The Parahippocampus Subserves Topographical Learning in Man

Transcription

1 The Parahippocampus Subserves Topographical Learning in Man Geoffrey K. Aguirre 1, John A. Detre 12, David C. Alsop 2 and Mark D'Esposito 1 Departments of 'Neurology and 2 Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA The hippocampus has been proposed as the site of neural representation of large-scale environmental space, based upon the identification of place cells (neurons with receptive fields for current position in the environment) within the rat hippocampus and the demonstration that hippocampal lesions impair place learning in therat. The inability to identify place cells within the monkey hippocampus and the observation that unilateral hippocampal lesions do not selectively impair topographic behavior in humans suggest that alternate regions may subserve this function in man. To examine the contribution of the hippocampus and adjacent medial-temporal lobe structures to topographic learning in the human, a 'virtual' maze was used as a task environment during functional magnetic resonance imaging studies. During the learning and recall of topographic information, medial-temporal activity was confined to the para- hippocampal gyri. This activity accords well with the lesion site known to produce topographical disorientation in humans. Activity was also observed in cortical areas known to project to the parahippocampus and previously proposed to contribute to a network subserving spatially guided behavior. The neural basis of allocentric (environment-centered) spatial learning and representation has been studied for several decades with lesion and single-unit recording studies in the rodent. These investigations have revealed that several different neuroanatomical areas are involved in the transformation of spatial information from its initial retinotopic form into a dynamic representation of place. Most significantly, in 1971 O'Keefe and Dostrovsky reported the presence of a population of 'place cells' within the rat hippocampus that fire preferentially when the animal is in a specific location within its environment. This finding led to the proposal that the hippocampus maintains a 'cognitive map' of learned environments, with the pattern of activity indicating the current position within that space (O'Keefe and Nadel, 1978). Additional evidence regarding the importance of the hippocampus in topographic learning was provided by the report of Morris and colleagues (1982) that rats with hippocampal lesions were impaired on a specific test of place learning, the water maze task. Attempts to demonstrate the importance of medial-temporal structures for topographical behavior in the primate have met with greater challenges, primarily because of the increased scale upon which these behaviors are conducted in the human and monkey. While numerous lesion (see e.g. George et al, 1989; Baylis and Moore, 1994) and neurophysiology (Cahusac et al, 1989; Miyashita et al, 1989) experiments have examined 'spatial' tasks in general, these studies have generally not captured the allocentric frame of reference crucial to topographic representation. However, recent studies by Rolls, O'Mara and their colleagues have examined hippocampal neuronal activity during whole body motion in the restrained (O'Mara et al, 1994; Rolls and O'Mara, 1995) and freely moving (Rolls et al., 1995) monkey. While these studies have identifed neurons with clearly spatial functions, including those responsive to the location of the monkey's gaze and whole body motion, 'place cells' per se have not been identified. Additionally, clinical case reports have shown that unilateral lesions of the hippocampus proper in human patients do not impair topographic memory (derenzi, 1982; Hublet and Demeurisse, 1992). These findings suggest that hippocampal function in spatial cognition may differ substantially between the rodent and primate. The anatomically closely linked cortical areas that surround the hippocampus, including the entorhinal, parahippocampal and perirhinal gyri, have also been examined with regard to their memory function. Lesions of the rat parahippocampal gyrus (which encompasses the entorhinal and perirhinal cortex in the rat) also cause deficits in place learning (Schenk and Morris, 1985; Wiig and Bilkey, 1994; Nagahara et al., 1995), and similar lesions in the pigeon disrupt local homing behavior (Bingman and Mench, 1990). These extra-hippocampal areas, in addition to the hippocampus proper, have been identified as important elements in human and non-human primates for declarative memory, the representation of information in a flexible form (Squire, 1992). In the monkey, parahippocampal and perirhinal lesions in conjunction with hippocampal lesions have been shown to produce a greater memory deficit on amnesia-sensitive tasks, such as delayed-match-to-sample and object retention, than hippocampal lesions alone (Zola-Morgan et al, 1993; Alvarez et al, 1995). Lesions of the perirhinal and parahippocampal areas also produce memory deficits equal to or greater than those produced by hippocampal lesions alone (Zola-Morgan et al, 1989; Suzuki et al, 1993). In an effort to address the conflicting evidence regarding the regional function of the medial temporal lobes in the rodent and primate we have used functional magnetic resonance imaging (fmri) to localize the neural substrates of human topographic spatial learning within the hippocampal system. A 'virtualreality' environment was used in order to allow subjects to engage in allocentric learning of a spatially extended place. Differences in activity observed while subjects explored a complex maze, as compared with a control environment with scant topographic detail, were hypothesized to reveal the neural basis of the acquisition of representations of extended environments. Because both conditions expose the subject to a virtual place, functional activity was expected to identify primarily those areas contributing to topographic learning, as opposed to those areas which activate only in response to motion within, or perception of, real-world environments. Materials and Methods We studied nine right-handed males, aged years. All subjects provided informed, written consent. Cerebral Cortex Nov/Dec 1996;6: ; /96/$4.00

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7 representation is not its sole function, this study provides evidence that the parahippocampus plays a crucial role in topographic learning in humans. The use of a virtual environment allowed the examination of topographical learning in intact human subjects confined to the magnet bore, a general approach with several potential applications within the cognitive neurosciences. Notes This research was supported in part by the Medical Scientist Training Program, the McDonnell-Pew Program in Cognitive Neuroscience, the Charles A. Dana Foundation, NS01668 (to J.A.D.) and NS01762 (to M.D.). Address correspondence to Mark D'Esposito, MD, Cognitive Neurology Section, Department of Neurology, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA , USA. References Alvarez P, Zola-Morgan S, Squire LR (1995) Damage limited to the hippocampal region produces long-lasting memory impairment in monkeys. 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