neurons could play an important role in how memories are represented in the brain,” Reddy says. “Understanding the mechanisms for encoding time and memory will be an important area of research.”
Matthew Self, a co-author of the study and a senior researcher in the department of vision and cognition at the Netherlands Institute for Neuroscience, emphasizes the importance of these hippocampal time cells’ role in encoding experiences into memory. “When we recall a memory, we are able to remember not only what happened to us but also where we were and when it happened to us,” he says. “We think that time cells may be the underlying basis for encoding when something happened.”
Although researchers have been aware of the existence of so-called time cells in the brains of mice for decades, these same markers were unknown in humans until fairly late in 2020 – discovered by researchers at the University of Texas Southwestern Medical Center. To further understand these cells, Reddy and colleagues analyzed the hippocampal activity in epileptic patients using electrodes implanted in their brains. The patients agreed to participate in two separate experiments following a surgical treatment for their condition.
“During the surgery, the electrodes are inserted through small holes of around two millimeters in the skull. These holes are sealed until the patients recover from the surgery and are monitored for up to two weeks with the electrodes in place in an epilepsy monitoring unit, or EMU,” says Self. “We record the hippocampal neuronal activity while the patients are performing tasks in the EMU for a period of about one week after the surgery.”
For their first experiment, they had study participants pore over a sequence of between five and seven different pictures of either people or panoramic scenes in a predetermined order that was then repeated multiple times verbatim. A single given image, such as a flower, would be visible to the audience for 1.5 seconds, with a half-second pause before another image—such as a horse, would appear on the screen. In just a random 20% of intervals between showing the images, the pictures stopped showing, and the participants were then asked to select which of two images was the right one in the sequence before it continued playing. Over the span of 60 repetitions of the entire image sequence, all of the brain’s time-sensitive neurons were firing in gaps between quizzes, regardless of what image was being shown.
There was second experiment that used the same format. The only exception was that after the image sequence was replayed for a pre-set number of times, there was a black screen displayed for 10 seconds—a new gap interval meant to distract the study’s participants. For half of them, these 10-second intervals took place after every five reruns of the image sequence (therefore, there were a total of six gaps for the experiment). For the other half of the participants, the gaps happened after two repeats of the sequence (making for a total of 15 gaps).
The study participants for the second experiment were then given a quiz on the order in which they saw the images, all while electrical activity coming from individual cells in their brain was tracked and recorded. Sometimes, the neurons fired in response to a particular image, while others found the next image to be more provocative. For others still, the highest rates of activity happened during a 10-second gap in which no pictures were shown and the images were being switched. Typically, 27% of the time cells were active during these moments.
In order to answer the question of whether our hippocampal neurons make use of time information, the researchers decided to activate a small subset of the time cell neurons using a chosen image as stimuli. The firing activity of each neuron was then charted as a function of time, along with image identity, and whether or not the temporal period corresponded with an image or the 0.5-second gaps between when the test subjects were given alternate pictures to look at.
The researchers were able to create an internal timecode held together by singular episodes in time following the activation of the entire batch of neurons— tangible evidence that our brains use time-tracking neurons. “We think that the population of time cells in the hippocampus is representing several different and overlapping timescales,” Self says. “The activity of these cells is present throughout the trial, providing a time stamp for an event.” Because these particular cells are also representative of our memory’s content (the episodes themselves along with encoding “when” they took place) makes it all a bit more complicated. “We don’t fully understand how the memory is encoded,” Self says, “but the activity pattern across the hippocampus appears to simultaneously provide us with both the time stamp and the contents of the experience.”
Self adds that this information may be combined with signals that indicate the context of the experience, but further research is needed to understand this mechanism. “It’s no use encoding that you saw your friend at the beginning of an event without also encoding the context—that the event entailed ‘walking around the supermarket,’” he says. “Our future research aims to understand how time information is combined with contextual information to provide temporal structure to our memories.”
These results are revealing a pattern similar to what has been observed in previous studies using rats – where the so-called time cells are basically the same thing as “concept cells” which react to different manifestations of the same kind of stimulus— these are cells that encode both a particular concept along with a time. “Time cells in [the] rat hippocampus are also place cells that respond when the rat is in a particular location,” he says. “It appears that hippocampal cells are multidimensional and can encode different aspects of our experiences in their firing patterns.”
These findings could offer an answer for why some people who have suffered damage to the hippocampi—we have one in each hemisphere of the brain—are still able to recall life events but often have difficulty placing them chronologically — a common symptom of Alzheimer’s patients. “Hopefully a clear understanding of the cellular contributions to memory functions will bring us closer to understanding why memory functions are lost in some diseases and how these diseases can be treated,” says Jørgen Sugar, an associate professor of physiology at the University of Oslo, who did not partake in the study.
There are already researchers in the field who have their eyes on the future. “The next step is to develop noninvasive or invasive methods of modulating the activity of time cells and time cell circuits,” said Bradley Lega, who is an associate professor of neurological surgery at U.T. Southwestern, and the senior author of the first study to acknowledge the existence of time cells in the human brain back in 2020. “This may provide a neuromodulation strategy for memory restoration or enhancement. The activity of time cells can also be monitored to determine what is occurring as electrical impulses are applied during such a procedure.”
A growing number of scientists are optimistic that this research might one day build a bridge toward creating the field of “memory prosthetics”—a technique in which computers are able to either place pleasant memories or erase unpleasant ones with the use of electrodes inserted into the brain. There are, of course, ethical concerns whenever it comes to memory manipulation, but it seems only a matter of what time we’ll find ourselves facing these questions.
There is, of course, one major reason for people in the fields of medicine and mental health to be optimistic – that it could unlock new, less invasive ways to treat things like post-traumatic stress disorder and Alzheimer’s. “It could be tempting to develop such devices so that memories can be deleted or inserted, but I don’t see how these devices could be regulated to prevent misuse (insertion of false memories or deletion of important memories),” says Sugar. “I think a more reasonable strategy is to focus our efforts on preventive treatments of memory disorders.”
“I hope work in humans can reveal how time cells are actually contributing to encoding and recall of a unique one-shot memory,” he muses. “Then the human race would be optimistic of the time when this emerging research will be put into use in helping us understand how our brain knows the start and end of memories despite time gaps between events.”
