Kyoko Konishi

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.

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.

Decreased functional magnetic resonance imaging activity in the hippocampus in favor of the caudate nucleus in older adults tested in a virtual navigation task

The neuroimaging literature has shown consistent decreases in functional magnetic resonance imaging (fMRI) activity in the hippocampus of healthy older adults engaged in a navigation task. However, navigation in a virtual maze relies on spatial or response strategies known to depend on the hippocampus and caudate nucleus, respectively. Therefore, since the proportion of people using spatial strategies decreases with normal aging, we hypothesized that it was responsible for the observed decreases in fMRI activity in the hippocampus reported in the literature. The aim of this study was to examine the effects of aging on the hippocampus and caudate nucleus during navigation while taking into account individual navigational strategies. Young (N = 23) and older adults (N = 29) were tested using fMRI on the Concurrent Spatial Discrimination Learning Task, a radial task that dissociates between spatial and response strategies (in Stage 2) after participants reached criteria (in Stage 1). Success on Stage 2 requires that participants have encoded the spatial relationship between the target object and environmental landmarks, that is, the spatial strategy. While older adults required more trials, all participants reached criterion. fMRI results showed that, as a group, young adults had significant activity in the hippocampus as opposed to older adults who instead had significant activity in the caudate nucleus. Importantly, individual differences showed that the older participants who used a spatial strategy to solve the task had significant activity in the hippocampus. These findings suggest that the aging process involves a shift from using the hippocampus toward the caudate nucleus during navigation but that activity in the hippocampus is sustained in a subset of healthy older adults engaged in spatial strategies.

Habitual action video game playing is associated with caudate nucleus-dependent navigational strategies

The habitual playing of video games is associated with increased grey matter and activity in the striatum. Studies in humans and rodents have shown an inverse relationship between grey matter in the striatum and hippocampus. We investigated whether action video game playing is also associated with increased use of response learning strategies during navigation, known to be dependent on the caudate nucleus of the striatum, when presented in a dual solution task. We tested 26 action video game players (actionVGPs) and 33 non-action video game players (nonVGPs) on the 4-on-8 virtual maze and a visual attention event-related potential (ERP) task, which elicits a robust N-2-posterior-controlateral (N2pc) component. We found that actionVGPs had a significantly higher likelihood of using a response learning strategy (80.76%) compared to nonVGPs (42.42%). Consistent with previous evidence, actionVGPs and nonVGPs differed in the way they deployed visual attention to central and peripheral targets as observed in the elicited N2pc component during an ERP visual attention task. Increased use of the response strategy in actionVGPs is consistent with previously observed increases in striatal volume in video game players (VGPs). Using response strategies is associated with decreased grey matter in the hippocampus. Previous studies have shown that decreased volume in the hippocampus precedes the onset of many neurological and psychiatric disorders. If actionVGPs have lower grey matter in the hippocampus, as response learners normally do, then these individuals could be at increased risk of developing neurological and psychiatric disorders during their lifetime.

Caudate nucleus‐dependent navigational strategies are associated with increased use of addictive drugs

This study aimed to investigate the relationship between navigational strategies and the use of abused substances in a sample of healthy young adults. Navigational strategies were assessed with the 4‐on‐8 virtual maze (4/8VM), a task previously shown to dissociate between hippocampal‐dependent spatial navigational strategies and caudate nucleus‐dependent stimulus‐response navigational strategies. Spatial strategies involve learning the spatial relationships between the landmarks in an environment, while response learning strategies involve learning a rigid set of stimulus‐response type associations, e.g., see the tree, turn left. We have shown that spatial learners have increased gray matter and fMRI activity in the hippocampus compared with response learners, while response learners have increased gray matter and fMRI activity in the caudate nucleus. We were interested in the prevalence of use of substances of abuse in spatial and response learners because of the evidence that people who score high on traits such as novelty seeking, sensation seeking, reward seeking, and impulsivity, are more cue‐responsive and more likely to use substances of abuse. Since response learners show increased activity and gray matter in the caudate nucleus of the striatum, which is a brain area involved in addiction, we hypothesized that response learners would have a greater use of abused substances than spatial learners. Fifty‐five young adults were tested on the 4/8VM and completed a time‐line follow‐back assessment of drug and alcohol use. We found that response learners had smoked a significantly greater number of cigarettes in their lifetime than spatial learners, were more likely to have used cannabis, and had double the lifetime alcohol consumption. We discuss the possible relationship between substance abuse and response strategies as well as the implications for the hippocampus, risks of neurological and psychiatric disorders, and healthy cognition.

Decolorization of malachite green by cytochrome c in the mitochondria of the fungus Cunninghamella elegans

We studied the decolorization of malachite green (MG) by the fungus Cunninghamella elegans. The mitochondrial activity for MG reduction was increased with a simultaneous increase of a 9-kDa protein, called CeCyt. The presence of cytochrome c in CeCyt protein was determined by optical absorbance spectroscopy with an extinction coefficient (E(550-535)) of 19.7+/-6.3 mM(-1) cm(-1) and reduction potential of + 261 mV. When purified CeCyt was added into the mitochondria, the specific activity of CeCyt reached 440 +/- 122 micromol min(-1) mg(-1) protein. The inhibition of MG reduction by stigmatellin, but not by antimycin A, indicated a possible linkage of CeCyt activity to the Qo site of the bc1 complex. The RT-PCR results showed tight regulation of the cecyt gene expression by reactive oxygen species. We suggest that CeCyt acts as a protein reductant for MG under oxidative stress in a stationary or secondary growth stage of this fungus.

Modulation of spatial and response strategies by phase of the menstrual cycle in women tested in a virtual navigation task

Different memory systems are employed to navigate an environment. It has been consistently shown in rodents that estrogen impacts multiple memory system bias such that low estradiol (E2) is associated with increased use of a striatal-mediated response strategy whereas high E2 increases use of a hippocampal-dependent spatial memory. Low E2 also enhances performance on a response-based task whereas high E2 levels improve learning on a spatial task. The purpose of the present cross-sectional study was to investigate navigational strategies in young, healthy, naturally cycling women. Participants were split into either an early follicular (i.e., when E2 levels are low), ovulatory (i.e., when E2 levels are high) or mid/late luteal (i.e., end of the cycle, when E2 levels decrease and progesterone levels rise) phase group, using self-reported date of the menstrual cycle. Serum hormone level measurements (E2, progesterone, testosterone) were used to confirm cycle phase assignment. Participants were administered a verbal memory task as well as a virtual navigation task that can be solved by using either a response or spatial strategy. Women tested in the ovulatory phase, under high E2 conditions, performed better on a verbal memory task than women tested during the other phases of the cycle. Interestingly, women tested in the mid/late luteal phase, when progesterone is high, predominantly used a spatial strategy, whereas the opposite pattern was observed in the early follicular and ovulatory groups. Our data suggest that the specific memory system engaged differs depending on the phase of the menstrual cycle and may be mediated by both E2 and progesterone, rather than E2 alone.

Impact of video games on plasticity of the hippocampus

The hippocampus is critical to healthy cognition, yet results in the current study show that action video game players have reduced grey matter within the hippocampus. A subsequent randomised longitudinal training experiment demonstrated that first-person shooting games reduce grey matter within the hippocampus in participants using non-spatial memory strategies. Conversely, participants who use hippocampus-dependent spatial strategies showed increased grey matter in the hippocampus after training. A control group that trained on 3D-platform games displayed growth in either the hippocampus or the functionally connected entorhinal cortex. A third study replicated the effect of action video game training on grey matter in the hippocampus. These results show that video games can be beneficial or detrimental to the hippocampal system depending on the navigation strategy that a person employs and the genre of the game.