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Virtual human analogs to rodent spatial pattern separation and completion memory tasks
Learning and Motivation 42 (2011) 237–244
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Learning and Motivation journal homepage: www.elsevier.com/locate/l&m
Virtual human analogs to rodent spatial pattern separation and completion memory tasks Meera Paleja a,∗ , Todd A. Girard a , Bruce K. Christensen b a b
Ryerson University, Canada McMaster University, Canada
a r t i c l e
i n f o
Article history: Received 3 February 2011 Received in revised form 27 May 2011 Available online 3 July 2011 Keywords: Pattern separation Pattern completion Memory Navigation
a b s t r a c t Spatial pattern separation (SPS) and spatial pattern completion (SPC) have played an increasingly important role in computational and rodent literatures as processes underlying associative memory. SPS and SPC are complementary processes, allowing the formation of unique representations and the reconstruction of complete spatial environments based on partial spatial information. We present two novel computerized navigational tasks as human analogs of well-established rat SPS and SPC tasks. Results from these tasks show that human participants are sensitive to increasing SPS and SPC demands. Specifically, memory accuracy decreased with decreasing separation distance between target and foil locations in the SPS task and with decreasing number of distal spatial cues in the SPC task. These tasks set the stage for valuable future directions, including the use of these tasks with imaging and clinical populations. © 2011 Elsevier Inc. All rights reserved.
Rat studies have played a critical role in elucidating the nature of spatial-memory processes mediated by the hippocampus. However, the ability to draw meaningful inferences across rat and human memory studies has been hampered by the use of largely different paradigms. In recent years, efforts to address this limitation have spawned interest in the development of human memory tasks that more closely parallel those used with rats. One major advantage of using human analogs of rat tasks is that they enable us to better bridge human research with the well-established, well-controlled, and often finer-grained studies conducted with rodents. Moreover, the use of analogous tasks with humans and rats assists in setting a common platform for translational research between animal models and human clinical conditions with memory impairment (Steckler & Muir, 1996). A number of computerized analogs of rat spatial-memory tasks have been developed for use with humans in recent years (e.g., Canovas, Espinola, Iribarne, & Cimadevilla, 2008; Hanlon et al., 2006; Laurance et al., 2002; Livingstone & Skelton, 2007; Shipman & Astur, 2008; Shore, Stanford, MacInnes, Klein, & Brown, 2001). These tasks involve three-dimensional computerized virtual environments through which participants navigate, typically using a joystick or keyboard. Moreover, these tasks are amenable to functional brain imaging and have provided evidence for convergence across species in revealing involvement of the hippocampus in spatial navigation and memory (Astur et al., 2005; Shipman & Astur, 2008). These tasks have also proven informative in verifying spatial-memory deficits in clinical populations associated with hippocampal dysfunction, including traumatic brain injury (Livingstone & Skelton, 2007; Skelton, Ross, Nerad, & Livingstone, 2006) and schizophrenia (Hanlon et al., 2006). Here, we extend the analog-task approach to design human tasks sensitive to specific subprocesses of spatial memory. This direction is motivated by recent theoretical and empirical work indicating that spatial memory is mediated by subprocesses that differentially involve unique subregions of the hippocampus, including the dentate gyrus (DG) and cornu ammonis
∗ Corresponding author at: Ryerson University, Department of Psychology, 350 Victoria St., Toronto, ON M5B2K3, Canada. E-mail address: [email protected] (M. Paleja). 0023-9690/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.lmot.2011.05.003
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(CA) fields. It is important to note that there is conceptual overlap among these memory subprocesses. Although they are both related to associative memory, pattern separation is the ability to parse and represent places and times as individual components, whereas pattern completion is the ability to not only recognize a well-learned association but complete sparser representations with appropriate information. These processes are critical to forming coherent episodic memories. Pattern separation is the process of forming or transforming similar memories into different non-overlapping representations (Bakker, Kirwan, Miller, & Stark, 2008). In other words, pattern separation involves the orthogonalization of both objects and events in the environment spatially and temporally. This ability to initially create a fine-grained representation that allows one to later separate it from other similar input is a critical component of the pattern separation process. Spatial pattern separation (SPS) is important for remembering where something happened. For instance, if one is engaging SPS abilities, one should be able to distinguish a target object that is in close spatial proximity to a foil. Finer-grained representations (i.e., more engagement of SPS processes at encoding) would be required to later distinguish the target and foil at closer separations. In the real world, SPS abilities might for example allow us to form a fine-grained spatial representation of where we parked our car so we are later be able to distinguish that spatial location from other nearby spatial locations. In order to support contextual processing, and thus episodic memory, it is necessary to separate stimuli in the spatial environment, allowing us to form unique representations of the places where events occur. A common method for assessing SPS in rats is the delayed-matching-to-place paradigm. Using this task, Gilbert, Kesner, and Lee (2001) trained rats to displace an object covering a food well that was baited. At test, the rats were to choose between two identical objects, one of which covered the same well as the sample object (target; correct) or a second that covered a different unbaited well (foil; incorrect). Interestingly, lesions to the dorsal DG resulted in disproportionate deficits compared to rats with sham and CA1 lesions with decreasing target-foil distance (i.e., with increasing demands for SPS). In humans, Hopkins and Kesner (1993) compared SPS in healthy controls and patients who had suffered hippocampal atrophy due to hypoxia. Participants were asked to remember the location of cities on a map and subsequently to recall which of two cities was further East. Hypoxic patients were less accurate regardless of separation distance. Hartman (2002) created a twodimensional computerized version of the delayed-matching-to-place task in which participants were required to remember the locations of dots on the monitor screen. Patients with hypoxia performed more poorly at closer separation distances. Most recently, Stark, Yassa, and Stark (2010) asked participants to determine whether pairs of pictures were displayed in identical locations to those shown during study. Notably, participants demonstrated increased accuracy as the distances between the pictures increased. In the current study we present a virtual three-dimensional delayed-matching-to-place task that more closely resembles that used with rats. In contrast to SPS, spatial pattern completion (SPC) allows us to recall or generate well-established knowledge regarding the locations of objects and events based on partial or incomplete spatial information. This mechanism might work through an auto-associative network that retrieves patterns of activity, or memories, based on partial or degraded information or cues (Kesner & Hopkins, 2006; Rolls, 1997). In this vein, SPC involves the “completion” of partial or degraded information to form a coherent memory. If one is engaging their SPC abilities, one would be able to remember the location of a target that was previously presented even when there are cues in the environment that are missing. SPC might allow us to locate where we parked our car when the cars surrounding it have gone and we can no longer use them as cues to locate our car. In this situation, we may use cues such as other cars, or landmarks such as lamp posts, trees, or the road to locate our car. In this case, the subset of available cues leads to the retrieval of a complete memory of where the car is located. SPC is different from rigid stimulus-response or conditioned memories that are highly dependent on consistency. SPC being a hippocampal-dependent process, allows for flexibility in memory representations or their usage. For instance, if we parked our car during the daytime when the sun was shining, we would also be able to locate it at night. Accordingly, tasks used to assess SPC in rats generally require them to re-locate a target location, but in the face of some distal cues having been removed from the environment. For example, Gold and Kesner (2005) tested this ability in rats also using a delayed matching-to-place paradigm. Similar to the SPS task, the sample phase cued rats to approach and remove a block that covered a food well. However, at test, rats were to find the same well, but with the proximal block removed and thus, needed to relocate it using four distal, extramaze cues provided in the room. After they reached stable performance on this SPC task, rats were retested, but with zero, one, two, three, or all four extramaze cues missing. In order to find the correct well efficiently, rats presumably had to mentally “fill in” or complete the arrangement of extramaze cues. Rats with postacquisition CA3 or DG lesions, but not sham or CA1 lesions, were impaired on this SPC task. Similarly, Nakazawa et al. (2002) found that mice with N-methyl-d-asparate (NMDA) receptor gene ablated in the CA3 subregion performed equivalently to controls on the Morris water maze task when all extramaze cues were present, but were severely impaired on the task when three out of four extramaze cues were removed. Notably, tasks assessing SPC in rodents have manipulated cue availability in the environment and indicate a core role for the CA3 region. In contrast, evidence from primate view cells in the presence of obscured or removed visual stimuli suggests preferential firing of CA1 cells in pattern completion (Kesner & Hopkins, 2006; Rolls, 1999). Again, further study using comparable paradigms is needed to better form cross-species comparisons. Here we present a human analog of the rat delayed-matching-to-place SPC task. It should be noted that although the constructs of SPS and SPC appear similar to those of generalization and discrimination in the classical and operant conditioning literature (Mackintosh, 1974), there are some key differences. For example, SPC can be thought of as having a generalization component. Similar to performance decrements with decreasing perceptual similarity along a stimulus-generalization gradient, the ability to find the target location on an SPC task decreases as the perceptual difference of a well-learned environment at test decreases from the study environment. However, the processes
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SPS and SPC differ from discrimination and generalization, since the latter two traditionally refer to trained responses to conditioned stimuli. In contrast, the SPS and SPC tasks assess more flexible one-trial learning in a delayed matching-to-place paradigm. In sum, while tasks assessing pattern separation and completion in humans have been developed, none is an analog to the spatial rat tasks. The original rodent tasks allow us to formulate hypotheses about human processes. However, current task differences limit our ability to draw comparisons between these processes in rodents and in humans. Using similar paradigms may allow us to more closely interrogate in humans these associative memory processes that have been wellstudied in rodents. At a later stage, these tasks might be useful for elucidating the unique nature of episodic memory deficits in psychological disorders associated with subfield-specific pathology, such as Alzheimer’s disease and schizophrenia. The objective of this study was to develop human analogs of the well-established rat delayed-matching-to-place SPS and SPC tasks in a computerized virtual maze environment requiring navigation and the use of allocentric information. Towards this goal, there were two primary hypotheses driving task development: 1. Participants should demonstrate lower performance at closer target-foil separations versus further target-foil separations on a SPS task. 2. Participants should demonstrate lower performance when fewer extramaze cues are available versus when a greater number of extramaze cues are available on an SPC task. Material and methods Participants Young adults were recruited from the Ryerson University Psychology Participant Research Pool and on-campus advertisement. Exclusion criteria included lack of fluency in English, impaired vision, having a self-reported psychological disorder, or being on medication that could affect performance. The final sample comprised 31 participants (22 females), with a mean age of 22.87 years (SD = 4.54). Data from one participant on the training phase were lost due to technical reasons, but all data are presented for the SPS and SPC tasks. General experimental paradigm and procedure All tasks were performed in a circular computer-generated (CG) arena with brick walls (http://web.arizona.edu/∼arg/data.html; Jacobs, Laurance, & Thomas, 1997). Distances in the virtual environment were scaled such that 10 arena units, or the length of one virtual stride, can be taken as representative of about one meter. The arena floor was gray with a diameter of 92 units and was enclosed by a circular brick wall that was 8 units high. The arena was centered in a room 500 × 500 units squared in area with purple-colored walls 100 units high and a gray ceiling. To allow for the allocentric spatial processing required of these tasks, the external walls were each identified by an extramaze cue, a unique fractal pattern of similar coloring. These stimuli were selected in line with Steckler and Muir’s (1995) suggestion to design tasks with abstract stimuli that cannot be easily verbalized to aid comparisons of human with non-human tasks. The tasks were always administered in the following order: training on the associative memory paradigm, followed by the SPS task and then the SPC task. The associative memory task was a baseline task to ensure participants became familiar with the virtual environment and with navigation through the arena. The SPC task was administered last to ensure that the participants were first well-familiarized with the virtual environment, as this is important for pattern completion (Kesner & Hopkins, 2006). Participants were randomly assigned to receive one of three random sequences for the ordering of trials for each task to minimize the likelihood that the results were due to any particular sequence of target (and foil) locations (as described below). Of primary importance was the assessment of the sensitivity of performance to difficulty manipulations thought to place increasing demands on the subprocesses of interest. More specifically, target-foil distance and the availability of cues were manipulated to assess SPS and SPC, respectively. In this vein, the tasks presented below follow a number of preliminary pilot phases aimed at reducing floor and ceiling effects. For example, in a previous version of the SPS task that we had piloted, there was a single foil in addition to the target during the choice phase. Performance on this task was at ceiling and thus we found it necessary to increase the number of foils to three in order to increase difficulty. Associative memory training phase During the sample phase of each trial, a 5-by-5 unit green square was presented in one of 20 pre-determined spatial locations in the arena. Participants were required to use keyboard arrow keys to navigate to and situate themselves on the green square (Fig. 1A). Once they reached it, they were required to press the space bar to take them into a 5-s delay in an empty arena, followed by the choice phase. During the choice phase, participants were placed in the center of the arena in a random start orientation and required to navigate to the spatial location that had been marked in the sample phase, this time in the absence of a visible target (Fig. 1B). Thus, the participants were required to use extramaze cues as well as other
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Fig. 1. Screen shots of the associative memory training phase (A and B), SPS (C and D), and SPC (E and F) tasks. (A) In the sample phase of the training phase, participants navigated to a green square on the floor of the arena. (B) At choice, they were required to navigate to the same location in the absence of a target square. (C) In the sample phase of SPS, participants navigated to a green square on the floor of the arena. (D) During choice, they were asked to go to the target in the same location as the one presented during the study phase. (E) The sample and (F) choice phases for SPC were identical to the training phase, except the number of wall cues missing was manipulated in the choice phase of SPC. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
cues in the environment as a guide. Consistent with similar rat paradigms (e.g., Girard, Xing, Ward, Nguyen, & Wainwright, 2001), participants were allowed a maximum of 45 s to relocate the goal location. Twenty-one trials of study-choice pairs were completed. The CG-Arena program recorded both latency and whether the target was found for all trials.
Spatial pattern separation (SPS) task The SPS task was modeled after the rat delayed matching-to-place task used by Gilbert et al. (2001). On study trials, participants started in the center of the arena facing North and were again presented with a green square located in one of 20 pre-determined spatial locations on the floor of the CG Arena. Using the arrow keys on a keyboard, they navigated to the green square (Fig. 1C). Once the participants were situated on this target, they pressed the space bar to take them into the next phase following a 5-s delay. In the choice phase, participants started at a random orientation and were required to choose between four green circles arranged in a square formation (Fig. 1D). One of these circles was placed in the study location (target, correct choice). The others were placed to complete three remaining corners of the arrangement (foils, incorrect choices). Participants were required to discriminate the correct allocentric location of the target based on its spatial relation to extramaze cues. To make a selection, they navigated to one using the arrow keys, situated themselves on it and then pressed the space bar. The trial ended after a choice was made. If no choice was made within 45 s, the trial ended and the next study trial began. Across trials, one of three possible separation distances was presented in a pseudorandom order: 2, 4, or 6 units between the center of the target and the center of the adjacent foils, corresponding to 2.83 (close), 5.66 (medium), or 8.49 (far) area units between the target and the furthest foil. Twenty-one study-test pairs were presented overall (seven per separation condition), across which the relative position of the foils to the target were counterbalanced (i.e., equal representation of N, E, S, W sides).
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Fig. 2. Proportion of targets found on the SPS task as a function of target-foil distance. Participants performed worse at the closest separation (separation 1) than at both the medium separation (separation 2) and the furthest separation (separation 3).
Spatial pattern completion (SPC) task This version of the delayed matching-to-place task was modeled after the rat task used by Gold and Kesner (2005). The sample phase was identical to that in the associative memory training and SPS tasks. That is, participants started from a designated starting position in the center of the arena facing North and traveled to the green square placed on the floor of the arena (Fig. 1E). After a 5-s delay, participants were started facing a random orientation and required to use their allocentric spatial memory to relocate the target location (green square absent). They were allowed to explore the maze until they reached the correct location or a maximum of 45 s had elapsed (Fig. 1F). The only difference between this task and the associative training task was that the number of pictures on the walls (four, two, or zero) available was manipulated. These three possible cue conditions were repeated seven times each in a pseudorandom presentation sequence across 21 study-test trial pairs. Results Associative memory training phase An ANOVA with Trial Block as the independent variable and the proportion of targets relocated as the dependent variable demonstrated that across 3 blocks of 7 trials performance increased as trials progressed, F (2, 58) = 5.352, p = .007, MSE = .037, partial 2 = .156. Follow-up paired t-tests revealed a greater proportion of targets found in Block 2 (M = 0.63, SD = 0.01) versus Block 1 (M = 0.51, SD = 0.01), t(29) = 2.98, p = .006, d = 0.54, but no further improvement in Block 3 (M = 0.01) compared to Block 2, t(29) = 0.51, p = .612, d = 0.09. A complementary ANOVA also revealed significant differences in latency as a function of Trial Block, F (2, 56) = 5.82, p = .005, MSE = 38.67, partial 2 = .22. Participants were able to locate the hidden targets more quickly during Block 2 (M = 22.99 s, SD = 0.38) versus 1 (M = 29.28 s, SD = 0.33), t(29) = 4.02, p < .001, d = 0.73, but performance leveled off at Blocks 2 and 3 (M = 24.20 s, SD = 0.38), t(29) = −0.76, p = .451, d = −0.14. It is noteworthy that the latency data are under-estimates given that incorrect trials were coded as 45 s, the time at which the trial timed out. Due to this dependence of latency on the proportion-found data, we ran an additional analysis looking at latency differences between blocks only for trials on which the goal was found within the time limit. This ANOVA revealed no significant differences in latency across blocks, F(2, 58) = .395, p = .675, MSE = 21869.55, partial 2 = .01, indicating that the above latency differences between blocks were tied to the ability to locate the platform within 45 s. SPS A repeated-measures ANOVA on the proportion of correct trials revealed a significant effect of Foil Distance, F(2, 60) = 4.48, p = .015, MSE = 0.04, partial 2 = .13. Follow-up paired-samples t-tests revealed a lower proportion found for the closest compared to the medium, t(30) = −2.68, p = .012, d = −0.48, and far separation distances, t(30) = −2.53, p = .017, d = −0.45 (Fig. 2). There was, however, no difference in proportion found between the two greater separation distances, t(30) = 0.70, p = .349, d = 0.13. There were no significant differences in latency between the close (M = 15.89 s, SD = 6.61), medium (M = 14.73 s, SD = 6.75) and far (M = 15.42 s, SD = 7.30), separation conditions (ps > .05). This result was expected given that the target and foil were visible at all times; that is, participants had no difficulty finding the cued locations. SPC A repeated-measures ANOVA was conducted with Cue Condition as the independent variable and proportion of targets found as the dependent variable. Cue Condition was highly significant, F(2, 60) = 12.021, p < .001, MSE = .034, partial 2 = .286. In particular, performance declined relative to zero cues missing (M = 0.677, SD = 0.01) when two cues (M = 0.548, SD = 0.34),
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Fig. 3. Proportion of targets found on the SPC task as a function of number of wall cues missing (0, 2, or 4). Four cues missing corresponds to the absence of wall cues. Participants found more targets at the 0-cue missing condition compared to the 2-cue missing condition and 4-cue missing condition. The difference between proportion found in the 2-cue missing condition and 4-cue missing condition just failed to reach significance.
t(30) = 2.98, p = .006, d = 0.54 or four cues (M = 0.448, SD = 0.01) were missing, t(30) = 5.50, p < .001, d = 0.99. The difference between two and four cues missing conditions just failed to reach statistical significance although it was of medium effect size, t(30) = 0.10, p = .078, d = 0.33 (Fig. 3). A repeated-measures ANOVA with latency as the dependent variable was also significant, F(2, 60) = 23.140, p < .001, MSE = 38.396, partial 2 = .435. Participants relocated the target location faster with zero cues missing (M = 22.20 s, SD = 0.31) versus two cues missing (M = 26.60 s, SD = 0.34), t(30) = −4.40, p = .004, d = −0.56, which in turn was faster than when all four cues were missing (M = 32.86 s, SD = 0.22), t(30) = −3.54, p = .001, d = −0.64. Similarly to the associative memory baseline, we ran an additional repeated-measures ANOVA to assess whether differences in latency across cue conditions were also apparent when only correct trials were taken into account. There was a significant latency difference between cue conditions even when only correct trials were entered into the analysis, F(2, 54) = 8.89, p < .001, MSE = 36.67, partial 2 = 0.25. A follow-up paired-samples t test revealed significant latency differences between 0 cues missing (M = 11.75, SD = 0.14) and 4 cues missing (M = 17.87, SD = 0.28), t(29) = −3.646, p = .001, d = −.67 as well as between 2 cues missing (M = 12.59, SD = 0.20) and 4 cues missing, t(27) = −3.262, p = .003, d = −.62. However, there was no longer a difference in latency between 0 cues missing and 2 cues missing, t(27) = −.836, p = .411, d = −.16. Task inter-correlations SPS proportion found was positively correlated with SPC proportion found, r = .54, p = .002. Although these tasks are strongly correlated, sharing 29% explanatory variance, they are far from perfectly correlated, providing some divergent validity. Baseline task proportion found was also positively correlated with both SPS (r = .48, p = .008) and SPC (r = .81, p < .001). The stronger relation between the baseline task and SPC was expected since they are both very similar tasks; in fact, SPC with no cues missing is identical to the training task. A partial correlation analysis was conducted to assess the shared variance between SPS and SPC, controlling for baseline training. Albeit of medium effect size, the correlation between SPS and SPC was no longer significant when baseline training was controlled, rfound = .30, p = .116. Thus, after removing their shared variance with the basic task, SPS and SPC shared only 9% of explanatory variance, providing evidence for their divergent validity. In other words, their convergence is largely accounted for by what they share with the training phase in terms of task demands and general spatial abilities. Discussion In this study, two novel virtual-maze tasks were designed that were analogous to rat tasks and used to evaluate SPS and SPC in humans. Use of a three-dimensional virtual arena provided a similar environment to that used in rat tasks in which participants navigated to study and target locations. Further, it enabled us to closely parallel the difficulty manipulations used in rat delayed-matching-to-place tasks. Performance (proportion found) in the baseline associative memory phase, SPS, and SPC were all positively correlated supporting that these tasks rely on common spatial memory demands. Nonetheless, the imperfect correlation between SPS and SPC also supports divergent validity of these subprocesses. Importantly, performance profiles showed sensitivity to the separation and completion task manipulations. More specifically, participants demonstrated an improved ability to successfully discriminate the SPS task target location with increasing separation distance from foils. Furthermore, participants’ performance was dependent on the number of extramaze cues in the SPC task, supporting their reliance on these allocentric cues. These findings and their implications are discussed in more detail below, as well as possible future directions incorporating these tasks. Associative memory training phase Results were consistent with expectations for the training phase. Although the spatial location to be remembered differed on each trial, participants became faster and more able to locate the hidden target location as training progressed. This improvement likely reflects the participants’ increasing familiarity with the virtual room, including the wall cues that help
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the participants gauge their location relative to the target, as well as improvements in strategy. The former component is critical for the later SPC task, and the ordering of the tasks with SPC always completed last was to ensure the environment was well-learned. The lack of improvement between Trial Blocks 2 and 3 suggests that participants had reached a stable level of performance by trial 15. Therefore, the 21 trials of training were sufficient to produce gains in performance and to establish understanding of performance demands and the maze environment. SPS A major advantage of our paradigm compared to other pattern-separation tasks that have emerged in recent years is its demonstrated sensitivity to separation manipulations in an immersive virtual environment. At the closest target-foil distances, a “heavier” reliance on the pattern-separation process is thought to be required to successfully discriminate between the spatial locations. Presumably, the lower proportion of correct discriminations observed at the closest separation is reflective of this increased demand for SPS. While other studies have used tasks assessing pattern separation in humans (e.g., Bakker et al., 2008; Hartman, 2002; Hopkins & Kesner, 1993; Stark et al., 2010), our task includes demonstrated performance differences between spatial separations in healthy individuals as well as the presentation of analogous environmental and navigational features to the primary rodent SPS delayed-matching-to-place task (Gilbert et al., 2001). SPC Our choice of the delayed-matching paradigm was also driven primarily by our goals of developing a human analog to the rat SPC task used by Kesner and colleagues (i.e., Gold & Kesner, 2005) and of maintaining consistency in overall paradigm design to the SPS task. Our task yielded significant differences in both the proportion of targets found and latency based on cue availability. These results indicate that performance on this task was reliant on the number of cues in the environment for forming allocentric spatial memories (Gold & Kesner, 2005; Morris, 1984). Moreover, this sensitivity to cue availability reflects increased demands on pattern completion processes (Gold & Kesner, 2005; Kesner & Hopkins, 2006). Limitations and future directions Here we present novel human analogs of rat SPS and SPC tasks. Although task parameters were adequately developed, there are some domains deserving of further assessment and task development. First, generalizability of the findings must be interpreted in light of about two-thirds of our sample being female. We did not aim to assess sex differences in spatial navigation and thus, recruitment was open in this regard. Nonetheless, given the literature on differential spatial navigation strategies and overall performance on spatial memory tasks in males and females (Canovas et al., 2008; Ross, Skelton, & Mueller, 2006), we subsequently included sex as a factor in post hoc analyses (data not shown). A male advantage was observed during the initial training phase consistent with the literature, but importantly, this sex difference was not apparent in the SPS and SPC tasks. Second, the verbal instructions given to our human participants may have posed different cognitive demands than the learning that takes place in rats, which must learn the procedural task demands through trial and error. Arguably the processes required to perform a task when given verbal instructions may differ from learning task demands without these explicit instructions. A future study employing a learning paradigm that minimizes verbal instructions would address this limitation. Nonetheless, the current behavioral data support the contention that our tasks are analogous to the rat tasks after which they were modeled. Third, a possible confound may relate to the different retrieval demands of the SPS and SPC tasks. SPS may rely more on recognition of the correct item from four possible options. SPC may rely more on recall, in the sense that there is no discrete set of forced-choice options like there is for SPS; rather participants have to recall the precise location of the target within the entire arena. Nonetheless, our decision to maintain these task differences was in line with the main objective for this initial stage of task development to keep the tasks as analogous as possible to the rodent delayed-matching to place paradigms. It will be of theoretical interest to assess the extent to which different retrieval processes contribute to performance on these tasks and their functional relations to hippocampal subregions. Indeed, additional future directions of research include the use of functional magnetic resonance imaging to assess whether the spatial-pattern tasks involve similar hippocampal subfields in humans as established with findings from animal models (as reviewed by Kesner & Hopkins, 2006). Although largely similar, there are anatomical differences between the hippocampi of rodents and humans that warrant comparative consideration. Specifically the hippocampi of humans are smaller in relative size. That is, whereas the human neocortex occupies much more territory, the rodent hippocampi are much more prominent anatomically in the rodent brain (O’Keefe & Nadel, 1978). Additionally, the CA2 region subfield observed in humans is not identified in rat hippocampi. Emergence of hemispheric specialization of hippocampal function has also been noted in humans, where allocentric spatial memory particularly involves the right side (e.g., Iglói, Doeller, Berthoz, Rondi-Reig, & Burgess, 2010). Nonetheless, in both rodents and humans, the hippocampus as a whole supports the complex formation of arbitrary associations, involving the binding of associations among objects and/or events with places, as well as among places (i.e., as required to construct a “cognitive map”; O’Keefe & Nadel, 1978). However, rat studies and computational models suggest that different subprocesses of spatial memory are preferentially dependent on different hippocampal subfields. Namely, the CA and DG cell fields are thought to play different roles in the subprocesses of pattern separation and pattern completion that underlie associative memory (Bakker et al., 2008; Carr, Rissman, & Wagner, 2010;
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Kesner & Hopkins, 2006; Rolls, 1996). Testing for similar neural involvement in rats and humans will prove informative and might support evolutionary continuity in hippocampal cognitive function in humans and rats (Kesner & Hopkins, 2006). Moreover, functional dissociations between SPS and SPC, as they relate to hippocampal pathology at the subregion level, are of clinical relevance. That is, certain clinical disorders such as schizophrenia, Alzheimer’s disease, and hypoxia, show most damage to particular hippocampal subfields with relative sparing of other subfields (Benes, 1999; Harrison, 2004; Hartman, 2002; Mueller et al., 2007). Research demonstrating disparate hippocampal pathology in different disorders suggests that the pattern of memory deficits between disorders may also be unique. Thus, testing for similar neural involvement in rats and humans will prove informative and might support functional differences in subregion-specific hippocampally mediated spatial memory subprocesses and set the stage for valuable future translational research directions aimed at improved detection and intervention more specific to clinical conditions. Acknowledgments We thank Adina-Ioana Berindean-Coroiu and Vanessa Amodio for their assistance in data collection. These data contributed in part to the completion of an MA thesis by MP, Department of Psychology, Ryerson University. Portions of this research were also presented at the 2010 Society for Neuroscience annual meeting in San Diego, CA. This research was supported by a New Faculty SRC Development Fund award (Office of Research Services, Ryerson University) to TAG and MP is supported by a CIHR Canada Graduate Scholarship. References Astur, R. S., St. Germain, S. A., Baker, E. K., Calhoun, V., Pearlson, G. D., & Constable, R. T. 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Exposure to ethanol and nicotine during the brain growth spurt: Spatial DMP performance in male rats. Pharmacology Biochemistry and Behavior, 68, 515–523. Gold, A. E., & Kesner, R. P. (2005). The role of the CA3 subregion of the dorsal hippocampus in spatial pattern completion in the rat. Hippocampus, 15, 808–814. Hanlon, F. M., Weisend, M. P., Hamilton, D. A., Jones, A. P., Thoma, R. J., Huang, M., et al. (2006). Impairment on the hippocampal-dependent virtual Morris water maze task in schizophrenia. Schizophrenia Research, 87, 67–80. Harrison, P. J. (2004). The hippocampus in schizophrenia: A review of the neuropathological evidence and its pathophysiological implications. Psychopharmacology, 174, 151–162. Hartman, T. H. (2002). Spatial pattern separation in the human hippocampus. Retrieved from ProQuest Dissertations and Theses. (3064850). Hopkins, R. O., & Kesner, R. P. (1993). Memory for temporal and spatial distances for new and previously learned geographical information in hypoxic subjects. Society for Neuroscience Abstracts, 19, 1284. Washington, DC Iglói, K., Doeller, C. F., Berthoz, A., Rondi-Reig, L., & Burgess, N. (2010). Lateralized human hippocampal activity predicts navigation based on sequence or place memory. Proceedings of the National Academy of Sciences of the United States of America, 107, 14466–14471. Jacobs, W. J., Laurance, H. E., & Thomas, K. G. F. (1997). Place learning in virtual space. I. Acquisition, overshadowing, and transfer. Learning and Motivation, 28, 521–541. Kesner, R. P., & Hopkins, R. O. (2006). Mnemonic functions of the hippocampus: A comparison between animals and humans. Biological Psychology, 73, 3–18. Laurance, H. E., Thomas, K. G. F., Newman, M. C., Kaszniak, A. W., Nadel, L., & Jacobs, W. J. (2002). Older adults map novel environments but do not place learn: Findings from a computerized spatial task. Aging, Neuropsychology, and Cognition, 9, 85–97. Livingstone, S. A., & Skelton, R. W. (2007). Virtual environment navigation tasks and the assessment of cognitive deficits in individuals with brain injury. Behavioral Brain Research, 183, 21–31. Mackintosh, N. J. (1974). The Psychology of Animal Learning. London: Academic Press. Morris, R. (1984). Developments of a water-maze procedure for studying spatial learning in the rat. Journal of Neuroscience Methods, 11, 47–60. Mueller, S. G., Stables, L., Du, A. T., Schuff, N., Truran, D., Cashdollar, N., et al. (2007). Measurement of hippocampal subfields and age-related changes with high resolution MRI at 4 T. Neurobiology of Aging, 28, 719–726. Nakazawa, K., Quirk, M. C., Chitwood, R. A., Watanabe, M., Yeckel, M. F., Sun, L. D., et al. (2002). Requirement for hippocampal CA3 NMDA receptors in associative memory recall. Science, 297, 211–218. O’Keefe, J., & Nadel, L. (1978). The hippocampus as a cognitive map. New York: Oxford University Press. Rolls, E. T. (1996). A theory of hippocampal function in memory. Hippocampus, 6, 601–620. Rolls, E. T. (1997). An attractor network in the hippocampus: Theory and neurophysiology. Learning and Memory, 14, 714–731. Rolls, E. T. (1999). Spatial view cells and the representation of place in the primate hippocampus. Hippocampus, 9, 467–480. Ross, S. P., Skelton, R. W., & Mueller, S. C. (2006). Gender differences in spatial navigation in virtual space: Implications when using virtual environments in instruction and assessment. Virtual Reality, 10, 175–184. Shipman, S. L., & Astur, R. S. (2008). Factors affecting the hippocampal BOLD response during spatial memory. Behavioral Brain Research, 187, 433–441. Shore, D. I., Stanford, L., MacInnes, W. J., Klein, R. M., & Brown, R. E. (2001). Of mice and men: Virtual Hebb–Williams mazes permit comparison of spatial learning across species. Cognitive, Affective, and Behavioral Neuroscience, 1, 83–89. Skelton, R. W., Ross, S. P., Nerad, L., & Livingstone, S. A. (2006). Human spatial navigation deficits after traumatic brain injury shown in the arena maze, a virtual Morris water maze. Brain Injury, 20, 189–203. Stark, S. M., Yassa, M. A., & Stark, C. E. L. (2010). Individual differences in spatial pattern separation performance associated with healthy aging in humans. Learning and Memory, 17, 284–288. Steckler, T., & Muir, J. L. (1996). Measurement of cognitive function: Relating rodent performance with human minds. Cognitive Brain Research, 3, 299–308.
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Learning and Motivation journal homepage: www.elsevier.com/locate/l&m
Virtual human analogs to rodent spatial pattern separation and completion memory tasks Meera Paleja a,∗ , Todd A. Girard a , Bruce K. Christensen b a b
Ryerson University, Canada McMaster University, Canada
a r t i c l e
i n f o
Article history: Received 3 February 2011 Received in revised form 27 May 2011 Available online 3 July 2011 Keywords: Pattern separation Pattern completion Memory Navigation
a b s t r a c t Spatial pattern separation (SPS) and spatial pattern completion (SPC) have played an increasingly important role in computational and rodent literatures as processes underlying associative memory. SPS and SPC are complementary processes, allowing the formation of unique representations and the reconstruction of complete spatial environments based on partial spatial information. We present two novel computerized navigational tasks as human analogs of well-established rat SPS and SPC tasks. Results from these tasks show that human participants are sensitive to increasing SPS and SPC demands. Specifically, memory accuracy decreased with decreasing separation distance between target and foil locations in the SPS task and with decreasing number of distal spatial cues in the SPC task. These tasks set the stage for valuable future directions, including the use of these tasks with imaging and clinical populations. © 2011 Elsevier Inc. All rights reserved.
Rat studies have played a critical role in elucidating the nature of spatial-memory processes mediated by the hippocampus. However, the ability to draw meaningful inferences across rat and human memory studies has been hampered by the use of largely different paradigms. In recent years, efforts to address this limitation have spawned interest in the development of human memory tasks that more closely parallel those used with rats. One major advantage of using human analogs of rat tasks is that they enable us to better bridge human research with the well-established, well-controlled, and often finer-grained studies conducted with rodents. Moreover, the use of analogous tasks with humans and rats assists in setting a common platform for translational research between animal models and human clinical conditions with memory impairment (Steckler & Muir, 1996). A number of computerized analogs of rat spatial-memory tasks have been developed for use with humans in recent years (e.g., Canovas, Espinola, Iribarne, & Cimadevilla, 2008; Hanlon et al., 2006; Laurance et al., 2002; Livingstone & Skelton, 2007; Shipman & Astur, 2008; Shore, Stanford, MacInnes, Klein, & Brown, 2001). These tasks involve three-dimensional computerized virtual environments through which participants navigate, typically using a joystick or keyboard. Moreover, these tasks are amenable to functional brain imaging and have provided evidence for convergence across species in revealing involvement of the hippocampus in spatial navigation and memory (Astur et al., 2005; Shipman & Astur, 2008). These tasks have also proven informative in verifying spatial-memory deficits in clinical populations associated with hippocampal dysfunction, including traumatic brain injury (Livingstone & Skelton, 2007; Skelton, Ross, Nerad, & Livingstone, 2006) and schizophrenia (Hanlon et al., 2006). Here, we extend the analog-task approach to design human tasks sensitive to specific subprocesses of spatial memory. This direction is motivated by recent theoretical and empirical work indicating that spatial memory is mediated by subprocesses that differentially involve unique subregions of the hippocampus, including the dentate gyrus (DG) and cornu ammonis
∗ Corresponding author at: Ryerson University, Department of Psychology, 350 Victoria St., Toronto, ON M5B2K3, Canada. E-mail address: [email protected] (M. Paleja). 0023-9690/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.lmot.2011.05.003
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(CA) fields. It is important to note that there is conceptual overlap among these memory subprocesses. Although they are both related to associative memory, pattern separation is the ability to parse and represent places and times as individual components, whereas pattern completion is the ability to not only recognize a well-learned association but complete sparser representations with appropriate information. These processes are critical to forming coherent episodic memories. Pattern separation is the process of forming or transforming similar memories into different non-overlapping representations (Bakker, Kirwan, Miller, & Stark, 2008). In other words, pattern separation involves the orthogonalization of both objects and events in the environment spatially and temporally. This ability to initially create a fine-grained representation that allows one to later separate it from other similar input is a critical component of the pattern separation process. Spatial pattern separation (SPS) is important for remembering where something happened. For instance, if one is engaging SPS abilities, one should be able to distinguish a target object that is in close spatial proximity to a foil. Finer-grained representations (i.e., more engagement of SPS processes at encoding) would be required to later distinguish the target and foil at closer separations. In the real world, SPS abilities might for example allow us to form a fine-grained spatial representation of where we parked our car so we are later be able to distinguish that spatial location from other nearby spatial locations. In order to support contextual processing, and thus episodic memory, it is necessary to separate stimuli in the spatial environment, allowing us to form unique representations of the places where events occur. A common method for assessing SPS in rats is the delayed-matching-to-place paradigm. Using this task, Gilbert, Kesner, and Lee (2001) trained rats to displace an object covering a food well that was baited. At test, the rats were to choose between two identical objects, one of which covered the same well as the sample object (target; correct) or a second that covered a different unbaited well (foil; incorrect). Interestingly, lesions to the dorsal DG resulted in disproportionate deficits compared to rats with sham and CA1 lesions with decreasing target-foil distance (i.e., with increasing demands for SPS). In humans, Hopkins and Kesner (1993) compared SPS in healthy controls and patients who had suffered hippocampal atrophy due to hypoxia. Participants were asked to remember the location of cities on a map and subsequently to recall which of two cities was further East. Hypoxic patients were less accurate regardless of separation distance. Hartman (2002) created a twodimensional computerized version of the delayed-matching-to-place task in which participants were required to remember the locations of dots on the monitor screen. Patients with hypoxia performed more poorly at closer separation distances. Most recently, Stark, Yassa, and Stark (2010) asked participants to determine whether pairs of pictures were displayed in identical locations to those shown during study. Notably, participants demonstrated increased accuracy as the distances between the pictures increased. In the current study we present a virtual three-dimensional delayed-matching-to-place task that more closely resembles that used with rats. In contrast to SPS, spatial pattern completion (SPC) allows us to recall or generate well-established knowledge regarding the locations of objects and events based on partial or incomplete spatial information. This mechanism might work through an auto-associative network that retrieves patterns of activity, or memories, based on partial or degraded information or cues (Kesner & Hopkins, 2006; Rolls, 1997). In this vein, SPC involves the “completion” of partial or degraded information to form a coherent memory. If one is engaging their SPC abilities, one would be able to remember the location of a target that was previously presented even when there are cues in the environment that are missing. SPC might allow us to locate where we parked our car when the cars surrounding it have gone and we can no longer use them as cues to locate our car. In this situation, we may use cues such as other cars, or landmarks such as lamp posts, trees, or the road to locate our car. In this case, the subset of available cues leads to the retrieval of a complete memory of where the car is located. SPC is different from rigid stimulus-response or conditioned memories that are highly dependent on consistency. SPC being a hippocampal-dependent process, allows for flexibility in memory representations or their usage. For instance, if we parked our car during the daytime when the sun was shining, we would also be able to locate it at night. Accordingly, tasks used to assess SPC in rats generally require them to re-locate a target location, but in the face of some distal cues having been removed from the environment. For example, Gold and Kesner (2005) tested this ability in rats also using a delayed matching-to-place paradigm. Similar to the SPS task, the sample phase cued rats to approach and remove a block that covered a food well. However, at test, rats were to find the same well, but with the proximal block removed and thus, needed to relocate it using four distal, extramaze cues provided in the room. After they reached stable performance on this SPC task, rats were retested, but with zero, one, two, three, or all four extramaze cues missing. In order to find the correct well efficiently, rats presumably had to mentally “fill in” or complete the arrangement of extramaze cues. Rats with postacquisition CA3 or DG lesions, but not sham or CA1 lesions, were impaired on this SPC task. Similarly, Nakazawa et al. (2002) found that mice with N-methyl-d-asparate (NMDA) receptor gene ablated in the CA3 subregion performed equivalently to controls on the Morris water maze task when all extramaze cues were present, but were severely impaired on the task when three out of four extramaze cues were removed. Notably, tasks assessing SPC in rodents have manipulated cue availability in the environment and indicate a core role for the CA3 region. In contrast, evidence from primate view cells in the presence of obscured or removed visual stimuli suggests preferential firing of CA1 cells in pattern completion (Kesner & Hopkins, 2006; Rolls, 1999). Again, further study using comparable paradigms is needed to better form cross-species comparisons. Here we present a human analog of the rat delayed-matching-to-place SPC task. It should be noted that although the constructs of SPS and SPC appear similar to those of generalization and discrimination in the classical and operant conditioning literature (Mackintosh, 1974), there are some key differences. For example, SPC can be thought of as having a generalization component. Similar to performance decrements with decreasing perceptual similarity along a stimulus-generalization gradient, the ability to find the target location on an SPC task decreases as the perceptual difference of a well-learned environment at test decreases from the study environment. However, the processes
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SPS and SPC differ from discrimination and generalization, since the latter two traditionally refer to trained responses to conditioned stimuli. In contrast, the SPS and SPC tasks assess more flexible one-trial learning in a delayed matching-to-place paradigm. In sum, while tasks assessing pattern separation and completion in humans have been developed, none is an analog to the spatial rat tasks. The original rodent tasks allow us to formulate hypotheses about human processes. However, current task differences limit our ability to draw comparisons between these processes in rodents and in humans. Using similar paradigms may allow us to more closely interrogate in humans these associative memory processes that have been wellstudied in rodents. At a later stage, these tasks might be useful for elucidating the unique nature of episodic memory deficits in psychological disorders associated with subfield-specific pathology, such as Alzheimer’s disease and schizophrenia. The objective of this study was to develop human analogs of the well-established rat delayed-matching-to-place SPS and SPC tasks in a computerized virtual maze environment requiring navigation and the use of allocentric information. Towards this goal, there were two primary hypotheses driving task development: 1. Participants should demonstrate lower performance at closer target-foil separations versus further target-foil separations on a SPS task. 2. Participants should demonstrate lower performance when fewer extramaze cues are available versus when a greater number of extramaze cues are available on an SPC task. Material and methods Participants Young adults were recruited from the Ryerson University Psychology Participant Research Pool and on-campus advertisement. Exclusion criteria included lack of fluency in English, impaired vision, having a self-reported psychological disorder, or being on medication that could affect performance. The final sample comprised 31 participants (22 females), with a mean age of 22.87 years (SD = 4.54). Data from one participant on the training phase were lost due to technical reasons, but all data are presented for the SPS and SPC tasks. General experimental paradigm and procedure All tasks were performed in a circular computer-generated (CG) arena with brick walls (http://web.arizona.edu/∼arg/data.html; Jacobs, Laurance, & Thomas, 1997). Distances in the virtual environment were scaled such that 10 arena units, or the length of one virtual stride, can be taken as representative of about one meter. The arena floor was gray with a diameter of 92 units and was enclosed by a circular brick wall that was 8 units high. The arena was centered in a room 500 × 500 units squared in area with purple-colored walls 100 units high and a gray ceiling. To allow for the allocentric spatial processing required of these tasks, the external walls were each identified by an extramaze cue, a unique fractal pattern of similar coloring. These stimuli were selected in line with Steckler and Muir’s (1995) suggestion to design tasks with abstract stimuli that cannot be easily verbalized to aid comparisons of human with non-human tasks. The tasks were always administered in the following order: training on the associative memory paradigm, followed by the SPS task and then the SPC task. The associative memory task was a baseline task to ensure participants became familiar with the virtual environment and with navigation through the arena. The SPC task was administered last to ensure that the participants were first well-familiarized with the virtual environment, as this is important for pattern completion (Kesner & Hopkins, 2006). Participants were randomly assigned to receive one of three random sequences for the ordering of trials for each task to minimize the likelihood that the results were due to any particular sequence of target (and foil) locations (as described below). Of primary importance was the assessment of the sensitivity of performance to difficulty manipulations thought to place increasing demands on the subprocesses of interest. More specifically, target-foil distance and the availability of cues were manipulated to assess SPS and SPC, respectively. In this vein, the tasks presented below follow a number of preliminary pilot phases aimed at reducing floor and ceiling effects. For example, in a previous version of the SPS task that we had piloted, there was a single foil in addition to the target during the choice phase. Performance on this task was at ceiling and thus we found it necessary to increase the number of foils to three in order to increase difficulty. Associative memory training phase During the sample phase of each trial, a 5-by-5 unit green square was presented in one of 20 pre-determined spatial locations in the arena. Participants were required to use keyboard arrow keys to navigate to and situate themselves on the green square (Fig. 1A). Once they reached it, they were required to press the space bar to take them into a 5-s delay in an empty arena, followed by the choice phase. During the choice phase, participants were placed in the center of the arena in a random start orientation and required to navigate to the spatial location that had been marked in the sample phase, this time in the absence of a visible target (Fig. 1B). Thus, the participants were required to use extramaze cues as well as other
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Fig. 1. Screen shots of the associative memory training phase (A and B), SPS (C and D), and SPC (E and F) tasks. (A) In the sample phase of the training phase, participants navigated to a green square on the floor of the arena. (B) At choice, they were required to navigate to the same location in the absence of a target square. (C) In the sample phase of SPS, participants navigated to a green square on the floor of the arena. (D) During choice, they were asked to go to the target in the same location as the one presented during the study phase. (E) The sample and (F) choice phases for SPC were identical to the training phase, except the number of wall cues missing was manipulated in the choice phase of SPC. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
cues in the environment as a guide. Consistent with similar rat paradigms (e.g., Girard, Xing, Ward, Nguyen, & Wainwright, 2001), participants were allowed a maximum of 45 s to relocate the goal location. Twenty-one trials of study-choice pairs were completed. The CG-Arena program recorded both latency and whether the target was found for all trials.
Spatial pattern separation (SPS) task The SPS task was modeled after the rat delayed matching-to-place task used by Gilbert et al. (2001). On study trials, participants started in the center of the arena facing North and were again presented with a green square located in one of 20 pre-determined spatial locations on the floor of the CG Arena. Using the arrow keys on a keyboard, they navigated to the green square (Fig. 1C). Once the participants were situated on this target, they pressed the space bar to take them into the next phase following a 5-s delay. In the choice phase, participants started at a random orientation and were required to choose between four green circles arranged in a square formation (Fig. 1D). One of these circles was placed in the study location (target, correct choice). The others were placed to complete three remaining corners of the arrangement (foils, incorrect choices). Participants were required to discriminate the correct allocentric location of the target based on its spatial relation to extramaze cues. To make a selection, they navigated to one using the arrow keys, situated themselves on it and then pressed the space bar. The trial ended after a choice was made. If no choice was made within 45 s, the trial ended and the next study trial began. Across trials, one of three possible separation distances was presented in a pseudorandom order: 2, 4, or 6 units between the center of the target and the center of the adjacent foils, corresponding to 2.83 (close), 5.66 (medium), or 8.49 (far) area units between the target and the furthest foil. Twenty-one study-test pairs were presented overall (seven per separation condition), across which the relative position of the foils to the target were counterbalanced (i.e., equal representation of N, E, S, W sides).
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Fig. 2. Proportion of targets found on the SPS task as a function of target-foil distance. Participants performed worse at the closest separation (separation 1) than at both the medium separation (separation 2) and the furthest separation (separation 3).
Spatial pattern completion (SPC) task This version of the delayed matching-to-place task was modeled after the rat task used by Gold and Kesner (2005). The sample phase was identical to that in the associative memory training and SPS tasks. That is, participants started from a designated starting position in the center of the arena facing North and traveled to the green square placed on the floor of the arena (Fig. 1E). After a 5-s delay, participants were started facing a random orientation and required to use their allocentric spatial memory to relocate the target location (green square absent). They were allowed to explore the maze until they reached the correct location or a maximum of 45 s had elapsed (Fig. 1F). The only difference between this task and the associative training task was that the number of pictures on the walls (four, two, or zero) available was manipulated. These three possible cue conditions were repeated seven times each in a pseudorandom presentation sequence across 21 study-test trial pairs. Results Associative memory training phase An ANOVA with Trial Block as the independent variable and the proportion of targets relocated as the dependent variable demonstrated that across 3 blocks of 7 trials performance increased as trials progressed, F (2, 58) = 5.352, p = .007, MSE = .037, partial 2 = .156. Follow-up paired t-tests revealed a greater proportion of targets found in Block 2 (M = 0.63, SD = 0.01) versus Block 1 (M = 0.51, SD = 0.01), t(29) = 2.98, p = .006, d = 0.54, but no further improvement in Block 3 (M = 0.01) compared to Block 2, t(29) = 0.51, p = .612, d = 0.09. A complementary ANOVA also revealed significant differences in latency as a function of Trial Block, F (2, 56) = 5.82, p = .005, MSE = 38.67, partial 2 = .22. Participants were able to locate the hidden targets more quickly during Block 2 (M = 22.99 s, SD = 0.38) versus 1 (M = 29.28 s, SD = 0.33), t(29) = 4.02, p < .001, d = 0.73, but performance leveled off at Blocks 2 and 3 (M = 24.20 s, SD = 0.38), t(29) = −0.76, p = .451, d = −0.14. It is noteworthy that the latency data are under-estimates given that incorrect trials were coded as 45 s, the time at which the trial timed out. Due to this dependence of latency on the proportion-found data, we ran an additional analysis looking at latency differences between blocks only for trials on which the goal was found within the time limit. This ANOVA revealed no significant differences in latency across blocks, F(2, 58) = .395, p = .675, MSE = 21869.55, partial 2 = .01, indicating that the above latency differences between blocks were tied to the ability to locate the platform within 45 s. SPS A repeated-measures ANOVA on the proportion of correct trials revealed a significant effect of Foil Distance, F(2, 60) = 4.48, p = .015, MSE = 0.04, partial 2 = .13. Follow-up paired-samples t-tests revealed a lower proportion found for the closest compared to the medium, t(30) = −2.68, p = .012, d = −0.48, and far separation distances, t(30) = −2.53, p = .017, d = −0.45 (Fig. 2). There was, however, no difference in proportion found between the two greater separation distances, t(30) = 0.70, p = .349, d = 0.13. There were no significant differences in latency between the close (M = 15.89 s, SD = 6.61), medium (M = 14.73 s, SD = 6.75) and far (M = 15.42 s, SD = 7.30), separation conditions (ps > .05). This result was expected given that the target and foil were visible at all times; that is, participants had no difficulty finding the cued locations. SPC A repeated-measures ANOVA was conducted with Cue Condition as the independent variable and proportion of targets found as the dependent variable. Cue Condition was highly significant, F(2, 60) = 12.021, p < .001, MSE = .034, partial 2 = .286. In particular, performance declined relative to zero cues missing (M = 0.677, SD = 0.01) when two cues (M = 0.548, SD = 0.34),
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Fig. 3. Proportion of targets found on the SPC task as a function of number of wall cues missing (0, 2, or 4). Four cues missing corresponds to the absence of wall cues. Participants found more targets at the 0-cue missing condition compared to the 2-cue missing condition and 4-cue missing condition. The difference between proportion found in the 2-cue missing condition and 4-cue missing condition just failed to reach significance.
t(30) = 2.98, p = .006, d = 0.54 or four cues (M = 0.448, SD = 0.01) were missing, t(30) = 5.50, p < .001, d = 0.99. The difference between two and four cues missing conditions just failed to reach statistical significance although it was of medium effect size, t(30) = 0.10, p = .078, d = 0.33 (Fig. 3). A repeated-measures ANOVA with latency as the dependent variable was also significant, F(2, 60) = 23.140, p < .001, MSE = 38.396, partial 2 = .435. Participants relocated the target location faster with zero cues missing (M = 22.20 s, SD = 0.31) versus two cues missing (M = 26.60 s, SD = 0.34), t(30) = −4.40, p = .004, d = −0.56, which in turn was faster than when all four cues were missing (M = 32.86 s, SD = 0.22), t(30) = −3.54, p = .001, d = −0.64. Similarly to the associative memory baseline, we ran an additional repeated-measures ANOVA to assess whether differences in latency across cue conditions were also apparent when only correct trials were taken into account. There was a significant latency difference between cue conditions even when only correct trials were entered into the analysis, F(2, 54) = 8.89, p < .001, MSE = 36.67, partial 2 = 0.25. A follow-up paired-samples t test revealed significant latency differences between 0 cues missing (M = 11.75, SD = 0.14) and 4 cues missing (M = 17.87, SD = 0.28), t(29) = −3.646, p = .001, d = −.67 as well as between 2 cues missing (M = 12.59, SD = 0.20) and 4 cues missing, t(27) = −3.262, p = .003, d = −.62. However, there was no longer a difference in latency between 0 cues missing and 2 cues missing, t(27) = −.836, p = .411, d = −.16. Task inter-correlations SPS proportion found was positively correlated with SPC proportion found, r = .54, p = .002. Although these tasks are strongly correlated, sharing 29% explanatory variance, they are far from perfectly correlated, providing some divergent validity. Baseline task proportion found was also positively correlated with both SPS (r = .48, p = .008) and SPC (r = .81, p < .001). The stronger relation between the baseline task and SPC was expected since they are both very similar tasks; in fact, SPC with no cues missing is identical to the training task. A partial correlation analysis was conducted to assess the shared variance between SPS and SPC, controlling for baseline training. Albeit of medium effect size, the correlation between SPS and SPC was no longer significant when baseline training was controlled, rfound = .30, p = .116. Thus, after removing their shared variance with the basic task, SPS and SPC shared only 9% of explanatory variance, providing evidence for their divergent validity. In other words, their convergence is largely accounted for by what they share with the training phase in terms of task demands and general spatial abilities. Discussion In this study, two novel virtual-maze tasks were designed that were analogous to rat tasks and used to evaluate SPS and SPC in humans. Use of a three-dimensional virtual arena provided a similar environment to that used in rat tasks in which participants navigated to study and target locations. Further, it enabled us to closely parallel the difficulty manipulations used in rat delayed-matching-to-place tasks. Performance (proportion found) in the baseline associative memory phase, SPS, and SPC were all positively correlated supporting that these tasks rely on common spatial memory demands. Nonetheless, the imperfect correlation between SPS and SPC also supports divergent validity of these subprocesses. Importantly, performance profiles showed sensitivity to the separation and completion task manipulations. More specifically, participants demonstrated an improved ability to successfully discriminate the SPS task target location with increasing separation distance from foils. Furthermore, participants’ performance was dependent on the number of extramaze cues in the SPC task, supporting their reliance on these allocentric cues. These findings and their implications are discussed in more detail below, as well as possible future directions incorporating these tasks. Associative memory training phase Results were consistent with expectations for the training phase. Although the spatial location to be remembered differed on each trial, participants became faster and more able to locate the hidden target location as training progressed. This improvement likely reflects the participants’ increasing familiarity with the virtual room, including the wall cues that help
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the participants gauge their location relative to the target, as well as improvements in strategy. The former component is critical for the later SPC task, and the ordering of the tasks with SPC always completed last was to ensure the environment was well-learned. The lack of improvement between Trial Blocks 2 and 3 suggests that participants had reached a stable level of performance by trial 15. Therefore, the 21 trials of training were sufficient to produce gains in performance and to establish understanding of performance demands and the maze environment. SPS A major advantage of our paradigm compared to other pattern-separation tasks that have emerged in recent years is its demonstrated sensitivity to separation manipulations in an immersive virtual environment. At the closest target-foil distances, a “heavier” reliance on the pattern-separation process is thought to be required to successfully discriminate between the spatial locations. Presumably, the lower proportion of correct discriminations observed at the closest separation is reflective of this increased demand for SPS. While other studies have used tasks assessing pattern separation in humans (e.g., Bakker et al., 2008; Hartman, 2002; Hopkins & Kesner, 1993; Stark et al., 2010), our task includes demonstrated performance differences between spatial separations in healthy individuals as well as the presentation of analogous environmental and navigational features to the primary rodent SPS delayed-matching-to-place task (Gilbert et al., 2001). SPC Our choice of the delayed-matching paradigm was also driven primarily by our goals of developing a human analog to the rat SPC task used by Kesner and colleagues (i.e., Gold & Kesner, 2005) and of maintaining consistency in overall paradigm design to the SPS task. Our task yielded significant differences in both the proportion of targets found and latency based on cue availability. These results indicate that performance on this task was reliant on the number of cues in the environment for forming allocentric spatial memories (Gold & Kesner, 2005; Morris, 1984). Moreover, this sensitivity to cue availability reflects increased demands on pattern completion processes (Gold & Kesner, 2005; Kesner & Hopkins, 2006). Limitations and future directions Here we present novel human analogs of rat SPS and SPC tasks. Although task parameters were adequately developed, there are some domains deserving of further assessment and task development. First, generalizability of the findings must be interpreted in light of about two-thirds of our sample being female. We did not aim to assess sex differences in spatial navigation and thus, recruitment was open in this regard. Nonetheless, given the literature on differential spatial navigation strategies and overall performance on spatial memory tasks in males and females (Canovas et al., 2008; Ross, Skelton, & Mueller, 2006), we subsequently included sex as a factor in post hoc analyses (data not shown). A male advantage was observed during the initial training phase consistent with the literature, but importantly, this sex difference was not apparent in the SPS and SPC tasks. Second, the verbal instructions given to our human participants may have posed different cognitive demands than the learning that takes place in rats, which must learn the procedural task demands through trial and error. Arguably the processes required to perform a task when given verbal instructions may differ from learning task demands without these explicit instructions. A future study employing a learning paradigm that minimizes verbal instructions would address this limitation. Nonetheless, the current behavioral data support the contention that our tasks are analogous to the rat tasks after which they were modeled. Third, a possible confound may relate to the different retrieval demands of the SPS and SPC tasks. SPS may rely more on recognition of the correct item from four possible options. SPC may rely more on recall, in the sense that there is no discrete set of forced-choice options like there is for SPS; rather participants have to recall the precise location of the target within the entire arena. Nonetheless, our decision to maintain these task differences was in line with the main objective for this initial stage of task development to keep the tasks as analogous as possible to the rodent delayed-matching to place paradigms. It will be of theoretical interest to assess the extent to which different retrieval processes contribute to performance on these tasks and their functional relations to hippocampal subregions. Indeed, additional future directions of research include the use of functional magnetic resonance imaging to assess whether the spatial-pattern tasks involve similar hippocampal subfields in humans as established with findings from animal models (as reviewed by Kesner & Hopkins, 2006). Although largely similar, there are anatomical differences between the hippocampi of rodents and humans that warrant comparative consideration. Specifically the hippocampi of humans are smaller in relative size. That is, whereas the human neocortex occupies much more territory, the rodent hippocampi are much more prominent anatomically in the rodent brain (O’Keefe & Nadel, 1978). Additionally, the CA2 region subfield observed in humans is not identified in rat hippocampi. Emergence of hemispheric specialization of hippocampal function has also been noted in humans, where allocentric spatial memory particularly involves the right side (e.g., Iglói, Doeller, Berthoz, Rondi-Reig, & Burgess, 2010). Nonetheless, in both rodents and humans, the hippocampus as a whole supports the complex formation of arbitrary associations, involving the binding of associations among objects and/or events with places, as well as among places (i.e., as required to construct a “cognitive map”; O’Keefe & Nadel, 1978). However, rat studies and computational models suggest that different subprocesses of spatial memory are preferentially dependent on different hippocampal subfields. Namely, the CA and DG cell fields are thought to play different roles in the subprocesses of pattern separation and pattern completion that underlie associative memory (Bakker et al., 2008; Carr, Rissman, & Wagner, 2010;
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Kesner & Hopkins, 2006; Rolls, 1996). Testing for similar neural involvement in rats and humans will prove informative and might support evolutionary continuity in hippocampal cognitive function in humans and rats (Kesner & Hopkins, 2006). Moreover, functional dissociations between SPS and SPC, as they relate to hippocampal pathology at the subregion level, are of clinical relevance. That is, certain clinical disorders such as schizophrenia, Alzheimer’s disease, and hypoxia, show most damage to particular hippocampal subfields with relative sparing of other subfields (Benes, 1999; Harrison, 2004; Hartman, 2002; Mueller et al., 2007). Research demonstrating disparate hippocampal pathology in different disorders suggests that the pattern of memory deficits between disorders may also be unique. Thus, testing for similar neural involvement in rats and humans will prove informative and might support functional differences in subregion-specific hippocampally mediated spatial memory subprocesses and set the stage for valuable future translational research directions aimed at improved detection and intervention more specific to clinical conditions. Acknowledgments We thank Adina-Ioana Berindean-Coroiu and Vanessa Amodio for their assistance in data collection. These data contributed in part to the completion of an MA thesis by MP, Department of Psychology, Ryerson University. Portions of this research were also presented at the 2010 Society for Neuroscience annual meeting in San Diego, CA. This research was supported by a New Faculty SRC Development Fund award (Office of Research Services, Ryerson University) to TAG and MP is supported by a CIHR Canada Graduate Scholarship. References Astur, R. S., St. Germain, S. A., Baker, E. K., Calhoun, V., Pearlson, G. D., & Constable, R. T. 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