Autobiographical Cerebral Network Activation in Older Adults Before and After Reminiscence Therapy: A Preliminary Report.

INTRODUCTION: Reminiscence therapy (RT), which engages individuals to evoke positive memories, has been shown to be effective in improving psychological well-being in older adults suffering from PTSD, depression, and anxiety. However, its impact on brain function has yet to be determined. This paper presents functional magnetic resonance imaging (fMRI) data to describe changes in autobiographical memory networks (AMN) in community-dwelling older adults. METHODS: This pilot study used a within-subject design to measure changes in AMN activation in 11 older adults who underwent 6 weeks of RT. In the scanner, participants retrieved autobiographical memories which were either recent or remote, rehearsed or unrehearsed. Participants also underwent a clinical interview to assess changes in memory, quality of life, mental health, and affect. FINDINGS: Compared to pretreatment, anxiety decreased (z = -2.014, p = .040) and activated significant areas within the AMN, including bilateral medial prefrontal cortex, left precuneus, right occipital cortex, and left anterior hippocampus. CONCLUSION: Although RT had subtle effects on psychological function in this sample with no evidence of impairments, including depression at baseline, the fMRI data support current thinking of the effect RT has on the AMN. Increased activation of right posterior hippocampus following RT is compatible with the Multiple Trace Theory Theory (Nadel & Moscovitch, 1997).

Theta oscillatory power decreases in humans are associated with spatial learning in a virtual water maze task.

Theta oscillations (4-8 Hz) in humans play a role in navigation processes, including spatial encoding, retrieval and sensorimotor integration. Increased theta power at frontal and parietal midline regions is known to contribute to successful navigation. However, the dynamics of cortical theta and its role in spatial learning are not fully understood. This study aimed to investigate theta oscillations via electroencephalogram (EEG) during spatial learning in a virtual water maze. Participants were separated into a learning group (n = 25) who learned the location of a hidden goal across 12 trials, or a time-matched non-learning group (n = 25) who were required to simply navigate the same arena, but without a goal. We compared all trials, at two phases of learning, the trial start and the goal approach. We also compared the first six trials with the last six trials within-groups. The learning group showed reduced low-frequency theta power at the frontal and parietal midline during the start phase and largely reduced theta combined with a short increase at both midlines during the goal-approach phase. These patterns were not found in the non-learning group, who instead displayed extensive increases in low-frequency oscillations at both regions during the trial start and at the parietal midline during goal approach. Our results support the theory that theta plays a crucial role in spatial encoding during exploration, as opposed to sensorimotor integration. We suggest our findings provide evidence for a link between learning and a reduction of theta oscillations in humans.

Examining individual learning patterns using generalised linear mixed models.

Everyone learns differently, but individual performance is often ignored in favour of a group-level analysis. Using data from four different experiments, we show that generalised linear mixed models (GLMMs) and extensions can be used to examine individual learning patterns. Producing ellipsoids and cluster analyses based on predicted random effects, individual learning patterns can be identified, clustered and used for comparisons across various experimental conditions or groups. This analysis can handle a range of datasets including discrete, continuous, censored and non-censored, as well as different experimental conditions, sample sizes and trial numbers. Using this approach, we show that learning a face-named paired associative task produced individuals that can learn quickly, with the performance of some remaining high, but with a drop-off in others, whereas other individuals show poor performance throughout the learning period. We see this more clearly in a virtual navigation spatial learning task (NavWell). Two prominent clusters of learning emerged, one showing individuals who produced a rapid learning and another showing a slow and gradual learning pattern. Using data from another spatial learning task (Sea Hero Quest), we show that individuals' performance generally reflects their age category, but not always. Overall, using this analytical approach may help practitioners in education and medicine to identify those individuals who might need extra help and attention. In addition, identifying learning patterns may enable further investigation of the underlying neural, biological, environmental and other factors associated with these individuals.

Landmark Distance Impacts the Overshadowing Effect in Spatial Learning Using a Virtual Water Maze Task with Healthy Adults.

Cue competition is a key element of many associative theories of learning. Overshadowing, an important aspect of cue competition, is a phenomenon in which learning about a cue is reduced when it is accompanied by a second cue. Overshadowing has been observed across many domains, but there has been limited investigation of overshadowing in human spatial learning. This experiment explored overshadowing using two landmarks/cues (at different distances to the goal) in a virtual water maze task with young, healthy adult participants. Experiment 1 initially examined whether the cues used were equally salient. Results indicated that both gained equal control over performance. In experiment 2, overshadowing was examined using the two cues from experiment 1. Results indicated that overshadowing occurred during spatial learning and that the near cue controlled searching significantly more than the far cue. Furthermore, the far cue appeared to have been completely ignored, suggesting that learning strategies requiring the least amount of effort were employed by participants. Evidence supporting an associative account of human spatial navigation and the influence of proximal cues was discussed.

Safety and feasibility of transcutaneous vagus nerve stimulation in mild cognitive impairment: VINCI-AD study protocol.

BACKGROUND: Over 55 million adults are living with dementia globally, which is projected to reach 157 million by 2050. Mild cognitive impairment (MCI), a syndrome of memory impairment with intact activities of daily living, may precede dementia by several years. Around 5-15% of individuals with MCI convert to dementia annually. Novel treatments which delay progression of MCI to dementia are urgently needed. Transcutaneous vagal nerve stimulation (tVNS) is a non-invasive neuromodulation technique that targets the vagus nerve. Importantly, tVNS has been shown to improve cognition in healthy volunteers, but has not been extensively examined as a potential therapeutic approach in MCI. VINCI-AD will examine the safety and feasibility of tVNS in older adults with MCI. DESIGN: VINCI-AD is an investigator-led, single-site, single-blind, sham-controlled crossover pilot study which aims to assess the safety and feasibility of tVNS in 40 participants with amnestic MCI. All participants will attend for three consecutive study visits during which they will be randomised to receive no stimulation (baseline), active tVNS stimulation (stimulation at cymba conchae of left ear) or sham tVNS stimulation (at earlobe). Safety will be primarily assessed by ascertainment of adverse events. Further safety assessment will examine the impact of acute tVNS on subjective (orthostatic symptoms), peripheral (finometry-based blood pressure) and central (assessed via Near Infrared Spectroscopy [NIRS]) haemodynamic responses to active stand. Feasibility will be determined using a custom-designed occupational assessment of device usability. Exploratory secondary analysis in VINCI-AD will examine the potential impact of acute tVNS on associative memory, spatial memory and inhibitory control to inform sample size estimates for future trials of tVNS in older adults with MCI. DISCUSSION: VINCI-AD will report on the safety (adverse events/haemodynamic responses to active stand) and feasibility of tVNS as a potential therapeutic option in MCI. Detailed reporting of study eligibility and completion rates will be reported. Exploratory analysis will examine the potential cognitive benefits of acute tVNS on cognitive function in MCI to report potential effect sizes that may inform future clinical trials in this cohort. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT05514756 . Trial Registration Number NCT05514756 (24th August 2022 for this protocol, version 1.0.).

Preservation of long-term memory in older adults using a spaced learning paradigm.

How much information we retain depends on type/schedule of training. It has been widely acknowledged that spaced learning is advantageous compared to massed learning for cognitively healthy young adults and should be considered an educational standard. Literature would suggest that the spacing effect is preserved with age, though it is unclear whether this effect translates to more ecologically valid concepts such as face-name associations, which are particularly susceptible to deterioration with age. Two experiments were conducted to investigate the effects of spacing across recent/remote retention intervals, and the effect of age on spacing in cognitively healthy older adults using the Face-Name Pairs task. Experiment 1 results suggest that the beneficial memory effects of spacing are particularly observed with long-term memory. Experiment 2 results suggest that older adults are impaired at learning compared to younger adults, that the spacing effect influences both older and younger adults at longer intervals, and that spaced-trained participants display similar forgetting patterns at longer intervals, irrespective of age. These results may have some implications regarding improving the conditions under which optimum retention occurs (namely, whether spacing is beneficial when learning ecologically valid concepts at longer intervals outside of laboratory settings), and may provide insight into the effect of age on our ability to learn and remember face-name associations.

"The Wandering Nerve Linking Heart and Mind" - The Complementary Role of Transcutaneous Vagus Nerve Stimulation in Modulating Neuro-Cardiovascular and Cognitive Performance.

The vagus nerve is the longest nerve in the human body, providing afferent information about visceral sensation, integrity and somatic sensations to the CNS via brainstem nuclei to subcortical and cortical structures. Its efferent arm influences GI motility and secretion, cardiac ionotropy, chonotropy and heart rate variability, blood pressure responses, bronchoconstriction and modulates gag and cough responses via palatine and pharyngeal innervation. Vagus nerve stimulation has been utilized as a successful treatment for intractable epilepsy and treatment-resistant depression, and new non-invasive transcutaneous (t-VNS) devices offer equivalent therapeutic potential as invasive devices without the surgical risks. t-VNS offers exciting potential as a therapeutic intervention in cognitive decline and aging populations, classically affected by reduced cerebral perfusion by modulating both limbic and frontal cortical structures, regulating cerebral perfusion and improving parasympathetic modulation of the cardiovascular system. In this narrative review we summarize the research to date investigating the cognitive effects of VNS therapy, and its effects on neurocardiovascular stability.

Predicting conversion of patients with Mild Cognitive Impairment to Alzheimer's disease using bedside cognitive assessments.

INTRODUCTION: Patients diagnosed with Mild Cognitive Impairment (MCI) often go on to develop dementia, however many do not. Although cognitive tests are widely used in the clinic, there is limited research on their potential to help predict which patients may progress to Alzheimer's disease (AD) from those that do not. METHODS: MCI patients (n = 325) from the longitudinal Alzheimer's Disease Neuroimaging Initiative (ADNI-2) dataset were tracked across a 5 year period. Upon initial diagnosis, all patients underwent a series of cognitive tests including the Mini Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA) and Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog 13). Twenty-five percent (n = 83) of those initially diagnosed with MCI subsequently developed AD within 5 years. RESULTS: We showed that those individuals that progressed to AD had significantly lower scores upon baseline testing on the MMSE and MoCA, and higher scores on the ADAS-13, compared to those that did not convert. However, not all tests were equivalent. We showed that the ADAS-13 offers the best predictability of conversion (Adjusted Odds ratio (AOR) = 3.91). This predictability was higher than that offered by the two primary biomarker Amyloid-beta (Aß, AOR = 1.99) and phospho-tau (Ptau, AOR = 1.72). Further analysis on the ADAS-13 showed that MCI patients that subsequently converted to AD performed particularly poorly on delayed-recall (AOR = 1.93), word recognition (AOR = 1.66), word finding difficulty (AOR = 1.55) and orientation (1.38) test items. CONCLUSIONS: Cognitive testing using the ADAS-13 may offer a simpler, less invasive, more clinically relevant and a more effective method of determining those that are in danger of converting from MCI to AD.

Spatial Recognition Memory: Differential Brain Strategic Activation According to Sex.

Human spatial memory research has significantly progressed since the development of computerized tasks, with many studies examining sex-related performances. However, few studies explore the underlying electrophysiological correlates according to sex. In this study event-related potentials were compared between male and female participants during the performance of an allocentric spatial recognition task. Twenty-nine university students took part in the research. Results showed that while general performance was similar in both sexes, the brain of males and females displayed a differential activation. Males showed increased N200 modulation than females in the three phases of memory process (encoding, maintenance, and retrieval). Meanwhile females showed increased activation of P300 in the three phases of memory process compared to males. In addition, females exhibited more negative slow wave (NSW) activity during the encoding phase. These differences are discussed in terms of attentional control and the allocation of attentional resources during spatial processing. Our findings demonstrate that sex modulates the resources recruited to performed this spatial task.

Older Users of a Befriending Service in Ireland and the Maintenance of Personal Autonomy during the COVID-19 Pandemic.

In the Republic of Ireland (RoI), COVID-19 public health guidelines have been most restrictive for people aged 70 and over. Such individuals are most likely to avail of befriending services offered by a network of Irish organisations. The aim of this study was to explore the impact of COVID-19 guidelines on befriending service users, and to develop recommended adaptations to befriending services compatible with such guidelines. A qualitative constructivist grounded theory approach was taken to the study design and analysis, using semi-structured interviews to collect data from 11 participants by telephone between May 2020 and January 2021. Results show a grounded theory describing how older users of a befriending service maintained their personal autonomy in the face of strict government guidelines. Participants described living life as usual, often contravening guidelines, and how they chose to adapt to the situation, yielding both positive and negative outcomes. Some potential adaptations were discussed to the befriending service (including a preserved focus on the social and emotional functions of the befriending relationship, and the accommodation of collaborative decision making about communicative alternatives), but ultimately it was made clear that participants would tailor the services to their own preferences. Results have implications for befriending service design and delivery, and for public health officials who wish to support the health of older adults during the COVID-19 pandemic.

Virtual Morris water maze: opportunities and challenges.

The ability to accurately recall locations and navigate our environment relies on multiple cognitive mechanisms. The behavioural and neural correlates of spatial navigation have been repeatedly examined using different types of mazes and tasks with animals. Accurate performances of many of these tasks have proven to depend on specific circuits and brain structures and some have become the standard test of memory in many disease models. With the introduction of virtual reality (VR) to neuroscience research, VR tasks have become a popular method of examining human spatial memory and navigation. However, the types of VR tasks used to examine navigation across laboratories appears to greatly differ, from open arena mazes and virtual towns to driving simulators. Here, we examined over 200 VR navigation papers, and found that the most popular task used is the virtual analogue of the Morris water maze (VWM). Although we highlight the many advantages of using the VWM task, there are also some major difficulties related to the widespread use of this behavioural method. Despite the task's popularity, we demonstrate an inconsistency of use - particularly with respect to the environmental setup and procedures. Using different versions of the virtual water maze makes replication of findings and comparison of results across researchers very difficult. We suggest the need for protocol and design standardisation, alongside other difficulties that need to be addressed, if the virtual water maze is to become the 'gold standard' for human spatial research similar to its animal counterpart.

Hippocampal and prefrontal contributions to memory retrieval: Examination of immediate early gene, NMDA receptor and environmental interactions.

Animals can use a range of strategies to recall important locations. These include simple stimulus-response strategies and more complex spatial (place) strategies, which are thought to have distinct neural substrates. The hippocampus-and NMDA receptor activation therein-is considered to be crucial for spatial, but not response strategies. The medial prefrontal cortex has also been implicated in memory retrieval; however, evidence concerning its specific role is equivocal. Both hippocampal and prefrontal regions have been associated with flexible behavioural responding (e.g. when task demands change). Here, we investigated the use of spatial and non-spatial strategies in the Morris water maze and their associated brain areas in rats using immediate early gene (IEG) imaging of Zif268 and c-Fos. Specifically, we charted the involvement of hippocampal and prefrontal subregions during retrieval of spatial and non-spatial memories. Behavioural flexibility was also examined using intact and partial cue configurations during recall. Results indicated that regions of both the hippocampus (area CA3) and prefrontal cortex (anterior cingulate cortex) were preferentially engaged in spatial memory recall compared to response learning. In addition, both spatial and non-spatial memories were dependent on NMDA receptor activation. MK801 impaired recall performance across all groups and reduced IEG activation across hippocampal and prefrontal regions. Finally, IEG results revealed divergent patterns of Zif268 and c-Fos activity and support the suggestion that Zif268 plays a functional role in the recall of long-term memories.

NavWell: A simplified virtual-reality platform for spatial navigation and memory experiments.

Being able to navigate, recall important locations, and find the way home are critical skills, essential for survival for both humans and animals. These skills can be examined in the laboratory using the Morris water maze, often considered the gold standard test of animal navigation. In this task, animals are required to locate and recall the location of an escape platform hidden in a pool filled with water. Because animals can not see the platform directly, they must use various landmarks in the environment to escape. With recent advances in technology and virtual reality (VR), many tasks originally used in the animal literature can now be translated for human studies. The virtual water maze task is no exception. However, a number of issues are associated with these mazes, including cost, lack of flexibility, and lack of standardization in terms of experimental designs and procedures. Here we present a virtual water maze system (NavWell) that is readily downloadable and free to use. The system allows for the easy design of experiments and the testing of participants on a desktop computer or fully immersive VR environment. The data from four independent experiments are presented in order to validate the software. From these experiments, a set of procedures for use with a number of well-known memory tests is suggested. This potentially can help with the standardization of navigational research and with navigational testing in the clinic or in an educational environment. Finally, we discuss the limitations of the software and plans for its development and future use.

The complexities of behavioural assessment in neurodegenerative disorders: A focus on Alzheimer's disease.

Rodent models of human diseases that accurately and reproducibly capture their pathology are key tools in furthering our understanding of the mechanisms behind these diseases and in the development of novel treatment approaches. However, pre-clinical studies in rodents are often criticised for the relative lack of replication and success upon translation to humans. Animal models of neurodegenerative diseases (and other CNS conditions) are very complex, often with multifactorial inputs into their development and progression. This complexity is a significant challenge. In addition to this, there are often concerns raised about the conduct, analysis and interpretation of the model results. This review focuses on Alzheimer's disease as a representative neurodegenerative disorder and will examine disease model end-points, in particular, behavioural phenotyping which, while appearing relatively straightforward, has the potential to be poorly conducted and the results misconstrued. This review uses a sample of the literature to illustrate the breadth of techniques used in behavioural assessment of Alzheimer's disease models, highlight the complexity, illustrate some procedural, interpretational and translational issues and provide recommendations to improve conduct of pre-clinical testing with the hope that this may lead to more consistency and translational success.

Comparable walking gait performance during executive and non-executive cognitive dual-tasks in chronic stroke: A pilot study.

BACKGROUND: Falls are a serious problem among stroke survivors due to subsequent injuries, recovery setbacks, dependence, and mortality. A growing body of dual-task (DT) studies suggests a role of executive functions in gait control and falls, particularly in subacute stroke. However, few studies have compared distinct executive and non-executive tasks, nor their effects on chronic stroke gait. RESEARCH QUESTION: The purpose of this cross-sectional study was to compare the effects of distinct working memory (2-back) and inhibition (Stroop) tasks on walking gait performance in chronic stroke survivors. METHODS: A pilot sample of chronic stroke survivors (n = 11, 8 males, mean age = 70.91, 6-12months post-stroke event) and age-matched healthy controls (n = 13, 4 male; mean age = 68.46) were tested. Gait performance (speed, stride time, stride time variability, stride length and stride length variability) was measured using 2 wireless inertial measurement sensors under 4 walking conditions: 1) preferred walking (single-task: ST), 2) walking with a 2-back DT, 3) walking with a Stroop DT, and 4) walking with a non-executive motor response DT. The secondary tasks were also carried out in both ST (seated) and DT conditions, to examine bidirectional effects. RESULTS: While the stroke survivor sample had a slower gait speed across conditions and tasks, there were no significant differences between the groups [F(1, 22) = 1.13, p =.299, η2p = .049] on the spatial or temporal gait characteristics recorded: gait performance was maintained during executive and non-executive DTs. In addition, we did not find a significant effect of group on cognitive task performance (all p > .052). However, we observed a cost in accuracy on the 2-back DT for both groups, suggesting resource overlap and greater cognitive load (all t > 19.72, all p < .001). SIGNIFICANCE: Our gait data contradict previous studies evidencing impaired gait post-stroke, suggesting functional recovery in this chronic stroke sample.

A novel control condition for spatial learning in the Morris water maze.

BACKGROUND: Assessing markers of neural activity in rodent behavioural tasks benefits from meaningful comparison with matched control conditions. The Morris water maze is a widely used learning and memory task, but currently implemented control conditions are not optimal. NEW METHOD: We created a novel control condition involving random escape platform placement for each trial, while increasing the frequency of platforms throughout the training period. These control rats could therefore escape the maze by swimming in a random fashion and were not required to learn a platform location. Crucially, because the number of available escape platforms increased throughout training, their escape latencies should decline in line with rats who were learning a fixed platform location. RESULTS: No evidence of place learning was observed in this novel condition, but their swimming behaviour, including escape latency, distance and velocity were well matched to spatially-trained rats throughout training. Further, they did not display stress-related behaviour. COMPARISON WITH EXISTING METHODS: We contrasted this new control condition against a frequently used control where animals swim freely in the maze and showed behaviour was more closely matched to spatially-trained animals. CONCLUSIONS: This novel control condition represents a significant advance from those currently available and may assist in the interpretation of task-related neural activity.

Understanding the role of distance, direction and cue salience in an associative model of landmark learning.

Navigation and spatial memory relies on the ability to use and recall environmental landmarks relative to important locations. Such learning is thought to result from the strengthening of associations between the goal location and environmental cues. Factors that contribute to the strength of this association include cue stability, saliency and cue location. Here we combine an autoregressive random walk model, that describes goal-directed swimming behaviour, with an associative learning model to provide an integrated model of landmark learning, using the water maze task. The model allows for the contribution of each cue, the salience and the vector information provided (both distance and directional) to be separately analysed. The model suggests that direction and distance information are independent components and can influence searching patterns. Importantly, the model can also be used to simulate various experimental scenarios to understand what has been learnt in relation to the cues, thereby offering new insights into how animals navigate.

Efficiency: an underlying principle of learning?

Learning is essential. It allows animals to change circumstances, deal with new situations and adapt to environments. Here, we argue that learning, at behavioral and neural levels, involves efficiency, reflected in metabolic cost reductions. Behaviourally, although multiple solutions to a novel problem may be available, all solutions are not learnt - it is too costly. Furthermore, once a strategy has been selected, it is reinforced producing an efficiency that leads to a maximisation of performance and metabolic cost reductions. Learning can be represented in the brain through many mechanisms; however, if learning is truly efficient, then, all such mechanisms should also be accompanied by a reduction in measurable metabolic costs. By thinking about learning in terms of efficiency, not simply as a descriptive term but rather in terms of metabolic costs, it allows learning to be examined more carefully and provides predictions that can be easily tested (and indeed refuted).

Autobiographical memory, the ageing brain and mechanisms of psychological interventions.

Elucidating the impact of healthy cognitive ageing and dementia on autobiographical memory (AM) may help deepen our theoretical understanding of memory and underlying neural changes. The distinction between episodic and semantic autobiographical memory is particularly informative in this regard. Psychological interventions, particularly those involving reminiscence or music, have led to differential effects on episodic and semantic autobiographical memory. We propose that executive function is a key mediator of psychological therapies on autobiographical memory. We also highlight that interventions that alleviate stress and improve mood, including in major depression, can enhance autobiographical memory. Future research employing more longitudinal approaches and examining moderating factors such as gender and education level will deepen our understanding of changes in AM in later life, enhance our theoretical understanding of the neuroscience of AM and ageing, and help to develop better targeted interventions for preserving AM in older adults.

Temporal dynamics of immediate early gene expression during cellular consolidation of spatial memory.

The consolidation of newly acquired memories on a cellular level is thought to take place in the first few hours following learning. This process is dependent on de novo protein synthesis during this time, which ultimately leads to long-term structural and functional neuronal changes and the stabilisation of a memory trace. Immediate early genes (IEGs) are rapidly expressed in neurons following learning, and previous research has suggested more than one wave of IEG expression facilitates consolidation in the hours following learning. We analysed the expression of Zif268, c-Fos and Arc protein in a number of brain regions involved in spatial learning either 90min, 4h or 8h following training in the Morris water maze task. Consistent with the role of IEGs in the earliest stages of consolidation, a single wave of expression was observed in most brain regions at 90min, however a subsequent wave of expression was not observed at 8h. In fact, Zif268 expression was observed to fall below the levels of naïve controls at this time-point in the medial prefrontal and perirhinal cortices. This may be indicative of synaptic downscaling in these regions in the hours following learning, and an important marker of the consolidation of spatial memory.