3T hippocampal glutamate-glutamine complex reflects verbal memory decline in aging

The hippocampus is a critical site for alterations that are responsible for age-related changes in memory. Here, we present a relatively novel approach of examining the relationship between memory performance and glutamate-glutamine levels using short echo time magnetic resonance spectroscopy. Specifically, we investigated the relationship between Glx (a composite of glutamate and glutamine) levels in the hippocampus, performance on a word-recall task, and resting-state functional connectivity. While there was no overall difference in Glx intensity between young and aging adults, we identified a positive correlation between delayed word-list recall and Glx, bilaterally in older adults, but not in young adults. Collapsed across age, we also discovered a negative relationship between Glx intensity and resting-state functional connectivity between the anterior hippocampus and regions in the subcallosal gyrus. These findings demonstrate the possible utility of Glx in identifying age-related changes in the brain and behavior and provide encouragement that magnetic resonance spectroscopy can be useful in predicting age-related decline before any physical abnormalities are present

Simple and Associative Recognition Memory in the Hippocampal Region

Although it is well established that the hippocampal region is involved in the formation of declarative memory, the exact nature of its involvement is unclear. One view is that the hippocampal region is involved only in tasks that require the formation or use of associations. According to this view, the hippocampal region is not involved in traditional tests of recognition memory. An alternative view is that the hippocampal region combines and extends the processing carried out by structures in the parahippocampal gyrus and that it is involved in all forms of declarative memory, including recognition memory. Using event-related functional magnetic resonance imaging (fMRI), we observed hippocampal activity during both traditional and associative recognition memory tasks. Critically, the hippocampal region was no more active in the associative recognition task than in the traditional recognition task

Virtual Environmental Enrichment through Video Games Improves Hippocampal-Associated Memory

The positive effects of environmental enrichment and their neural bases have been studied extensively in the rodent (van Praag et al., 2000). For example, simply modifying an animal's living environment to promote sensory stimulation can lead to (but is not limited to) enhancements in hippocampal cognition and neuroplasticity and can alleviate hippocampal cognitive deficits associated with neurodegenerative diseases and aging. We are interested in whether these manipulations that successfully enhance cognition (or mitigate cognitive decline) have similar influences on humans. Although there are many “enriching” aspects to daily life, we are constantly adapting to new experiences and situations within our own environment on a daily basis. Here, we hypothesize that the exploration of the vast and visually stimulating virtual environments within video games is a human correlate of environmental enrichment. We show that video gamers who specifically favor complex 3D video games performed better on a demanding recognition memory task that assesses participants' ability to discriminate highly similar lure items from repeated items. In addition, after 2 weeks of training on the 3D video game Super Mario 3D World, naive video gamers showed improved mnemonic discrimination ability and improvements on a virtual water maze task. Two control conditions (passive and training in a 2D game, Angry Birds), showed no such improvements. Furthermore, individual performance in both hippocampal-associated behaviors correlated with performance in Super Mario but not Angry Birds, suggesting that how individuals explored the virtual environment may influence hippocampal behavior. SIGNIFICANCE STATEMENT The hippocampus has long been associated with episodic memory and is commonly thought to rely on neuroplasticity to adapt to the ever-changing environment. In animals, it is well understood that exposing animals to a more stimulating environment, known as environmental enrichment, can stimulate neuroplasticity and improve hippocampal function and performance on hippocampally mediated memory tasks. Here, we suggest that the exploration of vast and visually stimulating environments within modern-day video games can act as a human correlate of environmental enrichment. Training naive video gamers in a rich 3D, but not 2D, video game, resulted in a significant improvement in hippocampus-associated cognition using several behavioral measures. Our results suggest that modern day video games may provide meaningful stimulation to the human hippocampus

Overcoming interference: An fMRI investigation of pattern separation in the medial temporal lobe

The medial temporal lobe (MTL) supports the formation and retrieval of long-term declarative memories, or memories for facts and everyday events. One challenge posed for this type of memory stems from the highly overlapping nature of common episodes. Within cognitive psychology, it is widely accepted that interference between information learned at different times is a major limitation on memory. In spite of several decades of intense research in the fields of interference theory and the neurobiological underpinnings of declarative memory, there is little direct evidence bearing on how the MTL resolves this interference to form accurate memories of everyday facts and events. Computational models of MTL function have proposed a mechanism in which the MTL, specifically the hippocampus, performs pattern separation, whereby overlapping representations are made less similar. However, there is little evidence bearing on how this process is carried out in the intact human MTL. Using high-resolution fMRI, we conducted a set of experiments that taxed behavioral pattern separation by using highly similar, interfering stimuli in a modified continuous recognition task. Regions within the parahippocampal gyrus demonstrated activity consistent with a “recall to reject” strategy. In contrast and critical to performing the task, activity within the hippocampus distinguished between correctly identified true stimulus repetitions, correctly rejected presentations of similar lure stimuli, and false alarms to similar lures. These data support the computational models’ assertion that the hippocampus plays a key role in pattern separation

Recognition Memory for Single Items and for Associations Is Similarly Impaired Following Damage to the Hippocampal Region

The formation of new associations between items is critical for establishing episodic memories. It has been suggested that the hippocampus is essential for creating such associations but is not involved, or is much less involved, in memory for single items. In Experiment 1, we tested controls and amnesic patients with bilateral lesions thought to be limited primarily to the hippocampal region in both single-item and associative recognition memory tasks. In the single-item task, a conventional recognition memory task was administered in which participants studied either houses or faces and were tested for their ability to recognize the individual items. In the associative task, participants studied paired pictures of houses and faces with instructions that encouraged associating the two stimuli, and were tested for their ability to recognize the specific pairings that were presented at study. Like the controls, the amnesic patients performed more poorly on the associative task. Relative to the controls, the amnesic patients were impaired to a similar extent on the single-item and associative tasks. In Experiment 2, the performance of the amnesic patients was improved by increasing the number of presentations of the study lists (eight presentations instead of one). On both the single-item and associative tests, the performance of the amnesic patients after eight presentations was now identical to the performance of the controls who had been given only one presentation of the study list. Thus, the associative condition was not disproportionally difficult for the amnesic patients. These results are consistent with the idea that the hippocampus is similarly involved in single-item and associative memory

Limbic Tract Integrity Contributes to Pattern Separation Performance Across the Lifespan

Accurate memory for discrete events is thought to rely on pattern separation to orthogonalize the representations of similar events. Previously, we reported that a behavioral index of pattern separation was correlated with activity in the hippocampus (dentate gyrus, CA3) and with integrity of the perforant path, which provides input to the hippocampus. If the hippocampus operates as part of a broader neural network, however, pattern separation would likely also relate to integrity of limbic tracts (fornix, cingulum bundle, and uncinate fasciculus) that connect the hippocampus to distributed brain regions. In this study, healthy adults (20–89 years) underwent diffusion tensor imaging and completed the Behavioral Pattern Separation Task-Object Version (BPS-O) and Rey Auditory Verbal Learning Test (RAVLT). After controlling for global effects of brain aging, exploratory skeleton-wise and targeted tractography analyses revealed that fornix integrity (fractional anisotropy, mean diffusivity, and radial diffusivity; but not mode) was significantly related to pattern separation (measured using BPS-O and RAVLT tasks), but not to recognition memory. These data suggest that hippocampal disconnection, via individual- and age-related differences in limbic tract integrity, contributes to pattern separation performance. Extending our earlier work, these results also support the notion that pattern separation relies on broad neural networks interconnecting the hippocampus

Contrasting Cortical Activity Associated with Category Memory and Recognition Memory

We collected functional neuroimaging data while volunteers performed similar categorization and recognition memory tasks. In the categorization task, volunteers first studied a series of 40 dot patterns that were distortions of a nonstudied prototype dot pattern. After a delay, while fMRI data were collected, they categorized 72 novel dot patterns according to whether or not they belonged to the previously studied category. In the recognition task, volunteers first studied five dot patterns eight times each. After a delay, while fMRI data were collected, they judged whether each of 72 dot patterns had been studied earlier. We found strikingly different patterns of brain activity in visual processing areas for the two tasks. During the categorization task, the familiar stimuli were associated with decreased activity in posterior occipital cortex, whereas during the recognition task, the familiar stimuli were associated with increased activity in this area. The findings indicate that these two types of memory have contrasting effects on early visual processing and reinforce the view that declarative and nondeclarative memory operate independently

Memory for sequences of events impaired in typical aging

Typical aging is associated with diminished episodic memory performance. To improve our understanding of the fundamental mechanisms underlying this age-related memory deficit, we previously developed an integrated, cross-species approach to link converging evidence from human and animal research. This novel approach focuses on the ability to remember sequences of events, an important feature of episodic memory. Unlike existing paradigms, this task is nonspatial, nonverbal, and can be used to isolate different cognitive processes that may be differentially affected in aging. Here, we used this task to make a comprehensive comparison of sequence memory performance between younger (18–22 yr) and older adults (62–86 yr). Specifically, participants viewed repeated sequences of six colored, fractal images and indicated whether each item was presented “in sequence” or “out of sequence.” Several out of sequence probe trials were used to provide a detailed assessment of sequence memory, including: (i) repeating an item from earlier in the sequence (“Repeats”; e.g., ABADEF), (ii) skipping ahead in the sequence (“Skips”; e.g., ABDDEF), and (iii) inserting an item from a different sequence into the same ordinal position (“Ordinal Transfers”; e.g., AB3DEF). We found that older adults performed as well as younger controls when tested on well-known and predictable sequences, but were severely impaired when tested using novel sequences. Importantly, overall sequence memory performance in older adults steadily declined with age, a decline not detected with other measures (RAVLT or BPS-O). We further characterized this deficit by showing that performance of older adults was severely impaired on specific probe trials that required detailed knowledge of the sequence (Skips and Ordinal Transfers), and was associated with a shift in their underlying mnemonic representation of the sequences. Collectively, these findings provide unambiguous evidence that the capacity to remember sequences of events is fundamentally affected by typical aging