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A Sense of Direction in Human Entorhinal Cortex

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A Sense of Direction in Human Entorhinal Cortex A sense of direction in human entorhinal cortex Joshua Jacobsa,1, Michael J. Kahanaa, Arne D. Ekstromb, Matthew V. Mollisona, and Itzhak Friedc,d aDepartment of Psychology, University of Pennsylvania, Philadelphia, PA 19104; bCenter for Neuroscience, University of California, Davis, CA 95616; cDepartment of Neurosurgery, David Geffen School of Medicine and Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095; and dFunctional Neurosurgery Unit, Tel-Aviv Sourasky Medical Center, and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel Edited* by Richard A. Andersen, California Institute of Technology, Pasadena, CA, and approved February 26, 2010 (received for review September 29, 2009). Finding our way in spatial environments is an essential part of daily locations (17, 18), EC “border cells” indicate the orientation and life. How do we come to possess this sense of direction? Extensive distance to the environment’s walls (19), and EC “path equivalent research points to the hippocampus and entorhinal cortex (EC) cells” indicate a location’s relative position along a common type as key neural structures underlying spatial navigation. To better of route (14). The different types of information that are encoded understand this system, we examined recordings of single-neuron by hippocampal and EC neurons play a critical role in computa- activity from neurosurgical patients playing a virtual-navigation tional models of human spatial navigation and memory (20, 21). video game. In addition to place cells, which encode the current However, this system is difficult to study in detail experimentally, virtual location, we describe a unique cell type, EC path cells, the because direct reports of EC neuronal activity are relatively rare, activity of which indicates whether the patient is taking a clockwise especially in humans. In particular, patterns of EC activity that or counterclockwise path around the virtual square road. We find could lead to direction-related place-cell remapping have not that many EC path cells exhibit this directional activity throughout been observed. the environment, in contrast to hippocampal neurons, which pri- Here we examined neuronal coding in the human medial tem- marily encode information about specific locations. More broadly, poral lobe—including EC and hippocampus—using recordings these findings support the hypothesis that EC encodes general of single-neuron activity from neurosurgical patients playing a properties of the current context (e.g., location or direction) that virtual-navigation game. Our primary goal was to compare the are used by hippocampus to build unique representations reflect- types of spatial information encoded by neuronal spiking in vari- ing combinations of these properties. ous brain regions. To do this, we designed a paradigm in which patients navigated a relatively simple virtual environment. In each NEUROSCIENCE electrophysiology | navigation | entorhinal cortex | direction | place cell trial of this game, patients drove along a narrow, square-shaped virtual road in either a clockwise or a counterclockwise direction to onvergent evidence from electrophysiological, lesion, and reach a destination landmark. In these recordings we observed Cimaging studies shows that the hippocampus plays an impor- place cells, which indicated the patient’s presence at certain virtual tant role in spatial navigation and episodic memory, both in locations, and we also observed a unique phenomenon, EC path humans and in animals (1–3). An important example of this comes cells, which varied their firing rate according to whether the patient from recordings of rodent hippocampal place cells during spatial was driving in a clockwise or counterclockwise direction, regard- COGNITIVE SCIENCES navigation (4). During navigation, the network of place cells enc- less of location. During navigation, path cells encoded directional PSYCHOLOGICAL AND odes the animal’s spatial location because each one activates when attributes of the current context and may be an important input to the animal is at a particular location in the environment, that cell’s unidirectional hippocampal place cells. “place field” (5). However, in addition to location, subsequent studies showed that hippocampal neurons also respond to other Results aspects of the current context, including the navigational goal We recorded 1,419 neurons from widespread brain regions of (6, 7), the phase of the behavioral task (8), and the direction of neurosurgical patients implanted with intracranial depth electro- movement (9). des. Electrodes were implanted to identify the seizure focus for In particular, the current direction of movement often has a potential surgical treatment for drug-resistant epilepsy. During dramatic effect on place-cell activity. In environments where ani- each recording session patients played Yellow Cab, a virtual-reality mals follow distinct routes, place cells often behave in a unidir- video game. In Yellow Cab, patients used a handheld joystick to ectional manner in which one cell’s place fields remap to different drive a taxicab through a virtual town to a randomly selected locations according to the direction of movement (10). In contrast, destination. The virtual town had six destination stores arranged when animals navigate unconstrained through open environ- along the outside of a narrow square road; the center of the ments, the location of each place field is typically fixed, regardless environment was obstructed to force patients to drive in a clock- of the animal’s direction. It is unknown whether direction-related wise or counterclockwise direction around the road to their des- place-cell remapping is caused by an afferent directional signal tination (Fig. 1). In each trial, the destination store was randomly outside the hippocampus or whether it originates from intra- selected, ensuring that patients repeatedly traversed every part of hippocampal computations (11–13). Examining this issue is the environment across multiple deliveries. important to better understand hippocampal processing. To characterize the patterns of neuronal activity during this A powerful way to probe hippocampal computation is to com- task, we examined the relation between each neuron’s firing rate pare the neuronal activity observed in the hippocampus with and the patient’s simultaneous behavior. We identified two func- activity recorded from its primary input, entorhinal cortex (EC). tional classes of neurons: path cells and place cells. Path cells Previous research in animals using this technique revealed a fun- damental dissociation between the types of information encoded by neurons in each of these regions (14–16). When a hippocampal Author contributions: J.J., M.J.K., and I.F. designed research; J.J., A.D.E., and M.V.M. neuron activates, it typically represents a specific behavioral con- performed research; J.J. analyzed data; and J.J., M.J.K., A.D.E., and I.F. wrote the paper. text, such as a place cell that activates when the animal is at a The authors declare no conflict of interest. particular location. In contrast, the spiking of EC neurons typically *This Direct Submission article had a prearranged editor. represents attributes of the current setting that are not exclusively 1To whom correspondence should be addressed. E-mail: [email protected]. “ ” linked to one location. For example, EC grid cells indicate This article contains supporting information online at www.pnas.org/cgi/content/full/ whether the animal is positioned at one of various equally spaced 0911213107/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.0911213107 PNAS | April 6, 2010 | vol. 107 | no. 14 | 6487–6492 Downloaded by guest on September 28, 2021 ≥ A B Dpref 0.95 (Fig. 3A). This indicates that they consistently had elevated firing during movement in the cell’s preferred direction throughout at least 95% of the environment—we refer to these as clockwise path cells or counterclockwise path cells. In one notable patient, in the right EC (Fig. S1) we observed a number of both clockwise path cells (Fig. 2 A and C) and counterclockwise path cells (Fig. 2B). Notably, across testing sessions conducted in this patient on different days, we sometimes repeatedly observed path cells at the same microelectrodes. In 10 of these 11 instances (binomial test, P < 0.001), we found that path cells observed in the second or third Fig. 1. The Yellow Cab virtual-navigation video game. (A) A patient’s on- testing session had the same preferred direction as the path cell screen view of the environment during the game. (B) Overhead map of the observed at that electrode in the first session (Fig. 2 A–C, Right, environment. Possible destination stores are brightly colored and outlined in Inset). Unfortunately, because of the limitations of the clinical red. Pale-colored buildings form the remainder of the outer and inner walls testing environment, we cannot determine whether the same neu- of the environment. rons were indeed recorded across multiple sessions. In addition to clockwise or counterclockwise path cells, our statistical framework also identified 49 complex path cells (62%), encode information about the patient’s clockwise or counter- which exhibited directional activity at widespread positions in the clockwise direction of movement, continuously representing virtual environment but had different preferred directions across directional information while the patient is at widespread loca- these locations. Thus,
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