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Sequences of associated concepts activate successively during the theta oscillation in the human brain

11 August 2021

Learning to encode a sequence of items in the right order (for example, a phone number) is an important cognitive ability. Until recently, the brain mechanisms underlying this process in the human brain were unclear. By recording from single neurons in the human hippocampus, researchers from the Netherlands Institute of Neuroscience (NIN), the Amsterdam University Medical Center (AUMC) and the Centre National de la Recherche Scientifique (CNRS) now show that neuronal firing activity in the hippocampus is tightly linked to specific phases of ongoing theta rhythms during sequence learning. These findings were published in Nature Communications on the 10th of August, 2021.

The ability to learn the order in which certain events occur is necessary for successfully interacting with our environment. The best-studied model to date for sequence learning has been the rodent hippocampus during spatial navigation. Spatial navigation can be thought of as the learning of a sequence of spatial positions. When a rat runs through its environment, position information is encoded by neurons in the hippocampus, which fire at specific phases of the underlying theta rhythm. This process is known as theta phase precession. The researchers now show that phase precession is also seen in the human brain during sequence learning of visual information.


The gold standard in Neuroscience is to record the activity of individual neurons in the brain. Most of the time, single neuron recording is performed in the brains of experimental animals, and cannot be performed in humans because it is an invasive procedure. However, the researchers in this study had the unique and valuable opportunity of also being able to record from single neurons in the human brain. This is possible in certain clinical populations, such as human patients with epilepsy, where doctors insert electrodes into the patient’s brain for a clinical diagnosis. While the patients were being monitored in the hospital, they volunteered to participate in this project.


The researchers asked the participants to learn the order of pictures that were presented to them in a repetitive sequence. “We chose visual sequence learning over spatial sequence learning because humans are more visual creatures than rodents, and we wanted to see whether phase precession would generalize to other experimental contexts”, explained Leila Reddy, the lead researcher of the study. While the participants learned the sequence order, the researchers observed that neurons in the hippocampus fired at particular phases (or moments) with respect to the underlying theta oscillation. Importantly, the order of phases at which the neurons fired reflected the picture order that was being learned, similar to the phenomenon of phase precession in the rodent hippocampus. “The time at which neurons fire appears to be an important part of the neural code for sequence order”, said Reddy.

This paper represents a major step forward in our understanding of how the human brain encodes sequences in memory, and helps bridge the gap between our knowledge of the rodent hippocampus model and the human hippocampus.

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