Varieties of human spatial memory: a meta-analysis on the effects of hippocampal lesions

Brain Research Reviews 35 (2001) 295–303 www.elsevier.com / locate / bres

Review

Varieties of human spatial memory: a meta-analysis on the effects of hippocampal lesions a, a b a Roy P.C. Kessels *, Edward H.F. de Haan , L. Jaap Kappelle , Albert Postma a

Helmholtz Instituut, Department of Psychonomics, Utrecht University, Heidelberglaan 2, 3584 CS Utrecht, The Netherlands b Department of Neurology, University Medical Center Utrecht, Utrecht, The Netherlands Accepted 1 May 2001

Abstract The current meta-analysis included 27 studies on spatial-memory dysfunction in patients with hippocampal damage. Each study was classified on the basis of the task that was used, i.e., maze learning, working memory, object-location memory, or positional memory. The overall results demonstrated impairments on all spatial-memory tasks. Clear differences in effect size were found between positional memory on the one hand and maze learning, object-location memory, and working memory on the other hand. Lateralization was found only on maze learning and object-location memory. These findings clearly indicate that specific aspects of spatial memory can be affected in various degrees in patients with hippocampal lesions. Moreover, these results strongly support the notion that the hippocampus is important in the processing of metric positional information, probably in the form of an allocentric cognitive map.  2001 Elsevier Science B.V. All rights reserved. Theme: Neural basis of behaviour Topic: Learning and memory: systems and functions Keywords: Hippocampus; Spatial memory; Cognitive mapping; Working memory; Binding; Meta-analysis

Contents 1. Introduction ............................................................................................................................................................................................ 2. Methods.................................................................................................................................................................................................. 2.1. Inclusion of studies ......................................................................................................................................................................... 2.2. Statistical analyses .......................................................................................................................................................................... 3. Results.................................................................................................................................................................................................... 4. Discussion .............................................................................................................................................................................................. Acknowledgements ...................................................................................................................................................................................... References...................................................................................................................................................................................................

1. Introduction Spatial memory involves the ability to encode, store and retrieve information about spatial locations, configurations or routes. This important cognitive function enables us to *Corresponding author. Tel.: 131-30-2533-651; fax: 131-30-2534511. E-mail address: [email protected] (R.P.C. Kessels).

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remember the locations of objects, or to find our way about in our environment [17,74]. In parallel to other memory constructs, spatial memory is of course not a unitary system, but consists of multiple cognitive mechanisms specialised in specific aspects of spatial mnemonic processing. There is, for example, converging evidence for a distinction between spatial memory for routes or paths on the one hand (requiring sequential processing of spatial information), and knowledge about spatial layouts, such as

0165-0173 / 01 / $ – see front matter  2001 Elsevier Science B.V. All rights reserved. PII: S0165-0173( 01 )00058-3

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involved in memory for object locations, on the other hand [84]. In turn, object-location memory can be divided further into exact, metric (or ‘coordinate’) processing, and memory for relative relations between objects and their features [44,45,75]. Moreover, active processing of information in spatial working memory can be distinguished from long-term spatial storage, sometimes referred to as ‘reference memory’ [64]. Further supporting the proposed fractionation, selective impairments for components of spatial memory have been reported after brain damage [8,40]. The current meta-analysis focuses on studies on spatial-memory dysfunction in patients with lesions in the hippocampal formation. Each study is classified on the basis of the spatial-memory task that was used, and the results are quantitatively analysed for each type of task separately. Concerning the neural basis of spatial cognition, a number of brain areas seem to be critically involved, such as the prefrontal cortex [42] and posterior parietal regions [37,38,76]. The hippocampal formation, however, is the brain region that has received the most attention from cognitive neuroscientists in relation to spatial memory [54,60,63]. The hippocampus is important for memory in general, and damage in this brain area can produce severe amnesia, as illustrated by the case of H.M. [53], but it may be critical especially for spatial memory. Spatial-memory deficits have been observed in hippocampally-lesioned rodents and primates [80], and have also been reported in humans with hippocampal damage [52,62,88]. In addition, it has been suggested that hippocampal function in humans is strongly lateralized, and that especially the right hippocampus is important in spatial memory in humans [89,90]. It should be noted, however, that that the results of animal studies are not always directly comparable to research in humans [81]. More specifically, spatial information might be processed in different ways in rodents and primates. In primates (and humans as well), there is clear evidence for a cortical dual-pathway model for the processing of visual information. That is, information about spatial aspects of a stimulus is processed via the so-called dorsal pathway in the posterior parietal cortex, whereas identification of the stimulus is subserved by the inferior temporal cortex [95]. However, it is unclear to what extent this dissociation also applies to spatial memory [39]. In rodents, a dissociation between localization and identification of stimuli also exists, but both cortical and sub-cortical brain areas seem involved. The retino-tectal pathway between the eye and the superior colliculus in the brainstem is used for spatial localization, whereas the cortical geniculostriate system processes identity information [85]. Although differences exist in the processing of spatial information between rodents and primates, there is ample evidence that the hippocampal formation receives input both from cortical and subcortical visual streams [9]. Most

theories on hippocampal involvement in spatial memory have originated from animal research (especially in rodents and monkeys), but predictions are made about spatialmemory function in humans as well. Generally, the hippocampus is thought to be involved in the formation of a mental representation of spatial information [9]. Three influential theories on hippocampal functioning have been proposed, in agreement with the aforementioned multicomponential idea of spatial memory: the cognitive map theory by O’Keefe and Nadel [63], the working-memory hypothesis by Olton et al. [65], and more recent ideas on the hippocampus as a binding device [11,18]. O’Keefe and Nadel’s theory [63] argues that the hippocampus stores spatial information in the form of an allocentric (or exocentric) cognitive map. That is, a representation is formed of information on absolute locations in our environment (both distances and directions), which is independent of the observer. This hippocampal ‘locale’ system is important for the identification of places in the environment, and is opposed to the so-called ‘taxon’ system. The latter is involved in route learning and forms of egocentric spatial behaviour, and may be dependent of other brain structures. The cognitive map theory is supported by behavioural studies in animals [69], and by the existence of place cells in the rat hippocampus that are sensitive to specific locations [7,19,79]. Additional evidence comes from studies reporting deficits in humans with hippocampal damage on allocentric, but not egocentric, spatial-memory tasks [29,30]. Moreover, O’Keefe and Nadel suggest that the left and right hippocampus in humans are differently important, the right hippocampus being involved in the mapping of allocentric spatial information, and the left hippocampus being important in linguistic mapping [63]. The presumed mapping function of the hippocampus might critically depend on the multiple reciprocal connections with other cortical areas that are important in spatial processing, such as the parietal cortex [6,37,83,92]. In contrast with the cognitive map hypothesis, the theory of Olton and co-workers [64,65] holds that the hippocampus is not specialised in spatial memory, but is crucial for short-term working memory in general, as opposed to a long-term reference memory system subserved by cortical areas. Several studies have found evidence for this theory, mostly based on research in rodents. For example, it has been demonstrated that rats with lesions in the hippocampal formation were able to relearn location discrimination, although they were impaired compared to control animals [4]. In addition, other studies claim that the hippocampus is involved in general memory processes rather than having a domain-specific function [5]. More recently, impairments have been demonstrated in rats with hippocampal lesions on a spatial working memory task, but not in long-term spatial memory [33]. Although there is support for this notion based on studies in humans with damage of the hippocampal formation [58], Olton’s view

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on working memory is clearly different from the concept as defined by Baddeley and Hitch [3]. This latter concept focuses on the active, online manipulation of information and is mainly subserved by the prefrontal cortex [2]. Thus, a discrepancy might exist between these two types of working memory with respect to spatial processing. Finally, it has been argued that the hippocampus – rather than being a cognitive map or general workingmemory structure – might act as a binding device, integrating different contextual features of information in our environments [11,12,18,21]. That is, separate features of an object or scene (such as the location or form) can be processed via separate pathways in the brain, but have to be bound together eventually [34,96]. This binding process especially takes place if information about identities has to be integrated with the spatial location (as involved in memory for the location of objects [27,55]). Although the role of the hippocampus in this view is not per se limited to spatial aspects of memory and might also be important in binding non-spatial aspects in memory [20], it should not be crucial for forms of spatial memory that do not require binding. For example, if only the information about the positions has to be remembered (i.e., without any object-identity information), this binding process is not involved. The notion that the hippocampus acts as a binding device or associator is in line with neuroanatomical evidence. That is, the hippocampus integrates multiple cortical areas that are important for perception and memory [98]. Further support comes from neurophysiological studies showing that the hippocampus is critically involved in the encoding of associations between features, such as the spatial or temporal position of items in our environment [97]. Clearly, different views exist on the precise role of the hippocampus in spatial memory. Also, contrastive results are sometimes reported. Therefore, the current paper examines in detail the pattern and magnitude of spatialmemory deficits in humans with hippocampal lesions. Four distinctive spatial-memory paradigms sampling a broad range of different cognitive mechanisms and representations will be compared, that is, maze learning, spatial working memory, positional memory, and object-location memory. Maze learning tasks, for example, employ spatiotemporal or sequence learning. In working-memory tasks, information about spatial layouts must be held active during a brief period of time. Positional memory relies on the mapping of metric, Euclidean spatial information. Finally, object-location memory involves the binding or integration of item information and location. If the hippocampus is specialized in specific aspects of spatial memory, lesions in this brain structure may give rise to selective spatial-memory deficits. Also, lateralization of function can be expected, as predicted especially by the cognitive map theory. By summarising the findings of studies on patients with hippocampal lesions, and by contrasting the various spatial-memory paradigms and their

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underlying cognitive mechanisms, this quantitative review may further clarify the role of the hippocampus in human spatial-memory processes.

2. Methods

2.1. Inclusion of studies Studies were selected by means of a literature search in PsycLit (1887–2000) and MedLine (1966–2000) using the keywords hippocampus, spatial, memory and human. Additional studies were identified by examining the lists of references of these studies. The following inclusion criteria were applied in order to perform the quantitative analyses. First, the paper reported original data. Second, spatial memory was studied in patients with focal lesions of the hippocampus (although other medial temporal lobe areas might be affected as well). Third, test scores were presented for both the patient and the control group (mean and standard deviation), or the exact P values, t values or F values were given. It should be noted that in most cases the selected studies focused on various aspects of spatial memory functioning (e.g., intentional versus incidental spatial memory), and did not necessarily address the theories described previously. Therefore, each study was classified on the basis of the task that was used rather than on the basis of its theoretical background.

2.2. Statistical analyses For each study, effect sizes (d) were calculated for patient vs. control group and for left- vs. right-hemisphere patients. If exact values were not reported for non-significant results, the effect size was included as d50.00 in the meta-analysis, adopting a conservative approach [82]. The direction of the effect size was negative if the patient group performed worse than the control group, or if the right-hemisphere patients performed worse than the lefthemisphere patients. In the meta-analysis, a combined d value was calculated, expressing the magnitude of associations across studies. This d value was weighted for sample size, in order to correct for upwardly biased estimation of the effect in small sample sizes [26]. Additionally, Stouffer’s Z weighted for sample size provided an indication of the significance of the difference in task performance between the compared groups. The homogeneity (Q) of the studies was determined, as well as a 95% confidence interval on the basis of the standard error. Spatial-memory tasks measuring the same function were clustered in four cognitive constructs: maze learning, spatial working memory, positional memory, and object-location memory (see the Results section for further details). An overall d value, in which all spatial-memory tasks were pooled, was computed first as a general index of spatial-memory impair-

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ment. Subsequently, meta-analyses were performed separately for the difference between patients and controls, and between patients with left and right hippocampal damage. All analyses were performed using the statistical package META [86].

3. Results The literature search identified 32 studies on hippocampal involvement in human spatial memory. Of these, five single-case reports were excluded [29,30,46,49,94]. Additional studies that were excluded used mixed-aetiology patients with only presumed hippocampal damage [11,87]. Twenty-seven studies fulfilled the aforementioned inclusion criteria (listed in Table 1). Hippocampal lesions were in most studies (k520) the result of medial temporal lobe excisions. In other studies, lesions were the consequence of medial temporal lobe sclerosis (k51), hypoxia (k52), amygdalo-hippocampectomy (k51), hippocampectomy (k51), or mixed aetiology (k52). Thus, only in two studies were the lesions limited to the hippocampal formation, and did not extend to the parahippocampal gyrus or the medial temporal lobe. In addition, 24 of these

studies reported the results for patients with unilateral lesions (i.e., in the left or right hippocampus) separately (shown in Table 2). The cognitive tasks that were used to assess spatial memory in these studies were divided into a number of subgroups measuring approximately the same underlying cognitive construct. The construct maze learning was assessed with the Nine-Box Maze [1,2], a radial maze [8], a T-maze [16], or a push-button maze [14,52]. The construct working memory was measured using tasks relying on the active maintenance of spatial information during a short time period, such as spatial supraspan learning [78], the Executive Golf Task [24,59], or the ‘Blue Token’ test [67,68]. The tasks included in the construct object-location memory measured memory for the location of toys on a table [61,89,90], pictures or line drawings of objects [43,71,91], or abstract patterns [62]. Finally, the construct positional memory included tasks using memory for locations sec. That is, only the precise, metric coordinates have to be remembered without any item information, for example the location of Xs [31,32], or by using pins in the tactile domain [77]. Table 1 also shows the effect sizes (Cohen’s d) for each study, i.e., the standardized difference between the patient

Table 1 Characteristics of the studies on hippocampal involvement in human spatial memory Study

Patient group

Control group

NE

NC

Spatial-memory task(s)

d

Abrahams et al. [1] Abrahams et al. [2] Bohbot et al. [8] Corkin [14] Daum et al. [16] Feigenbaum et al. [24] Milner [52] Owen et al. [67] Feigenbaum et al. [24] Morris et al. [59] Owen et al. [68] Rausch & Ary [78] Bohbot et al. [8] Cave & Squire [10] Grabowska et al. [25] Kopelman et al. [43] Nunn et al. [61] Nunn et al. [62] Owen et al. [68] Piggot & Milner [71] Pillon et al. [72] Smith & Milner [89] Smith & Milner [90] Smith et al. [91] Hopkins & Kesner [31] Hopkins et al. [32] Rains & Milner [77] Maguire et al. [47] Petrides [70] Ploner et al. [73]

MTL sclerosis MTL excisions Hippocampectomy MTL excisions MTL excisions MTL excisions MTL excisions MTL excisions MTL excisions MTL excisions MTL excisions MTL excisions Hippocampectomy Mixed aetiology Amygdalo-hippocampectomy Mixed aetiology MTL excisions MTL excisions MTL excisions MTL excisions MTL excisions MTL excisions MTL excisions MTL excisions Hypoxia Hypoxia MTL excisions MTL excisions MTL excisions MTL excisions

Healthy Healthy Epilepsy Healthy Healthy Healthy Healthy Healthy Healthy Healthy Healthy Healthy Epilepsy Healthy Healthy Healthy Healthy Healthy Healthy Healthy N.A. Healthy Healthy Healthy Healthy Healthy Healthy Healthy Healthy Healthy

47 47 14 29 22 40 41 60 40 40 31 36 14 7 7 13 38 38 31 27 24 34 18 41 11 11 53 20 20 8

20 20 10 11 21 20 11 60 20 20 40 43 10 28 11 20 16 19 40 15 N.A. 17 6 30 11 10 23 10 20 10

Maze learning Maze learning Maze learning Maze learning Maze learning Maze learning Maze learning Working memory Working memory Working memory Working memory Working memory Object-location memory Object-location memory Object-location memory Object-location memory Object-location memory Object-location memory Object-location memory Object-location memory Object-location memory Object-location memory Object-location memory Object-location memory Positional memory Positional memory Positional memory Topographical memory Association learning Memory-guided saccades

20.50 20.46 0.00 20.89 20.25 0.00 20.38 20.40 20.37 0.00 20.50 0.00 20.70 20.79 20.77 20.96 20.46 20.34 20.44 20.39 N.A. 20.49 20.40 0.00 21.86 21.57 20.46 22.60 20.47 21.22

MTL5Medial temporal lobe; N.A.5not available; NE 5number of patients in experimental group; NC 5number of participants in control group; d5effect size reflecting the standardised difference between the patient and control group (a negative d value indicates a worse performance of the patient group).

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Table 2 Studies reporting differences between patients with damage of the left and damage of the right hippocampus Study

NL

NR

Spatial-memory task(s)

d

Abrahams et al. [1] Abrahams et al. [2] Bohbot et al. [8] Corkin [14] Daum et al. [16] Feigenbaum et al. [24] Milner [52] Morris et al. [59] Owen et al. [67] Owen et al. [68] Rausch & Ary [78] Feigenbaum et al. [24] Bohbot et al. [8] Grabowska et al. [25] Kopelman et al. [43] Nunn et al. [61] Nunn et al. [62] Owen et al. [68] Piggot & Milner [71] Pillon et al. [72] Smith & Milner [89] Smith & Milner [90] Smith et al. [91] Maguire et al. [47] Rains & Milner [77] Petrides [70]

22 24 5 18 12 20 26 20 31 18 27 20 5 3 5 19 19 18 14 13 17 11 24 11 23 10

25 23 9 11 10 20 15 20 29 13 36 20 9 4 3 19 19 13 13 11 17 7 17 9 30 10

Maze learning Maze learning Maze learning Maze learning Maze learning Maze learning Maze learning Working memory Working memory Working memory Working memory Working memory Object-location memory Object-location memory Object-location memory Object-location memory Object-location memory Object-location memory Object-location memory Object-location memory Object-location memory Object-location memory Object-location memory Topographical memory Positional memory Association learning

20.63 20.56 N.A. 20.75 20.45 0.00 20.83 0.00 20.20 0.00 0.00 0.00 N.A. 0.00 22.03 20.94 20.67 0.00 0.00 20.86 21.04 20.55 0.00 20.43 20.53 N.A.

NL 5Number of left-hemisphere patients; NR 5number of right-hemisphere patients; d5effect size reflecting the standardised difference between the left and right hippocampal group (a negative d value indicates a worse performance of the right hippocampal group); N.A.5not available.

group and the healthy controls. In Table 2, the effect sizes of each study are presented for the differences between patients with left-hippocampal lesions compared to patients with right-hippocampal lesions. Three of the studies listed in Table 1, focusing on spatial-association learning [70], memory-guided saccades [73] and topographical memory [47] were not included in the meta-analysis due to the lack of other studies using similar research paradigms. Furthermore, only the studies with a control group of healthy participants (highly comparable in age and education) were

included in the meta-analysis comparing patients and controls. This was not the case in one study using epileptics as controls [8] and one without a control group at all [72]. Table 3 shows the results of the meta-analysis on spatial-memory function in hippocampally damaged patients. Compared to the control group of healthy participants, the patients demonstrated an overall lowered performance, as well as impairments on all four cognitive constructs. The effect sizes for maze learning and object-

Table 3 Results of the meta-analysis on spatial-memory impairments in patients with lesions of the hippocampus Spatial-memory task

k

N

d

Z

Q

95% CI

Patients vs. controls Overall Maze learning Working memory Object-location memory Positional memory

24 6 5 10 3

1233 329 390 456 119

20.51 20.37 20.27 20.41 21.12

24.51**** 23.07*** 22.58** 24.10**** 22.82**

41.66* 4.15 3.85 6.12 7.23

20.76–20.30 20.61–20.14 20.47–20.70 20.61–20.21 21.90–20.34

Left vs. right hemisphere Overall Maze learning Working memory Object-location memory Positional memory

21 6 5 10 1

728 226 234 266 53

20.40 20.51 20.05 20.49 20.53

24.88**** 23.73**** 20.39 23.12*** N.A.

22.18 3.85 0.43 12.33 N.A.

20.57–20.24 20.78–20.24 20.31–0.35 20.80–20.18 N.A.

k5Number of studies; N5total number of participants; d5mean weighted effect size; Stouffer’s Z5index of the level of statistical significance of d; Q5homogeneity; 95% CI595% confidence interval; N.A.5not available. *P,0.05; **P,0.01; ***P,0.001; ****P,0.0001.

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location memory are in the ‘small’ to ‘medium’ range (0.20,d,0.50), whereas the effect size for positional memory is in the ‘large’ range (d50.80). The effect size for working memory approaches a ‘small’ difference (d5 0.20) [13]. Overall analysis showed that these four effect sizes differed statistically ( x 2 [3]514.21, P,0.003). Posthoc analyses (with a Bonferroni-corrected a of 0.0085) revealed that the effect size for positional memory was statistically larger than maze learning ( x 2 [1]510.93, P,0.0009), object-location memory ( x 2 [1]59.31, P, 0.002), and working memory ( x 2 [1]513.70, P,0.002). All other comparisons were not statistically significant (all x 2 -statistics,1.34). Also listed are the results of the meta-analysis comparing left vs. right hippocampal lesions. Comparing left to right hippocampal patients resulted in an overall worse performance in the right hippocampal group. Further analyses demonstrated a worse performance in the right hippocampal patients on maze learning, object-location memory and positional memory (all effect sizes in the ‘medium’ range). No lateralization effect was found on the construct working memory.

4. Discussion The goal of this paper was to meta-analytically study the effects of hippocampal lesions on distinctive tasks measuring human spatial memory: maze learning, spatial working memory, positional memory, and object-location memory. The results show that patients with lesions in the hippocampal formation are impaired on all four types of spatial-memory tasks. Additionally, lateralization of function has been found on maze learning, positional memory and object-location memory (with a worse performance in patients with lesions of the right hippocampus), but not on working memory. With respect to the effects sizes of the different aspects of spatial memory, a very large impairment was found on the construct positional memory. This was measured by a task in which only precise metric information had to be remembered (such as the location of Xs or pins) regardless of the objects itself. This memory type relies on precise, metric (perhaps Euclidean) processing of spatial layouts in the environment [50]. Also, since environmental cues are always present in tasks like this, it is likely that positional memory uses allocentric frames of reference, and that information is stored independently of the observer [93]. This finding therefore strongly supports O’Keefe and Nadel’s [63] cognitive map theory. Moreover, although only one study reported data on lateralization on this task [77], patients with damage to the right hippocampal damage performed worse on positional memory than patients with lesions in the left hippocampus, as predicted by the cognitive map theory. It should be noted, however,

that at present only three studies have been performed that studied memory for positional information sec, but the total sample size for this task (N5119) was large enough to perform a separate analysis, which yielded a statistically significant result (weighted for sample size). In turn, these results seem to counter the binding theory, which claims that the hippocampus is specifically involved in the binding of object information and positions, as required in object-location memory [11,41]. The moderate impairment in object-location memory alone could have supported this binding function, but the impairment in positional memory clearly does not. As stated previously, binding involves the integration of multiple features, i.e., object identities and locations [55]. In positional memory for metric information, only one individual feature (the position in space) is relevant and, consequently, there is no binding process involved [56]. Rather than a deficit in binding, impairments in object-location memory could be the result of the inability to constitute an internally coherent spatial representation, probably in the form of an allocentric cognitive map [28]. Since research on feature binding in relation to the hippocampus has only started recently [55], future studies should explore the precise role of the underlying processes involved in feature binding within memory more thoroughly. Additionally, the current results show that hippocampal patients have only a relatively mild impairment in maze learning [57], compared to positional memory. Maze learning relies heavily on route learning strategies, which do not critically depend on the formation of an allocentric map, but might be subserved by the so-called taxon system [63]. This is in agreement with the idea that other brain areas than the hippocampus – especially the frontal cortices – are important in tasks that involve temporalorder route learning [42]. Finally, only a small impairment in spatial working memory was found, and no lateralization could be demonstrated here. This clearly does not support that the hippocampus is crucial for the processing of information within working memory, as suggested by Olton and co-workers [64,65]. Thus, the results of the present meta-analysis show a clear distinction between memory for positional information – requiring metric information processing in an Euclidean manner – and other forms of spatial memory (i.e., maze learning, object-location binding and spatial working memory). This indicates that these functions rely – at least in part – on separate cognitive processes, in agreement with recent suggestions [40,41,74,75]. The results of this meta-analysis also provide further evidence for specialised involvement of the human hippocampus in storing spatial information in the form of an allocentric cognitive map, especially if Euclidean processing is involved. A complicating factor is, however, that there is considerable variation in the size of the lesions of the studies included in this meta-analysis. Only very few studies [8,25] included patients with lesions restricted to

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the hippocampus (and amygdala) only. It could be that especially the temporal-lobe damage accounts for the deficits on spatial-memory tasks [25,73], although other studies report only spatial-memory dysfunction in patients with extensive damage to the hippocampal formation [71]. In line with this, there is evidence that not only the hippocampus itself is involved in spatial memory, but also the adjacent parahippocampal gyrus, perhaps acting as a gateway for the hippocampal formation [22,23,35,48,66]. Neuroimaging studies could clarify the involvement of these specific brain areas in greater detail. In sum, the hippocampal formation is important (and perhaps even crucial) in spatial-memory processing and route learning, especially for precise, metric information in the form of an allocentric cognitive map. Other aspects of spatial cognition are probably subserved by other brain structures, such as the frontal lobe for working memory [15,42,43,59,67] and the parietal cortex for spatial orientation, attention and egocentric (body-related) mapping [9,36,37,51]. Obviously, spatial-memory functioning as a whole depends on the integrity of a highly connected and interacting circuit, but sub-processes exist that can be linked to specialized neural substrates. The results of this meta-analyses clearly emphasize that it is important to study these distinct aspects of human spatial memory, both from a cognitive point of view (i.e., task-related) and at a neural level (i.e., the brain structures that might be involved).

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Acknowledgements A.P. was supported by a PIONIER grant from the Netherlands Organization for Scientific Research ([44020-000). The authors would like to thank Dr. Tjeerd Jellema and Dr. Chris Dijkerman for their helpful comments.

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