BRAIN IMAGING NEUROREPORT 0959-4965 & Lippincott Williams & Wilkins Vol 11 No 10 14 July 2000 2203 Object and spatial alternation tasks with minimal delays activate the right anterior hippocampus proper in humans Clayton E. Curtis, 1 David H. Zald, 2 Joel T. Lee and Jose  V. Pardo 2,CA Cognitive Neuroimaging Unit, Psychiatry Service, Veterans Affairs Medical Center, One Veterans Drive, Minneapolis, MN 55417; Departments of 1 Psychology and 2 Psychiatry, Division of Neuroscience Research, University of Minnesota, Minneapolis, MN 55455, USA CA Corresponding Author Received 15 March 2000; accepted 28 April 2000 Substantial evidence indicates that the hippocampus plays a critical role in long-term declarative memory. In contrast, the role of the human hippocampus in working memory, particu- larly when information needs to be maintained only for a few seconds, remains controversial. Using PET, we show robust activation of the right anterior hippocampus proper during the performance of both object and spatial alternation tasks. Hippocampal activation emerged even though subjects only had to remember a single, simple stimulus over a minimum delay of 1 s. No hippocampal activation occurred when the delay was increased to 5 s. This suggests that the role of the hippocampus in working memory is not to maintain information across a delay interval. Instead, its activity re¯ects a more transient function during encoding and/or retrieval. These data are among the ®rst observations to demonstrate human hippocam- pal involvement in working memory. NeuroReport 11:2203± 2207 & 2000 Lippincott Williams & Wilkins. Key words: Memory; Object alternation; PET; Positron emission tomography; Prefrontal cortex; Spatial alternation; Working memory INTRODUCTION Research into the cognitive neuroscience of memory has revealed that multiple memory systems exist that are subserved by separate neural substrates [1±3]. The division between long and short-term storage of information is thought to be one of the clearest. Lesions of the hippocam- pus produce de®cits in long-term memory with relative preservation of short-term memory. Studies of patients [4± 6] and monkeys [1,7] with medial temporal lobe lesions indicate that if information must be maintained for longer than several seconds, an intact hippocampus is necessary to perform normally on tests of declarative or episodic memory. In contrast, patients and animals with medial temporal lobe damage perform normally on most memory tasks in which information only needs to be maintained for a few seconds [4,5,7]. A recent neuroimaging study [8] suggests that the hippocampus is recruited only when material must be maintained for longer than several seconds. This has led to the belief that the hippocampus is a necessary neural substrate for long-term memory, while short-term and working memory can operate independent of a hippocampal contribution. However, animal data suggest that the hippocampus contributes to working memory even at short delay inter- vals. First, neuronal activity [9±11] and local cerebral glucose metabolism [12,13] in the monkey hippocampus increase during working memory tasks even at delays insuf®cient to cause impairment in hippocampal lesioned animals. Second, lesions to the rodent hippocampus se- verely disrupt performance of alternation tasks at relatively brief delays [14]. Alternation tasks require the continual updating of information from trial to trial based on previous responses, and thus make signi®cant demands on working memory [15]. Taken together, these animal studies suggest that the hippocampus plays an as yet unde®ned role in working memory processes. To date, however, no data have directly supported a role for the human hippo- campus in mnemonic processes at brief delays. Here, we used PET to study the mediating neuroanat- omy of alternation tasks. Correct performance on both object and spatial alternation tasks requires that subjects use a mnemonic representation of the stimulus (object or location) chosen on the just-preceding trial to determine the correct object or location on the current trial. Subjects simply alternate responses to either of two objects (OA) or of two spatial locations (SA) from trial to trial. A very brief delay (1 s) was used, substantially less than that required to produce memory impairments in hippocampal lesioned animals. Alternation tasks differ from most memory tasks in that they do not require the subject to encode or recognize new objects. Subjects must merely remember which one of two objects or locations was selected on the preceding trial. To examine regional cerebral blood ¯ow (rCBF) attributable to