Lesions Affecting the Right Hippocampal Formation Differentially Impair Short-Term Memory of Spatial and Nonspatial Associations Mischa Braun, 1 Christiane Weinrich, 1 Carsten Finke, 1 Florian Ostendorf, 1 Thomas-Nicolas Lehmann, 2 and Christoph J. Ploner 1 * ABSTRACT: Converging evidence from behavioral and imaging studies suggests that within the human medial temporal lobe (MTL) the hippocampal formation may be particularly involved in recognition memory of associative information. However, it is unclear whether the hippocampal formation processes all types of associations or whether there is a specialization for processing of associations involving spatial information. Here, we investigated this issue in six patients with postsur- gical lesions of the right MTL affecting the hippocampal formation and in ten healthy controls. Subjects performed a battery of delayed match- to-sample tasks with two delays (900/5,000 ms) and three set sizes. Subjects were requested to remember either single features (colors, locations, shapes, letters) or feature associations (color-location, color- shape, color-letter). In the single-feature conditions, performance of patients did not differ from controls. In the association conditions, a significant delay-dependent deficit in memory of color-location associa- tions was found. This deficit was largely independent of set size. By con- trast, performance in the color-shape and color-letter conditions was normal. These findings support the hypothesis that a region within the right MTL, presumably the hippocampal formation, does not equally support all kinds of visual memory but rather has a bias for processing of associations involving spatial information. Recruitment of this region during memory tasks appears to depend both on processing type (asso- ciative/nonassociative) and to-be-remembered material (spatial/nonspa- tial). V V C 2010 Wiley-Liss, Inc. KEY WORDS: associative memory; relational memory; short-term memory; medial temporal lobe; hippocampus INTRODUCTION It is well-established in neuroscience that the Medial Temporal Lobe (MTL) is an essential structure for conscious memory of facts and events. It consists of the hippocampal formation (i.e., hippocampus, dentate gyrus, subiculum, presubiculum, parasubiculum and the entorhi- nal cortex) and the perihinal and parahippocampal cortices (Insausti and Amaral, 2004; Amaral and Lavenex, 2007). Behavioral research in humans and animals has pointed to a divi- sion of labor between MTL subregions (Squire et al., 2004; Davachi, 2006; Eichenbaum et al., 2007; Morris, 2007; Murray et al., 2007). Although their re- spective contributions to perception and memory are still under debate, several theories of MTL function converge on the idea that the hippocampal formation is particularly involved in processing of associations between stimuli or stimulus features (Squire et al., 2004; Davachi, 2006; Eichenbaum et al., 2007; Mayes et al., 2007; Morris, 2007). For example, being one of the first accounts of hippocampal function, the cognitive map theory sug- gests that the hippocampus is particularly implicated in processing information on places and paths, i.e., spatial associative information (O’Keefe and Nadel, 1978; Burgess et al., 2002). While the observation of visuo- spatial associative memory deficits in humans with MTL damage is consistent with this theory (e.g., Smith and Milner, 1981, 1989; Owen et al., 1995, 1996; Crane and Milner, 2005; Olson et al., 2006; Hartley et al., 2007; Varga-Khadem et al., 2007; Braun et al., 2008; Finke et al., 2008), several studies on humans with MTL lesions involving the hippocampal forma- tion have revealed associative memory deficits which are clearly nonspatial, such as memory for word pairs, face pairs, face-word pairs, or pairs of visual objects (e.g., Kroll et al., 1996; Giovanello et al., 2003; Turri- ziani et al., 2004; Varga-Khadem et al., 2007). These results therefore support a broader role of the hippo- campal formation in mediating all manner of associa- tions, regardless of the stimulus material, as suggested by the relational theory (Cohen and Eichenbaum, 1993; Eichenbaum, 2004). This account of hippocam- pal function is further corroborated by hippocampal activation during memory of nonspatial associations in several functional imaging studies (e.g., Henke et al., 1997, 1999a; Miller et al., 2008; Staresina and Davachi, 2008; Troyer et al., 2008). Few imaging and patient studies, however, have directly compared contributions of the human hippo- campal formation to processing of spatial and nonspa- tial associative information. While some results from such studies are compatible with a relative specializa- tion of the hippocampal formation for perception and memory of spatial relations (Kumaran and Maguire, 1 Klinik fu ¨r Neurologie, Charite ´—Universita ¨tsmedizin Berlin, Charite ´- platz 1, D-10117 Berlin, Germany; 2 Klinik fu ¨r Neurochirurgie, Charite ´—Universita ¨tsmedizin Berlin, Charite ´platz 1, D-10117 Berlin, Germany Grant sponsor: Deutsche Forschungsgemeinschaft; Grant number: Pl 248/ 3-1; Grant sponsor: Bundesministerium fu ¨ r Bildung und Forschung; Grant number: 01GW0653; Grant sponsors: Sonnenfeld-Stiftung, Forschungsfo ¨r- derung of the Charite ´ Berlin. *Correspondence to: Prof. Dr. Christoph J. Ploner, Klinik fu ¨ r Neurologie, Charite ´—Universita ¨tsmedizin Berlin, Campus Virchow-Klinikum, Augus- tenburger Platz 1, D-13353 Berlin, Germany. E-mail: christoph.ploner@charite.de Accepted for publication 29 October 2009 DOI 10.1002/hipo.20752 Published online 15 January 2010 in Wiley Online Library (wileyonlinelibrary.com). HIPPOCAMPUS 21:309–318 (2011) V V C 2010 WILEY-LISS, INC.