Gamma neuromodulation improves episodic memory and its associated network in amnestic mild cognitive impairment: a pilot study.

Amnestic mild cognitive impairment (aMCI) is a predementia stage of Alzheimer's disease associated with dysfunctional episodic memory and limited treatment options. We aimed to characterize feasibility, clinical, and biomarker effects of noninvasive neurostimulation for aMCI. 13 individuals with aMCI received eight 60-minute sessions of 40-Hz (gamma) transcranial alternating current stimulation (tACS) targeting regions related to episodic memory processing. Feasibility, episodic memory, and plasma Alzheimer's disease biomarkers were assessed. Neuroplastic changes were characterized by resting-state functional connectivity (RSFC) and neuronal excitatory/inhibitory balance. Gamma tACS was feasible and aMCI participants demonstrated improvement in multiple metrics of episodic memory, but no changes in biomarkers. Improvements in episodic memory were most pronounced in participants who had the highest modeled tACS-induced electric fields and exhibited the greatest changes in RSFC. Increased RSFC was also associated with greater hippocampal excitability and higher baseline white matter integrity. This study highlights initial feasibility and the potential of gamma tACS to rescue episodic memory in an aMCI population by modulating connectivity and excitability within an episodic memory network.

Leveraging technology to personalize cognitive enhancement methods in aging.

As population aging advances at an increasing rate, efforts to help people maintain or improve cognitive function late in life are critical. Although some studies have shown promise, the question of whether cognitive training is an effective tool for improving general cognitive ability remains incompletely explored, and study results to date have been inconsistent. Most approaches to cognitive enhancement in older adults have taken a 'one size fits all' tack, as opposed to tailoring interventions to the specific needs of individuals. In this Perspective, we argue that modern technology has the potential to enable large-scale trials of public health interventions to enhance cognition in older adults in a personalized manner. Technology-based cognitive interventions that rely on closed-loop systems can be tailored to individuals in real time and have the potential for global testing, extending their reach to large and diverse populations of older adults. We propose that the future of cognitive enhancement in older adults will rely on harnessing new technologies in scientifically informed ways.

Validation of At-Home Application of a Digital Cognitive Screener for Older Adults.

Standardized neuropsychological assessments of older adults are important for both clinical diagnosis and biobehavioral research. Over decades, in-person testing has been the basis for population normative values that rank cognitive performance by demographic status. Most recently, digital tools have enabled remote data collection for cognitive measures, which offers the significant promise to extend the basis for normative values to be more inclusive of a larger cross section of the older population. We developed a Remote Characterization Module (RCM), using a speech-to-text interface, as a novel digital tool to administer an at-home, 25-min cognitive screener that mimics eight standardized neuropsychological measures. Forty cognitively healthy participants were recruited from a longitudinal aging research cohort, and they performed the same measures of memory, attention, verbal fluency and set-shifting in both in-clinic paper-and-pencil (PAP) and at-home RCM versions. The results showed small differences, if any, for how participants performed on in-person and remote versions in five of eight tasks. Critically, robust correlations between their PAP and RCM scores across participants support the finding that remote, digital testing can provide a reliable assessment tool for rapid and remote screening of healthy older adults' cognitive performance in several key domains. The implications for digital cognitive screeners are discussed.

Virtual reality video game improves high-fidelity memory in older adults.

Therapeutic interventions have not yet been shown to demonstrate restorative effects for declining long-term memory (LTM) that affects many healthy older adults. We developed a virtual reality (VR) spatial wayfinding game (Labyrinth-VR) as a cognitive intervention with the hypothesis that it could improve detailed, high-fidelity LTM capability. Spatial navigation tasks have been used as a means to achieve environmental enrichment via exposure to and learning about novel and complex information. Engagement has been shown to enhance learning and has been linked to the vitality of the LTM system in the brain. In the current study, 48 older adults (mean age 68.7 ± 6.4 years) with average cognitive abilities for their age were randomly assigned to 12 h of computer game play over four weeks in either the Labyrinth-VR or placebo control game arms. Promptly before and after each participant's treatment regimen, high-fidelity LTM outcome measures were tested to assess mnemonic discrimination and other memory measures. The results showed a post-treatment gain in high-fidelity LTM capability for the Labyrinth-VR arm, relative to placebo, which reached the levels attained by younger adults in another experiment. This novel finding demonstrates generalization of benefits from the VR wayfinding game to important, and untrained, LTM capabilities. These cognitive results are discussed in the light of relevant research for hippocampal-dependent memory functions.

Evidence of a Causal Role for mid-Ventrolateral Prefrontal Cortex Based Functional Networks in Retrieving High-Fidelity Memory.

Functional neuroimaging studies have implicated regions of both ventrolateral prefrontal cortex (VLPFC) and angular gyrus in processes associated with retrieving goal-relevant information, which increases the fidelity and richness of long-term memory (LTM). To further investigate the roles of these cortical regions as nodes in functional networks with memory regions of the medial temporal lobe (MTL), we used fMRI-guided, 1 Hz repetitive transcranial magnetic stimulation (rTMS) to perturb normal neuronal function. The aim was to test the causal roles of left mid-VLPFC and left angular gyrus (AG) in MTL-VLPFC-parietal networks that have been associated with high-fidelity memory retrieval. rTMS treatments were administered immediately before blocks in an old/new recognition test, which was based on a mnemonic similarity task requiring discrimination of previously studied pictures of common objects. Capability for mnemonic discrimination was evaluated after each of three conditions: placebo control (rTMS at somatosensory cortex), mid-VLPFC target (rTMS at left pars triangularis) and parietal target (rTMS at left AG). The results showed the effect of rTMS perturbation of mid-VLPFC diminished subsequent discrimination-based memory performance, relative to placebo control, and no significant effect of perturbation of AG. These findings show a causal role for functional networks with left mid-VLPFC in high-fidelity retrieval.

Retrieval of high-fidelity memory arises from distributed cortical networks.

Medial temporal lobe (MTL) function is well established as necessary for memory of facts and events. It is likely that lateral cortical regions critically guide cognitive control processes to tune in high-fidelity details that are most relevant for memory retrieval. Here, convergent results from functional and structural MRI show that retrieval of detailed episodic memory arises from lateral cortical-MTL networks, including regions of inferior frontal and angular gyrii. Results also suggest that recognition of items based on low-fidelity, generalized information, rather than memory arising from retrieval of relevant episodic details, is not associated with functional connectivity between MTL and lateral cortical regions. Additionally, individual differences in microstructural properties in white matter pathways, associated with distributed MTL-cortical networks, are positively correlated with better performance on a mnemonic discrimination task.

External distraction impairs categorization performance in older adults.

The detrimental influence of distraction on memory and attention is well established, yet it is not as clear whether irrelevant information impacts categorization abilities and whether this impact changes in aging. We examined categorization with morphed prototype stimuli in both younger and older adults, using an adaptive staircase approach to assess participants' performance in conditions with and without visual distractors. Results showed that distraction did not affect younger adults, but produced a negative impact on older adults' categorization such that there was an interaction of age and distraction. These results suggest a relationship between the increased susceptibility to visual distraction in normal aging and impairment in categorization.

Distractibility during retrieval of long-term memory: domain-general interference, neural networks and increased susceptibility in normal aging.

The mere presence of irrelevant external stimuli results in interference with the fidelity of details retrieved from long-term memory (LTM). Recent studies suggest that distractibility during LTM retrieval occurs when the focus of resource-limited, top-down mechanisms that guide the selection of relevant mnemonic details is disrupted by representations of external distractors. We review findings from four studies that reveal distractibility during episodic retrieval. The approach cued participants to recall previously studied visual details when their eyes were closed, or were open and irrelevant visual information was present. The results showed a negative impact of the distractors on the fidelity of details retrieved from LTM. An fMRI experiment using the same paradigm replicated the behavioral results and found that diminished episodic memory was associated with the disruption of functional connectivity in whole-brain networks. Specifically, network connectivity supported recollection of details based on visual imagery when eyes were closed, but connectivity declined in the presence of visual distractors. Another experiment using auditory distractors found equivalent effects for auditory and visual distraction during cued recall, suggesting that the negative impact of distractibility is a domain-general phenomenon in LTM. Comparisons between older and younger adults revealed an aging-related increase in the negative impact of distractibility on retrieval of LTM. Finally, a new study that compared categorization abilities between younger and older adults suggests a cause underlying age-related decline of visual details in LTM. The sum of our findings suggests that cognitive control resources, although limited, have the capability to resolve interference from distractors during tasks of moderate effort, but these resources are overwhelmed when additional processes associated with episodic retrieval, or categorization of complex prototypes, are required.

The limited usefulness of models based on recollection and familiarity.

A recent report concluded that magnetoencephalographic signals of neural activity associated with memory based on the recollection process are independent from signals associated with memory based on the familiarity process. These data can be interpreted equally well, however, as indications of memory aggregated from both processes and showing that signals associated with high-confidence recognition are dissociable from signals associated with low-confidence recognition. The usefulness of interpreting neural data according to psychological models based on recollection and familiarity is discussed.

Distractibility during episodic retrieval is exacerbated by perturbation of left ventrolateral prefrontal cortex.

The presence of irrelevant external stimuli during the retrieval of long-term memory (LTM) has a negative impact on the fidelity of recollected details. Top-down control processes that both guide the selection of internal information relevant to LTM goals and resolve interference on retrieval from irrelevant external information have been associated with the same region in left ventrolateral prefrontal cortex (VLPFC). The current study examined a causal role of the left VLPFC in memory performance when external distraction (i.e., visual stimuli irrelevant to the current task goals) was presented during retrieval of LTM. Immediately after functional perturbation of the left VLPFC with 1-Hz repetitive transcranial magnetic stimulation, participants' memory was tested when their eyes were closed and when their eyes were open and irrelevant visual stimuli were presented. The results showed that visual distraction diminished LTM performance based on an objective measure of recollection and that perturbation of left VLPFC exacerbated the disruptive effect. This is the first evidence of a direct role of the left VLPFC in diminishing the impact of distraction on recollection, elucidating neural mechanisms that are critically involved in how we reconstruct the past while navigating the external environment.

The impact of visual distraction on episodic retrieval in older adults.

Impairment in long-term memory is one of the most salient alterations in cognitive aging. Findings of age-related deficits in source monitoring and recollection have revealed a selective decline in memory for detailed information. The underlying mechanism of this phenomenon is not well understood. We hypothesized that the influence of task-irrelevant visual stimuli present in our environment interferes with retrieval of detailed memories more for older than younger adults. We compared memory performance on a recall test for visual details when older adult participants' eyes were closed versus performance when their eyes were open and irrelevant visual stimuli were presented. The results showed that the presence of irrelevant visual information diminished long-term memory performance based on an objective measure of recollection for visual details. Comparison of the current results to findings from our earlier study using the same experimental paradigm with younger adults revealed that visual distraction disrupted recollection of relevant details to a greater degree in older than younger adults. This result suggests that visual distraction overwhelms older adults' declining cognitive control resources that are instrumental in the retrieval and selection of mnemonic details. More generally, these findings explicate a mechanistic basis for selective impairment of recollection in normal aging.

The impact of auditory distraction on retrieval of visual memories.

Recent research has revealed that the presence of irrelevant visual information during retrieval of long-term memories diminishes recollection of task-relevant visual details. Here, we explored the impact of irrelevant auditory information on remembering task-relevant visual details by probing recall of the same previously viewed images while participants were in complete silence, exposed to white noise, or exposed to ambient sounds recorded at a busy café. The presence of auditory distraction diminished objective recollection of goal-relevant details, relative to the silence and white noise conditions. Critically, a comparison with results from a previous study using visual distractors showed equivalent effects for auditory and visual distraction. These findings suggest that disruption of recollection by external stimuli is a domain-general phenomenon produced by interference between resource-limited, top-down mechanisms that guide the selection of mnemonic details and control processes that mediate our interactions with external distractors.

Strong memories are hard to scale.

People are generally skilled at using a confidence scale to rate the strength of their memories over a wide range. Specifically, low-confidence recognition decisions are often associated with close-to-chance accuracy, whereas high-confidence recognition decisions can be associated with close-to-perfect accuracy. However, using a 20-point rating scale, the authors found that the ability to scale memory strength had its limitations in that a high proportion of list items received the highest rating of 20. Efforts to induce participants to differentiate between these strong memories using emphatic instructions and alternative scales were not successful. Remember/know judgments indicated that these strong and hard-to-scale memories were often based on familiarity (not just recollection). Providing error feedback on a plurals discrimination task finally produced a high-confidence criterion shift. The authors suggest that the ability to scale strong (and almost perfectly accurate) memories may be limited because of the absence of differential error feedback for very strong memories in the past (the kind of differential error feedback that may account for the memory-scaling expertise that participants otherwise exhibit).

Hippocampal signals for strong memory when associative memory is available and when it is not.

The paired-associate task has been used with functional magnetic resonance imaging (fMRI) in studies that assessed the role of the medial temporal lobe (MTL) subserving recollection and familiarity.Some researchers have interpreted their results to mean that the hippocampus selectively subserves recollection and not familiarity[cf., Eichenbaum et al., (2007) Annu Rev Neurosci 30:123­152]. Yet many of these results confound recollection and familiarity with strong and weak memories, and it is not clear whether the conclusions represent differences between memory processes or memory strength. In the current study, participants were scanned with fMRI during retrieval in a paired-associate task, and a new approach separated the analysis of memory strength from the analysis of memory processes. The data were sorted by confidence level in an old/new task, and the high-confidence responses were compared in categories when associative memory was highly accurate and when it was not available. The results show that high-confidence memory produced increased activity in the hippocampus,relative to the level for forgotten pairs, both when associative memory was available and when it was not. Two interpretations are discussed for the behavioral results for when associative memory was not available: one account based on familiarity and the other account based on noncriterial recollection. The conclusion is that recognition of the word-pairs was based on familiarity when associative memory was not available. Together with the fMRI results that activity in two regions associated with cognitive control (left ventrolateral prefrontal cortex and left inferior parietal lobule) was greater when responses were based on associative memory than when based on familiarity, the findings suggest that the hippocampus supports strong memory and that cortical regions make an additional contribution to recollection.

Neural mechanisms underlying the impact of visual distraction on retrieval of long-term memory.

Filtering information on the basis of what is relevant to accomplish our goals is a critical process supporting optimal cognitive performance. However, it is not known whether exposure to irrelevant environmental stimuli impairs our ability to accurately retrieve long-term memories. We hypothesized that visual processing of irrelevant visual information would interfere with mental visualization engaged during recall of the details of a prior experience, despite goals to direct full attention to the retrieval task. In the current study, we compared performance on a cued-recall test of previously studied visual items when participants' eyes were closed to performance when their eyes were open and irrelevant visual stimuli were presented. A behavioral experiment revealed that recollection of episodic details was diminished in the presence of the irrelevant information. A functional magnetic resonance imaging experiment using the same paradigm replicated the behavioral results and found that diminished recollection was associated with the disruption of functional connectivity in a network involving the left inferior frontal gyrus, hippocampus and visual association cortex. Network connectivity supported recollection of contextual details based on visual imagery when eyes were closed, but declined in the presence of irrelevant visual information. We conclude that bottom-up influences from irrelevant visual information interfere with top-down selection of episodic details mediated by a capacity-limited frontal control region, resulting in impaired recollection.

In search of recollection and familiarity signals in the hippocampus.

fMRI studies of recognition memory have often been interpreted to mean that the hippocampus selectively subserves recollection and that adjacent regions selectively subserve familiarity. Yet, many of these studies have confounded recollection and familiarity with strong and weak memories. In a source memory experiment, we compared correct source judgments (which reflect recollection) and incorrect source judgments (often thought to reflect familiarity) while equating for old-new memory strength by including only high-confidence hits in the analysis. Hippocampal activity associated with both correct source judgments and incorrect source judgments exceeded the activity associated with forgotten items and did so to a similar extent. Further, hippocampal activity was greater for high-confidence old decisions relative to forgotten items even when source decisions were at chance. These results identify a recollection signal in the hippocampus and may identify a familiarity signal as well. Similar results were obtained in the parahippocampal gyrus. Unlike in the medial temporal lobe, activation in prefrontal cortex increased differentially in association with source recollection.

Recollection is a continuous process: implications for dual-process theories of recognition memory.

Dual-process theory, which holds that recognition decisions can be based on recollection or familiarity, has long seemed incompatible with signal detection theory, which holds that recognition decisions are based on a singular, continuous memory-strength variable. Formal dual-process models typically regard familiarity as a continuous process (i.e., familiarity comes in degrees), but they construe recollection as a categorical process (i.e., recollection either occurs or does not occur). A continuous process is characterized by a graded relationship between confidence and accuracy, whereas a categorical process is characterized by a binary relationship such that high confidence is associated with high accuracy but all lower degrees of confidence are associated with chance accuracy. Using a source-memory procedure, we found that the relationship between confidence and source-recollection accuracy was graded. Because recollection, like familiarity, is a continuous process, dual-process theory is more compatible with signal detection theory than previously thought.

FMRI signals associated with memory strength in the medial temporal lobes: a meta-analysis.

To identify patterns of memory-related neural activity in the medial temporal lobes (MTL), a quantitative meta-analysis of 17 functional magnetic resonance imaging (fMRI) studies was performed. The analysis shows that increased activity in the hippocampus and the parahippocampal cortex predicts subsequent memory strength. During retrieval, activity in the hippocampus increases in association with strong memory. In the perirhinal cortex, increased activity predicts subsequent recognition, whether based on weak or strong memory, whereas during retrieval activity decreases below the level for misses in association with both weak and strong memory. The results are consistent with the claim that the hippocampus selectively subserves recollection, whereas adjacent structures subserve familiarity [Eichenbaum, H., Yonelinas, A., & Ranganath, C. (2007). The medial temporal lobe and recognition memory. The Annual Review of Neuroscience, 30, 123-152]. However, this conclusion depends on a specific dual-process theory of recognition memory that has been used to interpret the results. An alternative dual-process model holds that the behavioral methods used to differentiate recollection from familiarity instead separate strong memories from weak memories. When the fMRI data are interpreted in terms of the alternative theory, the fMRI results do not point to selective roles for the hippocampus or the adjacent MTL structures. The fMRI data alone cannot distinguish between these two models, so other methods are needed to resolve the issue.

Remember/know judgments probe degrees of recollection.

Remembering and knowing are states of awareness that accompany the retrieval of facts, faces, and experiences from our past. Although originally intended to separate episodic from semantic memory, the dominant view today is that recollection-based decisions underlie remember responses, whereas familiarity-based decisions underlie know responses. Many functional magnetic resonance imaging (fMRI) studies as well as lesion studies have relied on the remember/know procedure to identify the neural correlates of recollection and familiarity. An implicit assumption of this approach is that know responses, which are thought to tap familiarity-based decisions, are devoid of recollection. We investigated this issue by using a source memory procedure and found that the accuracy of source recollection was significantly above chance for studied words that were declared to be old and known. Critically, this held true even when the source decision was made before the old/new decision (i.e., even after successful recollection had just occurred). Our results show that although recollection and familiarity may be different processes, the remember/know paradigm does not probe them directly. As such, dissociations involving remember/know judgments in fMRI studies and in studies involving amnesic patients should not be construed as dissociations between recollection and familiarity.