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Seeing epileptic seizures and learning the medical histories of those affected makes a strong impressionGerman version/Deutsche Version
A Patient Who Made Medical History
Changes in the hippocampus can occur in severe forms of epilepsy. That is why some epilepsy patients whose response to medication has so far been inadequate have electrodes implanted at specialized clinics, in order to identify a possible involvement of the hippocampus in the generation of their seizures. And it is also the reason for groundbreaking discoveries about the importance of the hippocampus for human memory. Those discoveries go back to the operation on H. M., a young man who in 1953, because of severe epilepsy, had parts of the medial temporal lobe on both sides removed, including large portions of the hippocampus. He went on to live another 55 years, but with a serious disability that no one had anticipated: although his intellect, his perception, and his short-term memory continued to work, after the operation he could barely form new long-term memories that he could consciously retrieve. He was still able to learn motor skills, but he could no longer remember the learning process itself. Facts he had learned long before the operation were still available to him, but autobiographical memories from the period shortly before the procedure were not. These observations suggested that our memory consists of different systems.
ow Perceptions Become Concepts
Facts belong to semantic memory. It tells you, for example, that Berlin is the capital of Germany. Autobiographical memories belong to episodic memory. It tells you, for example, when you last went to the theater in Berlin and with whom. “If you combine episodes, you can extract their shared components,” Lukas Kunz explains. The face and the name of a conversation partner, for instance, which you have to link in order to recognize the person again two months after the first encounter. “That is the semanticization of episodic memory.” Kunz’s main interest is episodic memory — and the egocentric cells involved in forming it. That interest is rooted in his fascination with epistemology, which gripped him in his philosophy classes at school with questions such as “What can we know?” and “What do we perceive?” That he now looks for the answers to such questions primarily in neuroscience is due not least to the accident of belonging to a generation that still had to complete military or alternative civilian service. As a fellow of the German Academic Scholarship Foundation (Studienstiftung), he nevertheless kept his interests broad and earned a bachelor’s degree in philosophy and German studies alongside his medical studies.
Civilian Service at a Research Institute
Lukas Kunz completed his alternative civilian service at the Institute of Cellular Neurosciences at the University of Bonn. There he also assisted with electroencephalogram (EEG) recordings in mice, which served as an animal model for identifying disease mechanisms in various forms of epilepsy. “During the nursing internship I did before starting medical school, I then got to know people who had epilepsy.” Kunz completed that internship in the Department of Epileptology at University Hospital Bonn, one of the leading specialist clinics of its kind in Germany, which has been headed by Rainer Surges since 2019. Patients there are treated for a broad spectrum of epileptic disorders, ranging from brief absence seizures to major seizures with loss of consciousness and convulsions. “Seeing epileptic seizures and learning the medical histories of those affected makes a strong impression,” he says. From the very beginning of his medical studies, epileptology and its opportunities for neuroscientific research captivated him. And so, for his medical dissertation at the Bonn Department of Epileptology, he came across a topic centered on the grid cells of the entorhinal cortex (EC) – an important gateway to the hippocampus – which had been discovered only a few years earlier.
On the Trail of the Grid Cells
The information provided by these grid cells embeds the information from the place cells of the hippocampus in a coordinate system with measurable distances. Many of our place cells become active preferentially at one particular location in an environment. Only when we are at exactly that spot do they fire bursts of action potentials. From the interplay of all place cells, our brain constructs a cognitive map whose shape goes beyond the input from our eyes and ears. These place cells were discovered as early as 1971. They answer the question “Where am I?” for the individual. What they do not convey is how far and in which direction one has to walk to get somewhere else. That task is handled by the grid cells, discovered in 2005. They can solve it because each individual grid cell fires not at just one location but at several locations distributed regularly across the environment. If you mentally connect these locations, a hexagonal grid pattern emerges, which the grid cells lay over the space we move through like a coordinate system. This pattern helps the brain estimate distances and directions and calculate vectors to future positions. Together with place cells, grid cells function like a navigation system. In 2014, the discoverers of place cells and grid cells were jointly awarded the Nobel Prize in Physiology or Medicine.
A major accolade for a doctoral dissertation
These insights had been obtained in experiments with rodents, because it is not permissible to implant electrodes in humans for the sole purpose of studying the behavior of their grid cells. In 2010, however, Christian Doeller had published a method that makes it possible to derive human grid-cell signals indirectly and noninvasively using functional magnetic resonance imaging (fMRI). Using this method, Lukas Kunz set out to answer the following question in his dissertation: are there measurable changes in brain activity in healthy people who are genetically predisposed to Alzheimer’s dementia? In searching for an answer, he focused on the grid cells in the EC — because the tau proteins characteristic of Alzheimer’s dementia are deposited in the EC at an early stage. And because grid cells are essential for navigation, their dysfunction could explain the spatial disorientation of Alzheimer’s patients. As an indicator of predisposition, Kunz chose a variant of the APOE gene whose carriers have an elevated risk of Alzheimer’s. “We developed a spatial navigation task that the participants performed in the fMRI scanner. With it we measured grid-cell signals in a control group of 37 people and in a group of 38 adults at increased risk of Alzheimer’s. We found that the grid-cell signals were reduced in the at-risk group — and this well before any possible onset of the disease.” The finding was so strikingly novel that it was published in the top journal Science.
Single-Neuron Recordings in Epilepsy Patients
The grid cells became Lukas Kunz’s springboard into his postdoctoral years, three of which he spent at the University of Freiburg with Andreas Schulze-Bonhage and three at Columbia University in New York with Joshua Jacobs. Together with two colleagues, the two of them had launched a project to investigate the role of grid cells in episodic memory. No one had done that before. In 2013, Jacobs had been the first to demonstrate grid cells in humans. Kunz contacted Schulze-Bonhage, the head of the Epilepsy Center at the university hospital in Freiburg, completed part of his final clinical year there, and was subsequently taken on as a postdoc in the project. “There I carried out single-neuron recordings in epilepsy patients in order to record the activity of grid cells.” He then moved to Jacobs’s lab to devote himself to analyzing the data collected in this way. “These were very large volumes of data, and the Jacobs Lab has particularly strong expertise in analyzing them.”
Egocentric Cells in Focus
His work in Freiburg and New York resulted in several publications on neuronal processes in the human temporal lobe, all based on the method Jacobs had already used successfully: epilepsy patients navigate through a virtual environment. In it they are shown, one after another, various hidden everyday objects — a car key or a pair of glasses, for example — whose positions they are supposed to learn over the course of the roughly hour-long experiment. How and when individual neurons in their hippocampus, EC, and other parts of their medial temporal lobe fire while they do so is measured via the electrodes the patients are carrying for medical reasons. In one of these publications , Kunz achieved the first single-cell demonstration of egocentric nerve cells in the human brain. In doing so, he closed a gap between animal and human research. “Egocentric cells encode space relative to the self — that is, whether something is in front of us, behind us, to our right, or to our left,” Kunz explains. “Grid cells and place cells, by contrast, are allocentric; they encode space relative to the external environment.” Every person, he says, first grasps a space through egocentric impressions, which with practice they partly convert into allocentric maps. That, he adds, is comparable to the transformation of episodic memories into semantically retrievable knowledge.
The Pacemaker of Memory
In another publication , Kunz provided the first direct electrophysiological evidence that in awake humans, brief high-frequency oscillations in the hippocampus may be the pacemaker of associative memory — the kind of memory without which we could not find our way in everyday life and would never recover a misplaced key. In Alzheimer’s patients, this form of memory is impaired early on. “We identified neurons that fire only at particular locations, and neurons that fire only in response to particular objects,” Kunz sums up. “We were able to show that both become active together during memory retrieval and during learning. This presumably strengthens their synaptic connections. This learning process is accompanied by the high-frequency oscillations in the hippocampus.” Whether this is a causal relationship, he says, is currently almost impossible to decide in the living human brain, “because you cannot simply switch off one component and observe what remains of the other.”
A Starting Grant for Spatial Perception
In 2023, the state of North Rhine-Westphalia used funding from its return program for top-class scientists to lure Lukas Kunz back to Bonn from New York. Since then, he has held a fixed-term professorship there and heads his own research group. “The ability to record the activity of individual nerve cells in the human brain with my research group rests decisively on the great expertise and tireless work of the people I collaborate with at the Bonn Departments of Epileptology and Neurosurgery,” Kunz emphasizes. “I would particularly like to mention Florian Mormann, who established single-cell recordings in humans here in Bonn.” Above all, Kunz’s research is made possible only by the voluntary and committed participation of patients who suffer from treatment-resistant epilepsy. They undergo comprehensive diagnostic workups at specialized epileptology clinics such as the one in Bonn. A small proportion of these patients carry electrodes in the brain for about two weeks for this purpose, which is the prerequisite for nerve-cell measurements. “We explain our research to them, and many find it exciting,” Kunz says. “Most are happy to take part in our experiments. They want to help future patients, and they also see it as a meaningful way to pass the time.” Equipped with a Starting Grant from the European Research Council, Kunz will increasingly study brain processes in real-world scenarios. “ Several cameras record the entire room, so that you can trace exactly where a participant is sitting and how they interact with which object in the environment.” In addition, he wants to investigate whether egocentric cells in humans can also be activated by language alone — when someone says, for example, “The bookshelf is behind me” because they are picturing it at that moment, even though they are actually somewhere else entirely. His vision, Lukas Kunz says, is one day to be able to trace, nerve cell by nerve cell, how we encode, store, and retrieve memories through the coordinated activity of neural circuits. That would also create new foundations for the diagnosis and treatment of memory disorders. With its Life Sciences Bridge Award, the Aventis Foundation aims to support him on this path.
Author: Joachim Pietzsch, wissenswort
Photos: © Uwe Dettmar
Kunz L, Schröder TN, Lee H, Montag C, Lachmann B, Sariyska R, Reuter M, Stirnberg R, Stöcker T, Messing-Floeter PC, Fell J, Doeller CF, Axmacher N (2015). Reduced grid-cell–like representations in adults at genetic risk for Alzheimer’s disease. Science; 350, 430–433. https://doi.org/10.1126/science.aac8128 Kunz L, Brandt A, Reinacher PC, Staresina BP, Reifenstein ET, Weidemann CT, Herweg NA, Patel A, Tsitsiklis M, Kempter R, Kahana MJ, Schulze-Bonhage A, Jacobs J (2021). A neural code for egocentric spatial maps in the human medial temporal lobe. Neuron; 109, 2781–2796.e10. https://doi.org/10.1016/j.neuron.2021.06.019 Kunz L, Staresina BP, Reinacher PC, Brandt A, Guth TA, Schulze-Bonhage A, Jacobs J (2024). Ripple-locked coactivity of stimulus-specific neurons and human associative memory. Nature Neuroscience; 27, 587–599. https://doi.org/10.1038/s41593-023-01550-x