Deficits in spatial working memory after unilateral temporal lobectomy in man

Pergamon

0028-3932(95)00107-7

Neuropsychologia, Vol. 34, No. 3, pp. 163-176, 1996 Copyright © 1996 Elsevier Science Ltd. All rights reserved Printed in Great Britain 0028-3932/96 $15.00 + 0.00

Deficits in spatial working memory after unilateral temporal lobectomy in man JANET D. FEIGENBAUM,* CHARLES E. POLKEYt and ROBIN G. MORRIS Department of Psychology, Institute of Psychiatry, University of London, London, U.K.; and "~Neurosurgical Unit, The Maudsley Hospital, London, U.K. (Received 7 November 1994; accepted 22 June 1995) Abstract--Forty neurosurgical patients and 20 controls were tested on a series of computerized tasks (the executive golf, structured golf and rotate tasks) designed to investigate spatial working memory. As defined by Olton [Spatial Abilities, Academic Press, New York, 1982], spatial working memory involves the encoding of specific and contextual information within the spatial domain. Right temporal lobectomy patients were significantly impaired on all three tasks, while the left temporal lobectomy patients showed a less significant overall impairment only on the structured golf task. Although there was no statistically significant differences between the two patient groups on the three tasks, the results point towards a robust deficit in spatial memory associated with right temporal lobectomy. The results provide further evidence for the role of the mesial temporal lobe structures in the processing and encoding of spatial information. Key Words: temporal lobes; spatial working memory; allocentric; egocentric; mapping.

Introduction

working memory component of this task. Analogous tasks have been developed for use with non-human primates [42] and humans [25, 39]. According to Olton the hippocampus is important for spatial working memory, a term used to refer to the encoding of specific, personal and temporal contextual information in the spatial domain; analogous to long-term episodic memory in humans [54]. The theories of Olton and colleagues [23, 36, 37] tie in well with recent modifications to the 'cognitive mapping' theory of O'Keefe and Nadel [32, 33]. Studies by O'Keefe and colleagues have shown that single cells in the hippocampal formation respond when the rat is in a particular place as defined by the spatial configuration of objects in the environment. When the configuration of objects is distorted relative to each other the 'place cells' cease to fire [2931]. More recent theories by O'Keefe [32] and Speakman [34, 35] suggest that cognitive maps are created and modified, but not necessarily stored in the hippocampus. Further evidence to support this finding that the hippocampus plays a crucial role in the acquisition and utilization of spatial information comes from a variety of lesion studies designed to extinguish these functions [6, 16, 21, 23, 26]. Early work on non-human primates has shown that bilateral lesions of the hippocampus can produce impairments on left-right delayed alternation and on spatial position reversal, but not on a go/no-go delayed

Extensive research in animals and in man has suggested that the structures of the mesial temporal lobes play a vital role in anterograde memory processing. These memory impairments typically occur in the absence of other cognitive deficits as tested with conventional intelligence tests. Subjects often show normal scores on immediate memory tests and retrograde memory tests for remote events [53, 54]. Animal research to examine the function of the structures of the mesial temporal lobes has accumulated considerable evidence for their involvement in spatial memory. An example of this has been the use of the radial arm maze by Olton and colleagues to test spatial working memory in rodents [23, 36, 37]. In this task, the rat is required to traverse a number of runways radiating out from a central platform. An essential feature of this task is that the animal has to remember not to return to arms previously traversed to receive a food reward. Hippocampal lesions result in deficits in the spatial

*Address for correspondence: Janet D. Feigenbaum, Department of Psychology, Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, U.K.; fax: 0171-7083497. Correspondence about the computerized tests should be sent to Dr R. G. Morris at the same address. 163

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alternation, suggesting a deficit in spatial working memory, but not spatial processing [57, 58]. Although monkeys with hippocampal removal have been reported not to be impaired on spatial delayed response [7, 8, 27], significant deficits emerge when longer delays are used (30 sec or more) [58] or with more complex versions of delayed response involving memory for two positions [1, 41]. In addition, damage to the hippocampal formation impairs the monkey's ability to perform on tasks in which the animal must remember both the identity and the location of objects [18, 41]. More recent work by Gaffan and colleagues [16, 17] has suggested that the hippocampus in primates is involved in spatial organization or the association of objects to form complex (episodic) scenes in memory [15]. The results of electrophysiological recording in nonhuman primates has also related spatial processing to neuronal activity. Watanabe and Niki [56] have recorded from single neurons in the primate hippocampus during delayed response and report that 2.2% of the neurons respond differentially to one of the spatial stimuli during the sample presentation or during the delay. Rolls and colleagues [24, 48] have also shown that there are neurons in the hippocampal formation of primates which respond differentially with respect to the place in which a stimulus is presented. Some of these cells respond to location alone, while others responded to an interaction between spatial location and object recognition. In addition, work by Feigenbaum and Rolls [12; see also 55] indicates that there are cells in the hippocampal formation which respond differentially to allocentric and egocentric spatial information. These findings further confirm the suggestion that the hippocampal formation of the primate is involved in spatial information processing and in the formation of object-location associations. In humans, it has been shown that the left and right temporal lobes have lateralized functions. Various studies indicate that the right temporal lobes are important for remembering visuospatial information which is difficult to verbalize (abstract designs) [22] and unusual geometric patterns [20, 41]. Smith and Milner [49] found that patients with damage to the right temporal lobes were impaired in their ability to recall the locations of objects in an incidental learning paradigm. A later study by Smith and Milner [50] suggested that the spatial memory deficit seen in patients with right temporal damage (which includes the hippocampus) was only seen when a delay was introduced between presentation of the material and recall. Using a paradigm to test memory for complex visual scenes, Pigott and Milner [46] have shown that damage to the right temporal lobe impairs identification of changes in spatial location and spatial composition, thus further implicating the right temporal lobes in spatial memory. In their study, an impairment in detecting changes in spatial locations of specific objects was found to correlate with the extent of hippocampal removal. In order to test O'Keefe's

cognitive mapping theory in humans, Goldstein et al. [20] employed a design recall task involving 'place learning' and 'cue guidance', and present results which indicate that both left and right temporal lobectomy patients are able to perform non-egocentric cognitive mapping. These results suggest the need for further studies investigating whether the right hippocampus and mesial temporal structures in humans are preferentially involved in the processing of allocentric spatial information, necessary for the formation of cognitive maps, The present investigation explores spatial memory in patients who have undergone a unilateral en-bloc resection for the relief of intractable temporal lobe epilepsy using computerized human analogues of the Olton radial-arm maze [36]. The term 'spatial working memory' employed by Olton for rats is also analogous to long-term spatial memory as defined by Baddeley [2] for humans, such that in long-term spatial memory information is retained throughout the period of time necessary to complete the task correctly in the presence of interference and delay. The first experiment involves the executive-golf task based on the spatial memory task designed originally by Morris [25, 39, 40]. This task, which is represented in three-dimensional computer graphics to simulate a game of golf, tests a person's memory for a series of places or 'holes', in which the 'golfer' putts a ball. However, because performance on this task is confounded by the ability to use self-ordered search strategies, a second experiment, the structuredgolf task, was used to limit the subject's search strategies by the use of a forced-choice design, thus predetermining the subjects' search path. In the final experiment, the task used is analogous to the previous ones, but enhances the use of allocentric spatial processing through rotating the coordinates of the spatial array within a three-dimensional space. Specifically, between searches, the spatial array 'rotates' around a centre position, but with the directions and distances between the positions remaining the same. This 'rotating spatial memory' (rotate) task effectively requires the subject to view the array from different directions when performing the task and so tests allocentric spatial memory.

Method Subjects

The same subjects were included in all three experiments described below. All neurosurgical subjects had undergone surgery for the relief of intractable epilepsy at the Neurosurgical Unit, Maudsley Hospital, London, U.K. They divide into those who had undergone a right temporal lobectomy (RTL; n = 20) and those who had undergone a left temporal lobectomy (LTL; n = 20). The standard 'en-bloc' resection [10], was performed by Mr C. E. Polkey, with the removal of 5.56.5 cm of mesial temporal tissue from the anterior pole including the amygdala and anterior hippocampus [9, 47]. These patients were seen a minimum of 6 months post-

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Equipment

The tasks were presented on a DELL 486P/50 desk top computer with a Taxan 775 14 in. monitor fitted with a touch sensitive screen and were written in Qbasic-45.

Statistical analysis

All statistical analyses were performed using SPSS-PC+ [51]. The data for all tasks were divided into three groups and analysed using analyses of variance (MANOVA) where appropriate.

Experiment h the executive golf task Procedure

This task is based upon the spatial memory paradigm devised by Morris et al. [25] [see also 39, 40]. In the executive golf task the subject is initially presented with

a screen on which there is a representation of a golf course and a golfer (Fig. 2). On the golf course there are a specified number of holes with flags into which the golfer must 'putt' and an equal number of golf balls. The subject is instructed to guess into which hole the golfer is going to putt the first ball by touching the chosen hole. If this is correct, the computer emits a tone to represent a correct 'guess' and the ball can be seen moving to the hole. I f the hole is not correct, a different, incorrect, tone is played and the subject is instructed to try again. If the subject touches an inappropriate part of the screen the computer simply does not respond. In the initial instructions the subject is informed that there can only be one ball putted into each hole. Therefore they must not return to a hole which contains a ball again during this trial. The subject then proceeds with a series of searches until all the balls have been placed into separate holes. Once the subject has correctly putted all the balls for that level of difficulty into the holes, the word 'finished' appears at the top of the screen. After a brief (10 sec) pause, the subject is informed that a new trial is about to commence with fresh balls and holes. In practice, the rules of the task are easily understood. The task increases in difficulty over trials. Initially there are two trials with two flags and balls, then three trials with three flags and balls, three trials with four flags and balls, four trials with six flags and balls and four trials with eight flags and balls. The sequence of 'correct' holes for the ball is determined by a pseudorandom function based upon the pattern of searching by the subject.

Table 1. Comparison of the three groups by sex, age, IQ (as estimated using the NART), and time since operation (for the neurosurgical groups) Group

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IQ (NART)

Time since operation (years)

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Fig. 3. (a) The rotate task at level 6. The red spot indicates an incorrect touch by the subject. (b) A correct touch on the rotate task at level 6. The spots will next rotate to a new position. (c) The new position of the spots after the correct touch shown in (b).

J. D. Feigenbaum et al./Deficits in spatial working memory The computer collects the following data for each trial: (1) Within search errors: in which during a single search sequence, the subject 'guesses' the same hole more than once while searching for the correct hole into which the golfer will putt the ball, and (2) Between search errors: in which the subject 'guesses' a hole which already contains a ball. The computer also records the sequence of touches by the subject which can be analysed for search strategies.

Results

The results of the analysis for executive golf are divided into 'within search errors' and 'between search errors'. For each error type the results were analysed for level of difficulty (number of flags and balls) and group effect. Level two of difficulty was treated as learning/ practice trials in which the subject learned the rules of the task and for practice, thus was not used in the statistical analysis. On multiple analyses of variance comparing all three groups together and each individual group with each other group, there were no significant differences for 'within search errors' for any of the three groups at any level of difficulty. The mean number of 'within search errors' and standard errors are shown in Fig. 4, with very few errors made by any subject at all levels of difficulty.

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Multiple analyses of variance were performed to compare the three groups for 'between search errors' according to difficulty. The analyses indicated that while there was no significant group effect, there was a significant group x difficulty effect [S.S. = 52.76; d.f. = 6; F=2.25; P=0.041]. Further analyses of variance were performed to compare the groups on levels 4, 6 and 8. This analysis indicated that there was no significant difference between the R T L and L T L groups nor between the LTL and CON groups. However, there was a significant difference between the R T L and CON groups [group effect: S.S.=45.52, d . f . = l , F=5.08, P = 0.03; group x difficulty effect: S.S. = 40.98, d.f. = 2, F=4.28, P=0.017]. When multiple t-tests were performed to identify the source of the significant variation, the analyses suggest that at level of difficulty 8 the RTL group is significantly more impaired than tile controls [t--2.21, d.f.=38, P<0.033]. Finally, an analysis was performed to identify the use of strategy by the different groups. The most efficient search strategy would be to follow a predetermined search sequence in which one begins each search at the same location. To quantify the use of this strategy, the number of searches within a trial which begin with the same location were counted. An example of such a search strategy is shown in Fig. 5. A high score (many sequences beginning with different locations) represents a low use of this strategy, and a low score (many sequences beginning with the same location) represents a

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Summary In summary, there were no significant differences between any of the three groups on 'within search errors' at any level of difficulty. This suggests that neither left nor right mesial temporal damage results in a deficit on an individual's ability to search a small number of locations ( < 8) and retain this information in working memory. However, on 'between search errors', which places a greater demand on spatial memory, it was found that subjects with damage to the right temporal lobe were more impaired compared to controls and more so as the level of difficulty increased.

It was apparent from the data that the subjects were able to use an organized search strategy to improve spatial memory. This has been observed on the previous version of the task in normal controls and is found to be disrupted in patients with frontal lobe neurosurgical lesions [39, 40]. There was no apparent significant difference between groups with regard to use of strategy. Nevertheless, it is possible that the spatial memory deficit in the right temporal lobectomy patients is the result of greater difficulty in implementing the strategy, drawing processing resources away from remembering the locations. In other words, an efficient use of the strategy could be produced at the cost of spatial memory. To prevent the task confounding spatial memory, strategy formation and implementation, the structured golf task was designed, which uses a forced choice method in which the subject is required to search in a pseudo-random fashion dictated by the task, thus eliminating the self-ordered search path created by the subject and 'purifying' the task as a test of spatial memory.

Experiment 2: the structured goff task

Procedure The format for the structured golf task (structured golf) was essentially the same as for the executive golf task, with a golfer and a matched number of holes and balls. In this case, the search path of the subject is structured by the computer. The subject is presented with a series of choices indicated by circles around two of the golf holes. For each choice pair, they must select one of the two indicated holes, the remaining holes do not respond to touch. A series of pairs of holes were constructed in a pseudorandom fashion and then presented in a pseudorandom order, with the target hole being contained in only one of the pairs. The computer cycles through the pairs in a continuous fashion until the subject selects the target hole and the 'golfer' putts the ball. On subsequent searches, the previous target or targets may be presented again and the subject has to avoid selecting them. Within each search, holes that have just been selected can be represented, but there are never two previously obtained targets in any one pair. In certain instances, the logic of the task dictates that the computer presents one hole

Table 2. Analysis of the use of strategy on the executive golf task and the rotate task

Executive golf Rotate

LTL group Mean S.E.

RTL group Mean S.E.

Controls Mean S.E.

32.65+ 1.18 32.61 4- 1.01

32.7 ± 1.35 30.95 =k0.81

29.65+ 1.28 29.85 + 0.63

The values indicate the amount of strategy used combined for levels 6 and 8. There were no significant differences in the use of strategy between levels of difficulty. A higher value indicates a lower use of strategy.

J. D. Feigenbaum et al./Deficits in spatial working memory that has been a target before and one that has been tried already within a particular search. In this case, the subject has the option of touching the word 'neither', which is present in the upper right hand corner of the screen. As before, the subject is instructed to search for the hole they think the golfer is going to putt, whilst avoiding selecting a hole tried before within the search or one the golfer has putted into previously. They are also told that sometimes it is possible that neither of the holes circled might be correct, in which case they should touch the 'neither' word. As in executive-golf, the level of difficulty increases from two flags and balls, to eight flags and balls with the same number of trials per level of difficulty as before. Once again, the following information is collected for each trial: (1) ~Tthin search errors: in which the subject 'guesses' the same hole more than once while searching for the correct hole into which to place the ball, and (2) Between search errors: in which the subject 'guesses' a hole in which the golfer has already putted.

Resuhs

The results of the analysis for the structured golf task are divided into 'within search errors' and 'between search errors'. For each error type the results were

169

analysed for level of difficulty and group effect. As in the previous task, level of difficulty two was not used in the analysis. On multiple analyses of variance comparing all three groups together and each individual group with each other group, there were no significant differences for 'within search errors' for any of the three groups at any level of difficulty (Fig. 6). Multiple analyses of variance were performed to compare the three groups for 'between search errors' according to length of problem (level of difficulty). The analyses indicated that there was a significant group effect [S.S. = 63.43, d.f. = 2, F = 5.81, P=0.005] and a significant group xdifficulty effect [S.S.=48.27, d.f.=6; F=2.72, P=0.015]. Further analyses of variance were performed to compare each pair of different groups on levels 4, 6 and 8 to determine which group was contributing to the significant effect. This analysis indicated that there was no significant difference between the RTL and LTL groups. However, the RTL group was significantly impaired in relation to controls [group effect: S.S. =79.89, d.f. = 1, F--11.27, P = 0.002; group x difficulty effect: S.S. = 28.09, d.f. = 2, F=3.74, P=0.028]. There was a somewhat less significant difference between the L T L and control groups [group effect: S.S.=30.31, d . f . = l , F=5.81, P=0.021; group xdifficulty: not significant]. Multiple t-tests, performed to identify the source of the significant variations, suggest that at level of difficulty 6 both the

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RTL and LTL groups are significantly more impaired than controls [RTL vs CON: t=3.07, d.f.=38, P<0.004; LTL vs CON: t=2.34, d.f.=38, P<0.025] and at level of difficulty 8 only the R T L group made significantly more 'between search errors' than controls [t=2.93, d.f.=38, P<0.006].

The aim was to investigate whether the additional allocentric processing proved more sensitive to loss of right mesiotemporal lobe functioning associated with the right temporal lobectomy group.

Procedure Summary

Again, as in the executive golf task, there were no significant differences between groups for 'within search errors'. However, as can be seen from the data, all groups made m a n y more 'within search errors' than on the executive golf task. This indicates that the forcedchoice method did disrupt individual mnemonic strategies and increased the level of difficulty of the task. On 'between search errors' there was a significant group effect with the right temporal lobe group making significantly more errors than controls. This effect was more significant as problem difficulty increased. However, while there was no significant difference between the right and left temporal groups, the left temporal group were also impaired when compared to controls. When the data was further analysed, it became apparent that the left temporal group show more variability in their responses such that the deficit is significant at level of difficulty 6 but not at level of difficulty 8. Only the right temporal group is consistently impaired compared to controls.

Experiment 3: the rotating spatial memory task The previous two experiments indicate a long-term spatial memory deficit in the right temporal lobectomy group, irrespective of whether an organized search strategy is used. Both utilize a 'three-dimensional' space, created by the computer graphics. This space, however, is always viewed from one vantage point and thus emphasizes egocentric (viewer-centred) spatial processing and memory. In everyday tasks, however, the person moves within a spatial environment and, whilst the geometric relationship between locations remains constant, the directions alter, hence the need for a coordinate system that serves as a reference fi'amework [32]. In the Olton radial-arm maze the animal moves around the environment creating the spatial map, which can be used for navigation between positions. In order to emphasize the use of an allocentric, viewer independent framework, the rotating spatial memory task was developed. This was graphically achieved by 'rotating' the spatial array around a central point on the computer screen, giving the appearance of a rotating gramophone turntable. Within the represented three-dimensional space the distances between locations remain the same, whilst their position and inter-relationships differ on the computer screen.

In the rotating spatial memory task (rotate), a large circular disc is presented on the screen on which appears a specified number of locations (Fig. 3). The disc is divided into three concentric elliptical rings (not visible on the screen), on which the locations fall, which gives the impression that they are placed in a three-dimensional plane. The positioning of the locations were designed to try and disrupt attempts at clustering as much as possible. The subject is instructed to touch one of the 'holes' to 'find the treasure'. If the hole touched is the correct location of the treasure, a 'correct' tone will play, the location will turn green and the array will begin to rotate on the screen (as described below). If the location is not correct, an 'incorrect' tone will play and it will turn red and the array does not rotate. The subject must continue searching for the correct location by touching other locations on the screen until the 'correct' one has been found. Once the subject has found a correct hole, he/she is instructed that to find the next treasure they must not return to this hole again until all of the treasures have been found and a new game is started. When the subject has correctly identified all of the treasures, the word 'finished' appears at the top of the screen to signal an end to the trial. As stated above, after a hole has been correctly identified as containing a treasure, the array of holes rotates. The relationship of the locations relative to each other remains constant in pseudo-three-dimensional space, but the relationship to the individual's body axis and to the edges of the screen changes. In half of the trials, the locations rotate to a new position; in the other half, they rotate half way and then reverse and return to the original position. In half the trials, the total angle of rotation is 90 ° and 180 ° in the other half. There are four trials at each level of difficulty which comprise level 2 (two holes), level 4 (four holes), level 6 (six holes), and level 8 (eight holes). The search sequence to determine 'correct' and 'incorrect' locations of the treasure is predetermined by a pseudorandom function based on the pattern of searching by the subject. Thus, as with the golf data described above, the data collected for this task include: (I) Within search errors: in which the subject 'guesses' the same hole more than once while searching for the treasure, and (2) Between search errors: in which the subject 'guesses' a hole in which a treasure has already been found. The data can also be analysed with respect to whether the holes have rotated (rot) or rotated and returned (ret).

J. D. Feigenbaum et al./Deficits in spatial working memory Resuhs

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between any o f the three groups on any o f the different comparisons. F o r 'between search errors' there was a significant group x difficulty effect when c o m p a r i n g all three groups together [S.S. = 85.35, d.f. = 4 , F = 2.9, P = 0.025]. W h e n the different groups were c o m p a r e d to each other in order to further determine the source o f variance, there was no significant difference between the R T L and L T L groups for any o f the comparisons, and a small difference between the L T L and C O N groups [group x difficulty effect: S.S. = 38.1, d.f. = 2, F = 3.03, P = 0.054; rotation x difficulty: S.S. = 18.96, d f = 2, F = 3.37,

The results for the rotate task were divided into 'within search errors' and 'between search errors' for each level o f difficulty with level 2 o f difficulty again excluded from the analysis. Figure 7 shows the results for the rotate task separated by rotation and error type. Multiple analyses o f variance were performed to compare: group, rotation, difficulty, group by difficulty, g r o u p by rotation, rotation by difficulty and g r o u p by rotation by difficulty. F o r 'within search errors' there were no significant differences

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J.D. Feigenbaum et al./Deficits in spatial working memory

P=0.04]. However, there was a significant difference between the R T L and CON groups when the data was analysed for levels of difficulty 6 and 8 only [group: S.S.=142.66, d . f . = t , F=4.44, P=0.042; rotation: S.S.=13.66, d . f . = l , F=4.28, P=0.046; groupxdifficulty: S.S.=41.11, d.f. = 1, F = 5.42, P=0.025; group x rotation xdifficulty: S.S.= 12.27, d.f.= 1, F=3.58, P=0.066]. When a series of t-tests were performed to further identify the source of greatest variation in the data, the only significant comparisons were for level 8 return trials [LTL vs CON: t = 1.92, d.f. = 37, P = 0.063; RTL vs CON: t=2.65, d.f.=37, P=0.012]. Finally an analysis was performed to analyse the use of strategy by the different groups (see Table 2). The analysis of strategy was the same as for the executivegolf task described above. An analysis of variance showed no significant differences between groups for use of strategy. However, when the data from the three groups were collapsed, a correlation analysis to compare the use of strategy with 'between search errors' and 'within search errors' revealed a significant correlation between high use of this strategy and fewer 'between search errors' [r=0.73; P<0.001]. Subjects were asked at the end of the task what technique or strategy they used to solve the task. Only two subjects, both controls, noted a formal search strategy; these involved visualizing the pattern of spots as an image (e.g. "this looks like a horse").

Summary

in summary, when compared on 'within search errors', very few errors were made by subjects in any of the three groups on the rotate task. When comparing the three groups for 'between search errors' there was a significant impairment of the right temporal group which increased with level of difficulty. There was no significant difference between the RTL and LTL groups and only a very small (not quite significant) difference between the LTL and control groups. Further examination of the deficits suggests that there is a significant effect of rotation. This effect is due to the fact that the controls found the 'rotate then return' trials easier (fewer errors) than 'rotate alone' trials. The RTL group made the same number of errors on both types of rotations.

Discussion

The aims of this research were to investigate the role of the mesial temporal lobes in spatial working memory using surgical patients who had undergone unilateral enbloc temporal lobectomy for the relief of intractable epilepsy. The 60 subjects were divided into 20 subjects with left temporal lobectomy, 20 subjects with right temporal lobectomy, and 20 matched controls. All

subjects selected were right-handed, between the ages of 18 and 65, and had an estimated IQ above 85. There were no significant differences between the three groups for age and estimated IQ, nor between surgical groups for time since operation and postoperative seizure outcome. It is important to note the very good match between the two neurosurgical groups on Engel's classification and the high percentage of subjects who were seizure-free since operation, as further postoperative seizure activity could interfere with the individuals' abilities and indicate further neuropathology. The executive golf task is based upon the paradigm designed by Morris et al. [25, 39, 40] to provide a human analogue of the Olton maze used in the animal research. This spatial task was altered to bring the task more in line with everyday memory by simulating a familiar activity, golf. The results were divided into 'within search errors' in which the subject returned to guess a hole which had been tried during that search sequence, and 'between search errors' in which the subject returned to guess a hole into which the golfer had already putted a ball. The analysis showed that there were very few errors and no significant differences between any of the three groups for 'within search errors'. This suggests that the very short period of time and the limited number of locations to remember (max = 7) were not difficult for any of the subjects. On this task, the 'within search' conditions may employ a very immediate form of spatial memory (e.g. a shortterm visual storage system [3]). For example, with Baddeley and Hitch's [3] working memory model in which there is the Visual Spatial Scratchpad, a temporary workspace is in which a visual image can be stored and manipulated. The lack of 'within search errors' in either patient group points towards this system not being reliant on the structures removed during unilateral temporal lobectomy. In contrast, ~he 'between search' condition produced a significant memory impairment in the right temporal lobectomy patients. It seems that this condition draws upon the resources of a longer-term spatial memory system in which the subject must remember the location of the 'filled' hole over delays and interference. As such it is akin to Olton's own use of the term 'working memory' referring to the retention of information in context over a longer time period [37, 38]. Spatial working memory therefore appears to be dependent on mesial temporal lobe structures. Of note, a similar pattern has been reported when exploring spatial delayed response and related tasks in non-human primates. Short delays (e.g. 10 sec or less) invariably produce no impairment following hippocampectomy [7, 8], whilst long delays (30 sec or less) have been shown to produce an impairment [41]. It is not clear in human or non-human primates, however, whether time is the critical factor, or whether the degree of visual distraction that occurs within the retention

J. O. Feigenbaum et al./Deficits in spatial working memory interval is important. In the current task, the searches can distract from remembering which 'holes' have been used. In spatial delayed response, a longer retention interval also increases the opportunity for distraction. An additional factor is the added complexity of the 'between search' process, which again mirrors the increased complexity of the modified spatial delayed response task that produced a deficit in hippocampectomized monkeys in the studies by Parkinson et al. [41] and Angeli et al. [1]. These current results are in accordance with the results reported by Smith and Milner [50] in which they suggest that damage to the hippocampus results in an abnormally rapid rate of forgetting, not a deficit in the initial encoding of spatial location. However, the results for 'between search' errors begins to show a different picture. On this measure, the right temporal lobe group show a significant deficit compared to controls as level of difficulty increases. Thus for shorter length searches, in which the load on spatial memory is less, all three groups performed well, but as the load on memory increases, both in time and amount to remember, the right temporal group show a deficit in retaining spatial information in memory. The left temporal group appear to have some difficulties with the task, but this deficit is not significant compared to controls. This may suggest that damage to the left temporal lobes interferes with efficient mnemonic processing, but not as severely as right temporal damage. When use of strategy was assessed, it was found that there were no significant differences between any of the three groups. However, it was found that there is a significant correlation between the use of an efficient search strategy and number of 'between search' errors. This suggests that those with a morc efficient search strategy were making fewer errors not necessarily based upon using spatial processing. Therefore it was decided to introduce a version of the task designed to disrupt the use of self-ordered search strategies. The structured golf task disrupted organized search strategies by only allowing the subject to guess between two holes designated in a pseudo-random fashion by the computer. The introduction of this disruption resulted in a significant increase in the number of 'within search errors' for all three groups. However, there were no significant differences between the three groups on this measure. This suggests that the structured golf does disrupt efficient search strategies but that this disruption is equal for all three groups. Again the analysis of 'between search errors' indicates that the right temporal lobe group are most impaired on this task. However, the left temporal group are also impaired on this task, which suggests that when alternative search strategies are removed, and therefore possibly the load on memory increased, both surgical groups show deficits in spatial memory processing. These findings would suggest that while the right temporal lobes may be more involved in the processing of spatial memory, the left temporal lobes

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may play a role in this paradigm. Various possibilities exist to explain this result. One is that the lateralization of spatial memory in humans is not complete. This is a clear possibility, given that spatial memory is not completely disrupted in the right temporal lobectomy group. It should be noted that unilateral brain damage in these patients, prior to surgery, took place in infancy or early childhood [45]. Nevertheless, the more consistent impairment in the right temporal lobectomy group points towards some degree of lateralization. Secondly, the tasks are unlikely to be completely 'pure' tests of spatial memory, with some verbal re-coding of the spatial information. The random positioning of locations reduces this factor, but cannot be eliminated entirely in humans. It is possible that a verbal memory deficit produced a mild, but not significant impairment on the tasks in the left temporal lobectomy group. Allocentric (extrapersonal) space is defined as the relationship of objects in the environment irrespective of the location of the individual. Egocentric (personal) space is that which is occupied by our own bodies and is defined by the orientation of the body in relation to gravity and the position of the head and limbs. Both allocentric and egocentric information are necessary for the creation and utilization of spatial maps. It has been suggested that allocentric information is processed by the parietal lobes [52] and egocentric information is processed by the frontal lobes [4, 5]. Both types of information could then be integrated in the temporal lobes (by way of the pathways to and from the entorhinal cortex) to create and utilize spatial maps [see also 1 I]. As mentioned earlier, Goldstein et al. [20], using a 'place learning' and 'cue guidance' task, have shown that the right temporal lobe in humans is involved in spatial memory. In order to test further the hypothesis that the hippocampus is a critical structure in the synthesis of allocentric and egocentric spatial information and the processing of cognitive maps, the third task, the rotate task, was designed. The task utilizes the same spatial memory paradigm described in the two g o l f tasks in which the subject must remember both the holes which have been searched in a given sequence and the holes which have been 'tagged'. However, between searches the holes either rotate to a new location or rotate and return to the original location. It was hypothesized that this rotation would disrupt egocentric and allocentric processing by disrupting the relationship between the holes and the individual (egocentric processing) and the holes and the edges of the screen or the room (allocentric processing). The results show that there were no significant differences between any of the three groups for 'within search' errors which is expected as the 'within search' errors are made prior to any rotation of the holes. However, after the holes have rotated, 'between search' errors are made by all three groups. The results show that the right temporal group are most impaired by this paradigm, but nevertheless, the degree of impairment is

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not strikingly different from that observed on the golf tasks. Looking at the data, the most interesting finding is that while the right temporal lobe group are equally impaired on both rotate and rotate/return trials, the controls made many more errors on rotate trials. This suggests that rotating to a new location does disrupt spatial information processing. One hypothesis is that it is more difficult for subjects to retain the original information in memory during the rotation whereas when the holes return to the original location it is not necessary to keep the information in rotational memory. Once again the left temporal group show a nonsignificant but definite intermediate level of impairment. A comparison across tasks shows broadly the same pattern of deficits in each group. The tasks were designed to differ both in the degrees to which strategies could be used (executive vs structured golf) and the emphasis on allocentric-egocentric processing (rotate). Although a quantifiable strategy in the first task was found to correlate with performance, it is unlikely that this strategy can explain the spatial memory performances on all three tasks. Specifically, both structured go/f and rotate appear to rule out the use of this strategy. In addition, the same degree of use of strategy in the patients and controls on executive golf suggests that the temporal lobes may not be involved in strategy. This is in contrast to the frontal lobe patients studied by Owen et al. [39, 40], where there was a clear impairment in these patients. Nevertheless, there may be additional strategies which are less readily measurable. Whilst the patients are unlikely to show a deficit in these, if identified, their use could mask any potential spatial memory deficit. In the first two tasks, the subject could mentally measure locations, for example estimating distances of places from reference points on the side of the monitor; however, in the rotate task this type of strategy is less likely to be of use because of the way the locations shift position. For this reason, this particular task may be of potential interest, in addition to the fact that it emphasizes allocentric processing. On the rotate task, however, there may also be additional strategies, but these have yet to be identified. It should be noted that whilst a strategy may exist or be created by a subject, it does not necessarily aid performance. For example, the processing resources used to implement the strategy may paradoxically reduce the degree of 'mental effort' available for attending to and remembering the locations. A similar deficit in spatial memory has been observed in patients with frontal lobe neurosurgical lesions by Owen et al. [39, 40] using a previous version of the executive golf task, the spatial working memory task [25]. As noted above, not only are the patients consistently impaired on the task, but they are significantly less efficient in their use of the repetitive search strategy. The task has certain features in common with the spatial conditional associative learning or the self-ordered pointing tasks shown by Petrides and

Milner [45]. In the former task, the patients are presented with an array of randomly positioned lights and have to associate each light with a specific white card from a line of cards placed in front of the patient. Patients with both left and right frontal lobectomies were impaired on this task, but only right temporal lobectomy patients showed an impairment. Positron emission tomography (PET) studies in humans conducted by Petrides et al. [44], have recently shown that performance on the task is specifically associated with activation of area 8 in the posterior dorsolateral prefrontal cortex. The self-ordered pointing task requires the patient to point sequentially to different stimulus cards in an array, taking care not to touch the same item twice. In this case, the similarity with executive golf is the idea of not going back to a previously chosen location, although the main difference is that the cards are distinguished either by having different words (verbal) or abstract patterns. Of note, frontal lobe lesion patients were impaired in this task, and those with right unilateral temporal lobectomies were impaired in the visual version, but only when extensive hippocampal lesions were made [43]. The conjoint deficit in spatial memory associated both with frontal and right temporal lesions may suggest a neural system for spatial memory involving both regions of the cortex. Such a possibility has, for example, been put forward by Goldman-Rakic [19], who proposes reciprocal synaptic connections between the prefrontal cortex and hippocampus involving spatial memory. This is supported by the finding, in non-human primates, of cells in the pefrontal cortex whose activity is correlated to the retention of spatial information, including those observed using an oculomotor delayed-response paradigm [14]. 2-Deoxyglucose functional mapping has also shown differential metabolic activity in the dentate gyrus and hippocampal subfields consistent with distinct multi-synaptic connections between the prefrontal cortex and hippocampus, which may involve the transfer of spatial information across these structures [13]. In summary, the results taken together suggest that the right temporal lobes in man are involved in the processing of spatial working memory. By using computer simulations of tasks similar in paradigm to the Olton maze designed for rats, it is possible to draw parallels between the animal literature and human deficits after neurosurgery to understand the functions of the temporal lobes. The tasks presented here are unique in that they begin to approach the question of spatial working memory by presenting information in an interactive form. In addition, the tasks were designed to simulate information as it would be presented in 'everyday memory', both as games many people would play, and in three-dimensional space. By simulating three-dimensional space we can draw further parallels between the data from the real world experiments with rats and primates, and the computerized experiments performed with humans.

J. D. Feigenbaum et al./Deficits in spatial working memory

Acknowledgements--This work was supported by a Fellowship from the Wellcome Trust to Dr J. Feigenbaum with Dr R. G. Morris and Professor J. A. Gray. We would like to thank Ms B. Schena for help with the data collection. We would also like to thank Drs S. Abrahams and J. Nunn for discussions about the data at earlier stages.

16.

References

17.

1. Angeli, S. J., Murray, E. A. and Mishkin, M. Hippocampectomized monkeys can remember one place but not two. Neuropsyehologia 31, 1021-1030, 1993. 2. Baddeley, A. Human Memory: Theory and Practice. Lawrence Erlbaum Associates, London, 1990. 3. Baddeley, A. Working Memory. Clarendon Press, Oxford, 1986. 4. Brody, B. A. and Pribram, K. H. The role of frontal and parietal cortex in cognitive processing: Tests of spatial and sequential functions. Brain 101, 607633, 1978. 5. Butters, N., Soeldner, C. and Fedio, P. Comparison of parietal and frontal lobe spatial deficits in man: Extrapersonal versus personal (egocentric) space. Percept. Motor Skills 34, 27-34, 1972. 6. Chiba, A. A., Kesner, R. P. and Reynolds, A. M. Memory for spatial location as a function of temporal lag in rats: Role of hippocampus and medial prefrontal cortex. Behav. Neural Biol. 61, 123-131, 1994. 7. Correll, R. E. and Scoville, W. B. Significance of delay in the performance of monkeys with medial temporal lobe resection. Exp. Brain Res. 4, 85-96, 1967. 8. Diamond, A., Zola-Morgan, S. and Squire, L. R. Successful performance by monkeys with lesions of the hippocampal formation on AB and object retrieval, two tasks that mark developmental changes in human infants. Behav. Neurosci. 103, 526-537, 1989. 9. Engel, J., Jr. In Surgical Treatment of the Epilepsies, J. Engel, Jr. (Editor), pp. 553-571. Raven Press, New York, 1987. 10. Falconer, M. A. In Operative Surgery, Vol. 14, V. Logue (Editor), pp. 142-149. London, Butterworths, 1971. 11. Farah, M. J., Brunn, J. L., Wong, A. B., Wallace, M. A. and Carpenter, P. A. Frames of reference for allocating attention to space: Evidence from the neglect syndrome. Neuropsychologia 28, 335-347, 1990. 12. Feigenbaum, J. and Rolls, E. T. Allocentric and egocentric spatial information processing in the hippocampal formation of the behaving primate. Psychobiol. 19, 21-40, 1991. 13. Freedman, H. and Goldman-Rakic, P. S. Activation of the hippocampus by working memory: A 2dcoxyglucose study of behaving rhesus monkeys. J. Neurosci. 8, 4693-4706, 1988. 14. Funahashi, S., Bruce, C., and Goldman-Rakic, P. S. Mnemonic coding of visual space by neurons in the monkeys dorsolateral prefrontal cortex revealed by

15.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28. 29. 30. 31.

175

oculomotor delayed-response task. J. Neurophysiol. 61, 1-9, 1989. Gaffan, D. Spatial organization of episodic memory. Hippocampus 1, 262-264, 1991. Gaffan, D. and Harrison, S. A Comparison of the effects of fornix transection and sulcus principalis ablation upon spatial learning by monkeys. Behav. Brain Res. 31, 207-220, 1989a. Gaffan, D. and Harrison, S. Place memory and scene memory: Effects of fornix transection in the monkey. Exp. Brain Res. 74, 202-212, 1989b. Gaffan, D. and Saunders, R. C. Running recognition of configural stimuli by fornix-transected monkeys. Quart. J. Exp. Psychol. 37b, 61-71, 1985. Goldman-Rakic, P. S. Cellular and circuit basis of working memory in prefrontal cortex of nonhuman primates. In Progress in Brain Research, 85, H. B. M. Uylings, C. G. Van Eden, J. P. C. De Bruin, M. A. Corner and M. G. P. Feenstra (Editors), pp. 325-336. Elsevier Science Publishers B.V. (Biomedical Division), 1990. Goldstein, L. H., Canavan, A. G. M. and Polkey, C. E. Cognitive mapping after unilateral temporal lobectomy. Neuropsychologia 27, 167-177, 1989. Jarrard, L. E. On the neural bases of the spatial mapping system: Hippocampus vs hippocampal formation. Hippocampus 1, 236-239, 1991. Jones-Gotman, M. Right hippocampal excision impairs learning and recall of a list of abstract designs. Neuropsychologia 24, 659-670, 1986. Knowlton, B., McGowan, M., Olton, D. and Gamzu, E. Hippocampal stimulation disrupts spatial working memory even 8 hours after acquisition. Behav. Neural Biol. 44, 325-337, 1985. Miyashita, Y., Rolls, E. T., Cahusac, P. M. B., Niki, H. and Feigenbaum, J. Activity of hippocampal formation neurons in the monkey related to a conditional spatial response task. J. Neurophysiol. 61, 669-678, 1989. Morris, R. G., Downes, J. J., Sahakian, B. J., Evenden, J. L., Heald, A. and Robbins, T. W. Planning and spatial working memory in Parkinson's disease. J. Neurol. Neurosurg. Psych 51,757-766, 1988. Morris, R. G. M. Distinctive computations and relevant associative processes: Hippocampal role in processing, retrieval, but not storage of allocentric spatial memory. Hippocampus 1, 287-290, 1991. Murray, E. A. and Mishkin, M. Severe tactual as well as visual memory deficits follow combined removal of the amygdala and hippocampus in monkeys. J. Neurosci. 4, 2565-2580, 1984. Nelson, H. E. and Willison, J. R. National Adult Reading Test (NART): Test Manual, 2nd edn. Windsor, Berks, 1991. O'Keefe, J. A review of the hippocampal place cells. Prog. Neurobiol. 13, 419-439, 1979. O'Keefe, J. Place units in the hippocampus of the freely moving rat. Exp. Neurol. 51, 78-109, 1976. O'Keefe, J. In Neurobiology of the Hippocampus. W. Seifert (Editor), pp. 375-403. Academic Press, London, 1983.

176

J.D. Feigenbaum et al./Deficits in spatial working memory

32. O'Keefe, J. An allocentric spatial model for the hippocampal cognitive map. Hippocampus 1, 230235, 1991. 33. O'Keefe, J. and Nadel, L. The Hippocampus as a Cognitive Map. Clarendon Press, Oxford, 1978. 34. O'Keefe, J. and Speakman, A. Single unit activity in the rat hippocampus during a spatial memory task. Exp. Brain Res. 68, 1-27, 1987a. 35. O'Keefe, J. and Speakman, A. Hippocampal place field activity is not related to the location of the goal or the intended response in the cue-controlled environment. Neurosci. Lett. $29, $96, 1987b. 36. Olton, D. A. In Spatial Abilities, M. Potegal (Editor), pp. 325-360. Academic Press, New York, 1982. 37. Olton, D. S., Becker, J. T. and Handelmann, G. E. Hippocampus, space, and memory. Behav. Brain S¢i. 2, 315-365, 1979. 38. Olton, D. S. and Feustle, W. A. Hippocampal function required for non-spatial working memory. Exp. Brain Res. 41,380-389, 1981. 39. Owen, A. M., Downes, J. J., Sahakian, B. J., Polkey, C. E. and Robbins, T. W. Planning and spatial working memory following frontal lobe lesions in man. Neuropsychologia 28, 1021-1034, 1990. 40. Owen, A. M., Morris, R. G., Sahakian, B. J., Polkey, C. E. and Robbins, T. W. Double dissociations of memory and executive functions in working memory tasks following frontal lobe excisions, temporal lobe excisions, or amygdalo-hippocampectomy in man, in preparation. 41. Parkinson, J. K., Murray, E. A. and Mishkin, M. A selective mnemonic role for the hippocampus in monkeys: memory for the location of objects. J. Neurosci. 8, 4159-4167, 1988. 42. Passingham, R. E. Memory of monkeys (Macaca mulatta) with lesions in prefrontal cortex. Behav. Neurosci. 99, 3-21, 1985. 43. Petrides, M. Deficits on conditional associativelearning tasks after frontal- and temporal-lobe lesions in man. Neuropsychologia 23, 601-614, 1985. 44. Petrides, M., Alivisatos, E., Evans, A. C. and Meyers, E. Dissociation of human mid-dorsolateral from posterior dorsolateral frontal cortex in

45. 46.

47. 48.

49. 50.

51. 52. 53. 54. 55.

56. 57. 58.

memory processing. Proceedings of the National Academy of Science 90, 873-877, 1993. Petrides, M. and Milner, B. Deficits in subjectordered tasks after frontal and temporal-lobe lesions in man. Neuropsychologia 20, 249-262, 1982. Pigott, S. and Milner, B. Memory for different aspects of complex visual scenes after unilateral temporal- or frontal-lobe resection. Neuropsychologia 31, 1-15, 1993. Polkey, C. E. Surgery for epilepsy. Arch. Dis. Childhood 64, 185-187, 1989. Rolls, E. T., Cahusac, P. M. B., Feigenbaum, J. D. and Miyashita, Y. Responses of single neurons in the hippocampus of the macaque related to recognition memory. Exp. Brain Res. 93, 299-306, 1993. Smith, M. L. and Milner, B. The role of the right hippocampus in the recall of spatial location. Neuropsychologia 19, 781-793, 1981. Smith, M. L. and Milner, B. Right hippocampal impairment in the recall of spatial location: Encoding deficit or rapid forgetting? Neuropsychologia 27, 71-81, 1989. SPSS/PC + 4.0 Manual. SPSS Inc, Illinois, U.S.A. Stein, J. F. Representation of egocentric space in posterior parietal cortex. Quart. J. Exp. Physiol. 74, 583-606, 1989. Squire, L. R. Mechanisms of memory. Science 232, 1612-1619, 1986. Squire, L. R. Memory and the Brain. Oxford University Press, New York, 1987. Tamura, R., Ono, T., Fukuda, M. and Nakamura, K. Spatial responsiveness of monkey hippocampal neurons to various visual and auditory stimuli. Hippocampus 2, 307-322, 1992. Watanabe, T. and Niki, H. Hippocampal unit activity and delayed response in the monkey. Brain Research 325, 241-254, 1985. Zola-Morgan, S. In Neuropsychology of Memory, L. R. Squire and N. Butters (Editors), pp. 316-329. Guildford Press, London, 1988. Zola-Morgan, S. and Squire, L. Mesial temporal lesions in monkeys impair memory on a variety of tasks sensitive to human amnesia. Behav. Neurosci. 99, 22-34, 1985.