Véronique D. Bohbot

Spatial memory deficits in patients with lesions to the right hippocampus and to the right parahippocampal cortex.

Spatial memory tasks, performance of which is known to be sensitive to hippocampal lesions in the rat, or to medial temporal lesions in the human, were administered in order to investigate the effects of selective damage to medial temporal lobe structures of the human brain. The patients had undergone thermo-coagulation with a single electrode along the amygdalo-hippocampal axis in an attempt to alleviate their epilepsy. With this surgical technique, lesions to single medial temporal lobe structures can be carried out. The locations of the lesions were assessed by means of digital high-resolution magnetic resonance imaging and software allowing a 3-D reconstruction of the brain. A break in the collateral sulcus, dividing it into the anterior collateral sulcus and the posterior collateral sulcus is reported. This division may correspond to the end of the entorhinal/perirhinal cortex and the start of the parahippocampal cortex. The results confirmed the role of the right hippocampus in visuo-spatial memory tasks (object location, Rey-Osterrieth Figure with and without delay) and the left for verbal memory tasks (Rey Auditory Verbal Learning Task with delay). However, patients with lesions either to the right or to the left hippocampus were unimpaired on several memory tasks, including a spatial one, with a 30 min delay, designed to be analogous to the Morris water maze. Patients with lesions to the right parahippocampal cortex were impaired on this task with a 30 min delay, suggesting that the parahippocampal cortex itself may play an important role in spatial memory.

Spatial navigational strategies correlate with gray matter in the hippocampus of healthy older adults tested in a virtual maze

Healthy young adults use different strategies when navigating in a virtual maze. Spatial strategies involve using environmental landmarks while response strategies involve executing a series of movements from specific stimuli. Neuroimaging studies previously confirmed that people who use spatial strategies show increased activity and gray matter in the hippocampus, while those who use response strategies show increased activity and gray matter in caudate nucleus (Iaria et al., 2003; Bohbot et al., 2007). A growing number of studies report that cognitive decline that occurs with normal aging is correlated with a decrease in volume of the hippocampus. Here, we used voxel-based morphometry (VBM) to examine whether spatial strategies in aging are correlated with greater gray matter in the hippocampus, as found in our previous study with healthy young participants. Forty-five healthy older adults were tested on a virtual navigation task that allows spatial and response strategies. All participants learn the task to criterion after which a special “probe” trial that assesses spatial and response strategies is given. Results show that spontaneous spatial memory strategies, and not performance on the navigation task, positively correlate with gray matter in the hippocampus. Since numerous studies have shown that a decrease in the volume of the hippocampus correlates with cognitive deficits during normal aging and increases the risks of ensuing dementia, the current results suggest that older people who use their spatial memory strategies in their everyday lives may have increased gray matter in the hippocampus and enhance their probability of healthy and successful aging.

Hippocampal Function and Spatial Memory: Evidence From Functional Neuroimaging in Healthy Participants and Performance of Patients With Medial Temporal Lobe Resections

Several strategies can be used to find a destination in the environment. Using a virtual environment, the authors identified 2 strategies dependent on 2 different memory systems. A spatial strategy involved the use of multiple landmarks available in the environment, and a response strategy involved right and left turns from a given start position. Although a probe trial provided an objective measure of the strategy used, classification that was based on verbal reports was used in small groups to avoid risks of misclassification. The authors first demonstrated that the spatial strategy led to a significant activity of the hippocampus, whereas the response strategy led to a sustained activity in the caudate nucleus. Then, the authors administered the task to 15 patients with lesions to the medial temporal lobe, showing an impaired ability using the spatial strategy. Imaging and neuropsychological results are discussed to shed light on the human navigation system.

Gray Matter Differences Correlate with Spontaneous Strategies in a Human Virtual Navigation Task

Young healthy participants spontaneously use different strategies in a virtual radial maze, an adaptation of a task typically used with rodents. Functional magnetic resonance imaging confirmed previously that people who used spatial memory strategies showed increased activity in the hippocampus, whereas response strategies were associated with activity in the caudate nucleus. Here, voxel based morphometry was used to identify brain regions covarying with the navigational strategies used by individuals. Results showed that spatial learners had significantly more gray matter in the hippocampus and less gray matter in the caudate nucleus compared with response learners. Furthermore, the gray matter in the hippocampus was negatively correlated to the gray matter in the caudate nucleus, suggesting a competitive interaction between these two brain areas. In a second analysis, the gray matter of regions known to be anatomically connected to the hippocampus, such as the amygdala, parahippocampal, perirhinal, entorhinal and orbitofrontal cortices were shown to covary with gray matter in the hippocampus. Because low gray matter in the hippocampus is a risk factor for Alzheimers disease, these results have important implications for intervention programs that aim at functional recovery in these brain areas. In addition, these data suggest that spatial strategies may provide protective effects against degeneration of the hippocampus that occurs with normal aging.

Maze training in mice induces MRI-detectable brain shape changes specific to the type of learning.

Multiple recent human imaging studies have suggested that the structure of the brain can change with learning. To investigate the mechanism behind such structural plasticity, we sought to determine whether maze learning in mice induces brain shape changes that are detectable by MRI and whether such changes are specific to the type of learning. Here we trained inbred mice for 5 days on one of three different versions of the Morris water maze and, using high-resolution MRI, revealed specific growth in the hippocampus of mice trained on a spatial variant of the maze, whereas mice trained on the cued version were found to have growth in the striatum. The structure-specific growth found furthermore correlated with GAP-43 staining, a marker of neuronal process remodelling, but not with neurogenesis nor neuron or astrocyte numbers or sizes. Our findings provide evidence that brain morphology changes rapidly at a scale detectable by MRI and furthermore demonstrate that specific brain regions grow or shrink in response to the changing environmental demands. The data presented herein have implications for both human imaging as well as rodent structural plasticity research, in that it provides a tool to screen for neuronal plasticity across the whole brain in the mouse while also providing a direct link between human and mouse studies.

Memory Deficits Characterized by Patterns of Lesions to the Hippocampus and Parahippocampal Cortex

Abstract: Spatial and nonspatial memory tests were given to patients with small thermal lesions administered to the medial temporal lobes in an attempt at alleviating pharmacologically resistant epilepsy. In all three spatial memory experiments presented in this paper, patients with lesions that included the right parahippocampal cortex were seriously impaired. Their impairment, together with the performance of patients with lesions to the right hippocampus (sparing the right parahippocampal cortex), provides the different patterns of deficits that lead to different interpretations of the function of the parahippocampal cortex. The distinction between the effects of functional damage in hippocampus and the effects of a lesion to the hippocampus or to regions surrounding the hippocampus, such as the parahippocampal cortex, is emphasized. We conclude that the right parahippocampal cortex participates in spatial memory beyond serving as a gateway to the hippocampus.

Consolidation of memory

Animal studies have proven useful in addressing aspects of memory formation and consolidation that cannot be readily answered in research with humans. In particular, they offer the possibility of controlling both the extent and locus of brain lesions, and the exact nature of the experiences to be remembered. Taking advantage of these possibilities, recent studies indicated that the graded retrograde amnesia often seen after lesions to the hippocampal system is not uniform across lesion site and task, nor is it an indication that all of the remembered information available in intact subjects becomes available after hippocampal system lesions made a long time after learning. Rather, these studies support the notion that information is stored in both hippocampal and extrahipocampal sites, and that retrieval from different sites involves access to different kinds of information. The strongest evidence in support of this view is the set of findings indicating that when remote memories are retrieved, in either human or animal subjects that have suffered hippocampal system damage, these memories are not qualitatively the same as remote memories retrieved in intact subjects. In sum, memory appears to be rather more dynamic than most current conceptions allow, such that retrieval events trigger new encodings, and these new encodings engage the hippocampal system once again. As a result, older, reactivated memories become more resistant to disruption, and this mechanism helps to explain why graded retrograde amnesia is sometimes seen after brain damage. The use of new neuroimaging techniques, coupled with more sensitive neuropsychological tests in lesioned subjects, should further illuminate the complex nature of memory in coming years. It is likely that animal studies will continue to prove important in these developments. Hippocampus 2001;11:56–60.

Eye tracking, strategies, and sex differences in virtual navigation

Reports of sex differences in wayfinding have typically used paradigms sensitive to the female advantage (navigation by landmarks) or sensitive to the male advantage (navigation by cardinal directions, Euclidian coordinates, environmental geometry, and absolute distances). The current virtual navigation paradigm allowed both men and women an equal advantage. We studied sex differences by systematically varying the number of landmarks. Eye tracking was used to quantify sex differences in landmark utilisation as participants solved an eight-arm radial maze task within different virtual environments. To solve the task, participants were required to remember the locations of target objects within environments containing 0, 2, 4, 6, or 8 landmarks. We found that, as the number of landmarks available in the environment increases, the proportion of time men and women spend looking at landmarks and the number of landmarks they use to find their way increases. Eye tracking confirmed that women rely more on landmarks to navigate, although landmark fixations were also associated with an increase in task completion time. Sex differences in navigational behaviour occurred only in environments devoid of landmarks and disappeared in environments containing multiple landmarks. Moreover, women showed sustained landmark-oriented gaze, while mens decreased over time. Finally, we found that men and women use spatial and response strategies to the same extent. Together, these results shed new light on the discrepancy in landmark utilisation between men and women and help explain the differences in navigational behaviour previously reported.

Virtual navigation strategies from childhood to senescence: evidence for changes across the life span

This study sought to investigate navigational strategies across the life span, by testing 8-years old children to 80-years old healthy older adults on the 4 on 8 virtual maze (4/8VM). The 4/8VM was previously developed to assess spontaneous navigational strategies, i.e., hippocampal-dependent spatial strategies (navigation by memorizing relationships between landmarks) versus caudate nucleus-dependent response strategies (memorizing a series of left and right turns from a given starting position). With the 4/8VM, we previously demonstrated greater fMRI activity and gray matter in the hippocampus of spatial learners relative to response learners. A sample of 599 healthy participants was tested in the current study. Results showed that 84.4% of children, 46.3% of young adults, and 39.3% of older adults spontaneously used spatial strategies (p < 0.0001). Our results suggest that while children predominantly use spatial strategies, the proportion of participants using spatial strategies decreases across the life span, in favor of response strategies. Factors promoting response strategies include repetition, reward and stress. Since response strategies can result from successful repetition of a behavioral pattern, we propose that the increase in response strategies is a biological adaptive mechanism that allows for the automatization of behavior such as walking in order to free up hippocampal-dependent resources. However, the down-side of this shift from spatial to response strategies occurs if people stop building novel relationships, which occurs with repetition and routine, and thereby stop stimulating their hippocampus. Reduced fMRI activity and gray matter in the hippocampus were shown to correlate with cognitive deficits in normal aging. Therefore, these results have important implications regarding factors involved in healthy and successful aging.

Evidence for a virtual human analog of a rodent relational memory task: A study of aging and fMRI in young adults

A radial maze concurrent spatial discrimination learning paradigm consisting of two stages was previously designed to assess the flexibility property of relational memory in mice, as a model of human declarative memory. Aged mice and young adult mice with damage to the hippocampus, learned accurately Stage 1 of the task which required them to learn a constant reward location in a specific set of arms (i.e., learning phase). In contrast, they were impaired relative to healthy young adult mice in a second stage when faced with rearrangements of the same arms (i.e., flexibility probes). This mnemonic inflexibility in Stage 2 is thought to derive from insufficient relational processing by the hippocampus during initial learning (Stage 1) which favors stimulus‐response learning, a form of procedural learning. This was proposed as a model of the selective declarative and relational memory decline classically described in elderly people. As a first step to examine the validity of this model, we adapted this protocol to humans using a virtual radial‐maze. (1) We showed that performance in the flexibility probes in young and older adults positively correlated with performance in a wayfinding task, suggesting that our paradigm assesses relational memory. (2) We demonstrated that older healthy participants displayed a deficit in the performance of the flexibility probes (Stage 2), similar to the one previously seen in aged mice. This was associated with a decline in the wayfinding task. (3) Our fMRI data in young adults confirmed that hippocampal activation during early discrimination learning in Stage 1 correlated with memory flexibility in Stage 2, whereas caudate nucleus activation in Stage 1 negatively correlated with subsequent flexibility. By enabling relational memory assessment in mice and humans, our radial‐maze paradigm provides a valuable tool for translational research.