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Predicting and modeling human behavior and finding trends within human decision-making processes is a major problem of social science. Rock Paper Scissors (RPS) is the fundamental strategic question in many game theory problems and real-world competitions. Finding the right approach to beat a particular human opponent is challenging. Here we use an AI (artificial intelligence) algorithm based on Markov Models of one fixed memory length (abbreviated as "single AI") to compete against humans in an iterated RPS game. We model and predict human competition behavior by combining many Markov Models with different fixed memory lengths (abbreviated as "multi-AI"), and develop an architecture of multi-AI with changeable parameters to adapt to different competition strategies. We introduce a parameter called "focus length" (a positive number such as 5 or 10) to control the speed and sensitivity for our multi-AI to adapt to the opponent's strategy change. The focus length is the number of previous rounds that the multi-AI should look at when determining which Single-AI has the best performance and should choose to play for the next game. We experimented with 52 different people, each playing 300 rounds continuously against one specific multi-AI model, and demonstrated that our strategy could win against more than 95% of human opponents.

Resting-state functional magnetic resonance imaging (rs-fMRI) and brain functional connectome (we use 'brain connectome' hereafter for simplicity) have advanced our understanding of the ageing brain and age-related changes in cognitive function. Previous studies have investigated the association among brain connectome and age, global cognition, and memory function separately. However, very few have predicted age, overall cognitive functioning and memory performance in a single study to better understand their complex relationship. In this cross-sectional study, we applied an exploratory, data-driven method to investigate the brain connectome markers that could predict ageing, overall cognitive functioning assessed as intelligence quotient (IQ, measured by Wechsler Memory Scale) and memory performance assessed as memory quotient (MQ, measured by Wechsler Memory Scale) in a carefully designed, multicentre, normal ageing cohort (n = 313). Our results showed that brain connectome could predict ageing and IQ, but the association with MQ was weak. We found that the connectivity with orbital frontal cortex was associated with both ageing and IQ. Mediation analysis further showed that the brain connectome mediated the relationship between age and overall cognitive functioning, suggesting a protective brain connectomic mechanism for maintaining normal cognitive functions during healthy ageing. This work may shed light on the potential neural correlates of healthy ageing, overall cognitive functioning and memory performance., (© 2024 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Expressions such as 'sleep on it' refer to the resolution of distressing experiences across a night of sound sleep. Sleep is an active state during which the brain reorganizes the synaptic connections that form memories. This Perspective proposes a model of how sleep modifies emotional memory traces. Sleep-dependent reorganization occurs through neurophysiological events in neurochemical contexts that determine the fates of synapses to grow, to survive or to be pruned. We discuss how low levels of acetylcholine during non-rapid eye movement sleep and low levels of noradrenaline during rapid eye movement sleep provide a unique window of opportunity for plasticity in neuronal representations of emotional memories that resolves the associated distress. We integrate sleep-facilitated adaptation over three levels: experience and behaviour, neuronal circuits, and synaptic events. The model generates testable hypotheses for how failed sleep-dependent adaptation to emotional distress is key to mental disorders, notably disorders of anxiety, depression and post-traumatic stress with the common aetiology of insomnia., (© 2024. Springer Nature Limited.)

Motor skills are required for activities of daily living. Transcranial direct current stimulation (tDCS) applied in association with motor skill learning has been investigated as a tool for enhancing training effects in health and disease. Here, we review the published literature investigating whether tDCS can facilitate the acquisition, retention or adaptation of motor skills. Work in multiple laboratories is underway to develop a mechanistic understanding of tDCS effects on different forms of learning and to optimize stimulation protocols. Efforts are required to improve reproducibility and standardization. Overall, reproducibility remains to be fully tested, effect sizes with present techniques vary over a wide range, and the basis of observed inter-individual variability in tDCS effects is incompletely understood. It is recommended that future studies explicitly state in the Methods the exploratory (hypothesis-generating) or hypothesis-driven (confirmatory) nature of the experimental designs. General research practices could be improved with prospective pre-registration of hypothesis-based investigations, more emphasis on the detailed description of methods (including all pertinent details to enable future modeling of induced current and experimental replication), and use of post-publication open data repositories. A checklist is proposed for reporting tDCS investigations in a way that can improve efforts to assess reproducibility., (Copyright © 2017. Published by Elsevier B.V.)

Abstract: The aim of this systematic review and meta-analysis was to analyze the accuracy of memory of pain and the variables that may influence it in children with acute, experimental, and chronic pain. We conducted a search in electronic databases from inception to February 11, 2022. Twelve observational studies and 3 randomized controlled studies were included in the study. The main outcome measure was the accuracy of the memory of the pain intensity (experienced/recalled). To compare the outcomes reported by the studies, we calculated the standardized mean difference (SMD) over time for the continuous variables. The overall meta-analysis showed a small effect size in favor of an overestimation of experienced pain intensity (SMD = 0.28). Subanalyzing per pain context, there was a small effect size in favor of overestimation in the clinical context (SMD = 0.33), but there was no evidence of any change in the accuracy of memory of pain in the experimental context (SMD = 0.07). The mean age of the participants and the proportion of girls significantly predicted the accuracy of the memory of pain. The period since the experienced pain measurement, the intensity of expected and recalled fear, trait anxiety, and anxiety sensitivity did not significantly predict the accuracy of the memory of pain. Children showed an overestimation in pain memory between the experienced and recalled intensity of acute pain, especially in a clinical context. Furthermore, only gender and age were predictors of the accuracy of pain memory. These results highlight the relevance of pain memory to medical practice and future research., (Copyright © 2024 International Association for the Study of Pain.)

Memories are thought to be stored in neuronal ensembles referred to as engrams. Studies have suggested that when two memories occur in quick succession, a proportion of their engrams overlap and the memories become linked (in a process known as prospective linking) while maintaining their individual identities. In this Review, we summarize the key principles of memory linking through engram overlap, as revealed by experimental and modelling studies. We describe evidence of the involvement of synaptic memory substrates, spine clustering and non-linear neuronal capacities in prospective linking, and suggest a dynamic somato-synaptic model, in which memories are shared between neurons yet remain separable through distinct dendritic and synaptic allocation patterns. We also bring into focus retrospective linking, in which memories become associated after encoding via offline reactivation, and discuss key temporal and mechanistic differences between prospective and retrospective linking, as well as the potential differences in their cognitive outcomes., (© 2024. Springer Nature Limited.)

Background: The trends in medical publishing are towards electronic versions and the use of the English language. The objective of this study was to compare general practitioners' ability to retain information when reading on paper versus on screen, and in their mother tongue versus in the English., Material and Methods: Randomized controlled trial of 114 Scandinavian general practitioners. They read a review article for 10 minutes either on paper/in English, on screen/in English, on paper/in their mother tongue, or on screen/in their mother tongue. Afterwards they completed a questionnaire with six open questions from the article. The main outcome measure was sum score on a scale from 0 (no correct answers) to 13 (all questions answered correctly)., Results: We found no difference between readers of paper and screen versions (median (interquartile range) 4 (2-6) vs. 4 (2-5), p = 0.97). Those who read their mother tongue scored significantly higher than those who read English (4 (3-6) vs. 3 (2-4), p = 0.01)., Interpretation: The medium (paper vs. screen) does not influence the ability of general practitioners to retain medical information. Doctors best retain medical information when reading it in their mother tongue.

For researchers and psychologists interested in estimating a subject's memory capacity, the current standard for scoring memory span tasks is the partial-credit method: subjects are credited with the number of stimuli that they manage to recall correctly in the correct serial position. A critical issue with this method, however, is that intrusions and omissions can radically change the scores depending on where they occur. For example, when recalling the sequence ABCDE, "ABCD" is worth 4 points but "BCDE" is worth 0 points. This paper presents an improved scoring method based on the edit distance, meaning the number of changes required to edit the recalled sequence into the target. Edit-distance scoring gives results close to partial-credit scoring, but without the corresponding vulnerability to positional shifts. A reanalysis of memory performance in two large datasets (N = 1093 and N = 758) confirms that in addition to being more logically consistent, edit-distance scoring demonstrates similar or better psychometric properties than partial-credit, with comparable validity, a small increase in reliability, and a substantial increase of test information (measurement precision in the context of item response theory). Test information was especially improved for harder items and for subjects with ability in the lower range, whose scores tend to be severely underestimated by partial-credit scoring. Code to compute edit-distance scores with various software is made available at https://osf.io/wdb83/ ., (© 2022. The Psychonomic Society, Inc.)

In less than three decades, the concept "cerebellar neurocognition" has evolved from a mere afterthought to an entirely new and multifaceted area of neuroscientific research. A close interplay between three main strands of contemporary neuroscience induced a substantial modification of the traditional view of the cerebellum as a mere coordinator of autonomic and somatic motor functions. Indeed, the wealth of current evidence derived from detailed neuroanatomical investigations, functional neuroimaging studies with healthy subjects and patients and in-depth neuropsychological assessment of patients with cerebellar disorders shows that the cerebellum has a cardinal role to play in affective regulation, cognitive processing, and linguistic function. Although considerable progress has been made in models of cerebellar function, controversy remains regarding the exact role of the "linguistic cerebellum" in a broad variety of nonmotor language processes. This consensus paper brings together a range of different viewpoints and opinions regarding the contribution of the cerebellum to language function. Recent developments and insights in the nonmotor modulatory role of the cerebellum in language and some related disorders will be discussed. The role of the cerebellum in speech and language perception, in motor speech planning including apraxia of speech, in verbal working memory, in phonological and semantic verbal fluency, in syntax processing, in the dynamics of language production, in reading and in writing will be addressed. In addition, the functional topography of the linguistic cerebellum and the contribution of the deep nuclei to linguistic function will be briefly discussed. As such, a framework for debate and discussion will be offered in this consensus paper.

The Memory Orientation Screening Test (MOST(®)) is a 29-point scale for identifying and following mild and major neurocognitive disorders in older patients. Previous research demonstrated validity in separating patients with normal vs. impaired cognition and high correlations with tests of memory and attention. This study compares the original paper-based MOST(®) with a computerized (iPad app) version, the MOST(®)-96120, to determine the equivalence of formats. A total of 98 consecutive older patients were administered identical versions of the MOST and MOST-96120 in a random order, separated by 1 hour of interspersed testing, in a 3-hour neuropsychological evaluation. MOST and MOST-96120 scores were compared with each other, with global cognitive ratings, and with standardized tests of memory and attention. Both versions had equivalent means and standard deviations, very high inter-test correlation (r = .92, p < .001), and equal correlations with outcome measures. Both versions separated patients into normal vs. mild NCD vs. major NCD categories with equal accuracy. ANOVA showed no significant difference between versions or presentation order. Both versions correlated very highly with cognitive level and neuropsychological endpoints, confirming previous research. The MOST-96120 is a computerized neuropsychological assessment device that demonstrates equivalence with its paper-based original, allowing for confident reliance on the findings of previous research.

One function of the central executive component of the working memory model is the coordination of two simultaneous tasks (the dual-task method). The concept of a coordination function has proved effective in identifying brain damaged patients with severe behavioural problems and in discriminating the performance of patients with mild Alzheimer's disease from that of healthy elderly. A computerised version of the dual-task method was successfully used in previous laboratory studies but it is not suited to use in a practical, clinical setting. Thus a paper and pencil version of the dual-task method was devised. The present study was aimed at refining the paper and pencil dual-task method; investigating whether or not age per se affects performance; assessing its test-retest reliability and providing norms for the Georgian population. The new paper and pencil version of the dual-task was administered to 64 young and 64 middle-age and elderly participants. A new, modified, simpler version of the paper and pencil dual-task, the "Tbilisi paper and pencil motor task" was developed. This task has high test-retest reliability and correlates with the established computerised version of the task. No age or education effects were detected.

There is growing evidence that Internet-mediated psychological tests can have satisfactory psychometric properties and can measure the same constructs as traditional versions. However, equivalence cannot be taken for granted. The prospective memory questionnaire (PMQ; Hannon, Adams, Harrington, Fries-Dias, & Gibson, 1995) was used in an on-line study exploring links between drug use and memory (Rodgers et al., 2003). The PMQ has four factor-analytically derived subscales. In a large (N = 763) sample tested via the Internet, only two factors could be recovered; the other two subscales were essentially meaningless. This demonstration of nonequivalence underlines the importance of on-line test validation. Without examination of its psychometric properties, one cannot be sure that a test administered via the Internet actually measures the intended construct.

The group of papers on memory reactivation and consolidation during sleep included in this volume represents cutting edge work in both animals and humans. They support that the two types of sleep serve different necessary functions. The role of slow wave sleep (SWS) is reactivation of the hippocampal-neocortical circuits activated during a waking learning period, while REM sleep is responsible for the consolidation of this new learning into long-term memory. These studies provide further insights into mechanisms involved in brain plasticity. Robeiro has demonstrated the upregulation of an immediate-early gene (IEG zif 268) to waking levels, which occurs only in REM and only in connection with new learning. McNaughton and his group have identified electrical indicators that the hippocampus and neocortex are talking to each other by testing the coactivation of hippocampal sharp wave bursts in SWS and shifts from down to up states of activation in the neocortex. In human studies Smith's group reports work on individual differences such as intelligence and presleep alcohol that affect postsleep performance, and Stickgold and collaborators report that a short nap will improve performance if it contains REM sleep. Payne and Nadel suggest that the recall benefit associated with REM sleep may be due to its association with increased cortisol levels. These papers are important not only in their individual contributions but also in revitalizing the work coordinating waking and sleep. This promises to further the understanding of how our unique capacity to learn from experience and modify our behavior takes place.

There is a heated debate on a learning paradigm known as "fast mapping" for its early neocortical dependence and retained memory over time for amnesic patients with hippocampal system damage. Whether the fast mapping allows hippocampus independent learning and induces rapid integration is poorly understood. The present study aims to investigate the effect of fast mapping on very long-term retention, which to our knowledge has not been previously explored. We tested memory retention ranging from 10 min to 1.5 years, for novel word-object associations learned from fast mapping or explicit encoding procedures. The three-alternative forced choice recognition task was employed to assess memory performance. Besides the slight adjustment of the testing schedule, other settings remained the same in Experiment 2 to replicate and verify the findings of Experiment 1. Results showed that overall memory retrieval performance was higher after explicit encoding as compared to fast mapping. However, retrieval performance after explicit encoding dropped after 1.5 years, but remained stable in the fast mapping condition. Furthermore, matching the semantic category of the known and the novel items during the fast mapping paradigm might affect long-term retention. These results suggest that fast mapping creates more stable long-term memory representations as compared to the explicit encoding strategy., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Some of the earliest work on understanding how concepts are organized in memory used a network-based approach, where words or concepts are represented as nodes, and relationships between words are represented by links between nodes. Over the past two decades, advances in network science and graph theoretical methods have led to the development of computational semantic networks. This review provides a modern perspective on how computational semantic networks have proven to be useful tools to investigate the structure of semantic memory as well as search and retrieval processes within semantic memory, to ultimately model performance in a wide variety of cognitive tasks. Regarding representation, the review focuses on the distinctions and similarities between network-based (based on behavioral norms) approaches and more recent distributional (based on natural language corpora) semantic models, and the potential overlap between the two approaches. Capturing the type of relation between concepts appears to be particularly important in this modeling endeavor. Regarding processes, the review focuses on random walk models and the degree to which retrieval processes demand attention in pursuit of given task goals, which dovetails with the type of relation retrieved during tasks. Ultimately, this review provides a critical assessment of how the network perspective can be reconciled with distributional and machine-learning-based perspectives to meaning representation, and describes how cognitive network science provides a useful conceptual toolkit to probe both the structure and retrieval processes within semantic memory., (© 2021 Cognitive Science Society LLC.)

This article presents an overview of a theory for performing temporal smoothing on temporal signals in such a way that: (i) temporally smoothed signals at coarser temporal scales are guaranteed to constitute simplifications of corresponding temporally smoothed signals at any finer temporal scale (including the original signal) and (ii) the temporal smoothing process is both time-causal and time-recursive, in the sense that it does not require access to future information and can be performed with no other temporal memory buffer of the past than the resulting smoothed temporal scale-space representations themselves. For specific subsets of parameter settings for the classes of linear and shift-invariant temporal smoothing operators that obey this property, it is shown how temporal scale covariance can be additionally obtained, guaranteeing that if the temporal input signal is rescaled by a uniform temporal scaling factor, then also the resulting temporal scale-space representations of the rescaled temporal signal will constitute mere rescalings of the temporal scale-space representations of the original input signal, complemented by a shift along the temporal scale dimension. The resulting time-causal limit kernel that obeys this property constitutes a canonical temporal kernel for processing temporal signals in real-time scenarios when the regular Gaussian kernel cannot be used, because of its non-causal access to information from the future, and we cannot additionally require the temporal smoothing process to comprise a complementary memory of the past beyond the information contained in the temporal smoothing process itself, which in this way also serves as a multi-scale temporal memory of the past. We describe how the time-causal limit kernel relates to previously used temporal models, such as Koenderink's scale-time kernels and the ex-Gaussian kernel. We do also give an overview of how the time-causal limit kernel can be used for modelling the temporal processing in models for spatio-temporal and spectro-temporal receptive fields, and how it more generally has a high potential for modelling neural temporal response functions in a purely time-causal and time-recursive way, that can also handle phenomena at multiple temporal scales in a theoretically well-founded manner. We detail how this theory can be efficiently implemented for discrete data, in terms of a set of recursive filters coupled in cascade. Hence, the theory is generally applicable for both: (i) modelling continuous temporal phenomena over multiple temporal scales and (ii) digital processing of measured temporal signals in real time. We conclude by stating implications of the theory for modelling temporal phenomena in biological, perceptual, neural and memory processes by mathematical models, as well as implications regarding the philosophy of time and perceptual agents. Specifically, we propose that for A-type theories of time, as well as for perceptual agents, the notion of a non-infinitesimal inner temporal scale of the temporal receptive fields has to be included in representations of the present, where the inherent nonzero temporal delay of such time-causal receptive fields implies a need for incorporating predictions from the actual time-delayed present in the layers of a perceptual hierarchy, to make it possible for a representation of the perceptual present to constitute a representation of the environment with timing properties closer to the actual present., (© 2023. The Author(s).)

In recent years, the clinical usefulness of the Wada test (WT) has been debated among researchers in the field. Therefore, we aimed to assess its contribution to the prediction of change in verbal learning and verbal memory function after epilepsy surgery. Data from 56 patients with temporal lobe epilepsy who underwent WT and subsequent surgery were analyzed retrospectively. Additionally, a standard neuropsychological assessment evaluating attentional, learning and memory, visuospatial, language, and executive function was performed both before and 12 months after surgery. Hierarchical linear regression analyses were used to determine the incremental value of WT results over socio-demographic, clinical, and neuropsychological characteristics in predicting postsurgical change in patients' verbal learning and verbal memory function. The incorporation of WT results significantly improved the prediction models of postsurgical change in verbal learning (∆R 2  = 0.233, p = .032) and verbal memory function (∆R 2  = 0.386, p = .005). Presurgical performance and WT scores accounted for 41.8% of the variance in postsurgical change in verbal learning function, and 51.1% of the variance in postsurgical change in verbal memory function. Our findings confirm that WT results are of significant incremental value for the prediction of postsurgical change in verbal learning and verbal memory function. Thus, the WT contributes to determining the risks of epilepsy surgery and, therefore, remains an important part of the presurgical work-up of selected patients with clear clinical indications.

Adult semantic memory has been traditionally conceptualized as a relatively static memory system that consists of knowledge about the world, concepts, and symbols. Considerable work in the past few decades has challenged this static view of semantic memory, and instead proposed a more fluid and flexible system that is sensitive to context, task demands, and perceptual and sensorimotor information from the environment. This paper (1) reviews traditional and modern computational models of semantic memory, within the umbrella of network (free association-based), feature (property generation norms-based), and distributional semantic (natural language corpora-based) models, (2) discusses the contribution of these models to important debates in the literature regarding knowledge representation (localist vs. distributed representations) and learning (error-free/Hebbian learning vs. error-driven/predictive learning), and (3) evaluates how modern computational models (neural network, retrieval-based, and topic models) are revisiting the traditional "static" conceptualization of semantic memory and tackling important challenges in semantic modeling such as addressing temporal, contextual, and attentional influences, as well as incorporating grounding and compositionality into semantic representations. The review also identifies new challenges regarding the abundance and availability of data, the generalization of semantic models to other languages, and the role of social interaction and collaboration in language learning and development. The concluding section advocates the need for integrating representational accounts of semantic memory with process-based accounts of cognitive behavior, as well as the need for explicit comparisons of computational models to human baselines in semantic tasks to adequately assess their psychological plausibility as models of human semantic memory.

Memories affect nearly every aspect of our mental life. They allow us to both resolve uncertainty in the present and to construct plans for the future. Recently, renewed interest in the role memory plays in adaptive behavior has led to new theoretical advances and empirical observations. We review key findings, with particular emphasis on how the retrieval of many kinds of memories affects deliberative action selection. These results are interpreted in a sequential inference framework, in which reinstatements from memory serve as "samples" of potential action outcomes. The resulting model suggests a central role for the dynamics of memory reactivation in determining the influence of different kinds of memory in decisions. We propose that representation-specific dynamics can implement a bottom-up "product of experts" rule that integrates multiple sets of action-outcome predictions weighted based on their uncertainty. We close by reviewing related findings and identifying areas for further research. This article is categorized under: Psychology > Reasoning and Decision Making Neuroscience > Cognition Neuroscience > Computation., (© 2021 Wiley Periodicals LLC.)

Hippocampal neuroinflammation is present in multiple diseases and disorders that impact motivated behaviour in a sex-specific manner, but whether neuroinflammation alone is sufficient to disrupt this behaviour is unknown. We investigated this question here using mice. First, the application of an endotoxin to primary cultures containing only hippocampal neurons did not affect their activation. However, when the same endotoxin was applied to mixed neuronal/glial cultures it did increase neuronal activation, providing initial indications of how it might be able to effect behavioural change. We next showed neuroinflammatory effects on behaviour directly, demonstrating that intra-hippocampal administration of the same endotoxin increased locomotor activity and accelerated goal-directed learning in both male and female mice. In contrast, lipopolysaccharide-induced hippocampal neuroinflammation caused sex-specific disruptions to the acquisition of instrumental actions and to Pavlovian food-approach memories. Finally, we showed that LPS-induced hippocampal neuroinflammation had a sexually dimorphic effect on neuronal activation: increasing it in females and decreasing it in males., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Patients with diabetes mellitus show an elevated prevalence of psychiatric disorders such as anxiety. We have reported that fear memory, a model related to anxiety as reflected in the freezing response, is enhanced in diabetic mice and was ameliorated by an AMPA receptor antagonist. The present study investigated whether functions of AMPA receptors in the amygdala and hippocampus are altered in streptozotocin (STZ)-induced diabetic mice. While protein levels of the GluA1 subunit of AMPA receptors were not altered in the amygdala and hippocampus, protein levels of GluA1 phosphorylated at serine 845 in the amygdala and hippocampus and of GluA1 phosphorylated at serine 831 in the hippocampus were increased in STZ-induced diabetic mice. L-lactate, which is increased in the amygdala and hippocampus of STZ-induced diabetic mice, did not alter these protein levels in either brain area. In contrast, protein levels of phosphorylated protein kinase A (PKA) catalytic subunit and phosphorylated calcium calmodulin kinase II (CaMKII), which are known to phosphorylate serine 845 and serine 831 of GluA1, respectively, were increased in the amygdala and hippocampus of STZ-induced diabetic mice. In the fear memory test, the PKA inhibitor H-89 injected before test sessions and the CaMKII inhibitor KN-62 injected before conditioning or test sessions each reduced the increase in freezing in STZ-induced diabetic mice. These results indicate that the functions of AMPA receptors in the amygdala and hippocampus are enhanced due to increased phosphorylation by PKA and CaMKII, which enhances fear memory in diabetic mice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Whisker-mediated tactile perception is essential for rodent navigation, food acquisition, and social interactions. However, the molecular mechanisms underlying tactile information processing, learning, and memory have not been studied to the same extent as for other modalities. Using immunohistochemical staining, we investigated changes in regional c-Fos expression as an index of neuronal activity and phosphorylated (p)ERK1/2 as an index of ERK1/2 activity in mice trained on a tactile-cued 8-arm radial maze task. Over 12 trials, mice learned to selectively explore four baited arms covered with wire as the tactile cue while avoiding un-baited uncovered arms. The density of c-Fos + cells was significantly higher in somatosensory cortex but not frontal cortex or amygdala of mice exposed to tactile cue - bait pairing compared to mice exposed to the same maze with all arms baited with or without tactile cues (unpaired conditions). The density of pERK1/2 + cells was also increased after paired trials 7 and 12 but not after paired trials 1 and 3 in frontal cortex, amygdala, and somatosensory cortex compared to mice exposed to the unpaired condition. The MEK1/2 inhibitor SL327 reduced c-Fos expression in frontal cortex and amygdala when applied during early trials, but impaired working memory when applied before later trials without affecting c-Fos expression. Heterozygous BDNF knockout mice exhibited impaired task learning and reduced pERK1/2 expression in frontal cortex and amygdala but not somatosensory cortex. These findings suggest that the BDNF/MEK/ERK1/2 pathway selectively promotes memory trace formation in frontal cortex and amygdala but not encoding in somatosensory cortex., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In recent years, the problem of the multistability of neural networks has been studied extensively. From the research results obtained, the number of stable equilibrium points depends only on a power form of the network dimension. However, in practical applications, the number of stable equilibrium points needed is often not expressed in power form. Therefore, can we determine an appropriate activation function so that the neural network has exactly the required number of stable equilibrium points? This paper provides a new way to study this problem by means of an iteration method. The necessary activation function is constructed by an appropriate iteration method, and the neural network model is established. Based on the mathematical theories of matrix analysis and functional analysis and on the inequality method, the number and distribution of the network equilibrium points are determined by dividing the state space reasonably, and some multistability criteria that are related to the number of iterations and are independent of the network dimension are established., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Ethnopharmacological Relevance: Epimedium Tourn. ex L. is a traditional Chinese medicine used for thousands of years in China to treat forgetfulness. Icariin is a principal component of the genus Epimedium., Aim of the Study: The metabolic mechanism of icariin treating forgetfulness is explored., Materials and Methods: A D-galactose-induced senescent mouse model was employed. The cognitive performance of mice was assessed in the fear conditioning test. Hippocampal pathology was assessed in the immunohistochemistry assay. Plasma metabolome was analyzed using GC-MS method, and the differential metabolites were further identified by UPLC-MS/MS or GC-MS method. The liver function, including ALT and AST, was assessed by enzyme reaction. Icariin was administered intraperitoneally at 50 and 100 mg/kg. Mice were administered five consecutive days per week for 8 weeks., Results: Icariin treatment improved hippocampus-related fear memory but not amygdala-related memory, whereas Pexidartinib (PLX3397), a microglial scavenger, did not. Icariin treatment maintained the TMEM119-positive microglial population and decreased the accumulation of the senescent biomarker p16 in the dorsal hippocampus in senescent mouse brains, whereas PLX3397 did not. Notably, p16 in the CA2 subregion significantly decreased in icariin-treated mice than the other hippocampal subregions. The senescent mice exhibited the circulating metabolic characteristics of mild ketoacidosis, active tricarboxylic acid (TCA) cycle, lactic acidosis, hyperglycemia, active detoxification, active cis-oleic acid metabolism, and inhibitory GABA shut. R-3-Hydroxybutyric acid primarily produced in the liver was selectively and robustly decreased by icariin treatment, which was not observed with PLX3397 treatment. The TCA cycle was rescued in senescent mice by icariin treatment. Icariin also protected liver function (plasma ALT) in D-gal-induced senescent mice., Conclusions: Icariin may protect mouse hippocampal cognition from D-gal-induced senescence by protecting microglial homeostasis, and facilitating the utilization of R-3-hydroxybutyric acid is one of the underpins., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

An enriched environment (EE) constitutes a proficient strategy that instigates social, cognitive, and motor faculties, fostering healing and heightening learning and memory function after ischemia, while fucoidan derived from brown seaweed encompasses a diverse array of bioactivities and is known to possess neuroprotective properties. This study aims to investigate the effectiveness of combining fucoidan and EE in a rat model of vascular dementia to overcome cognitive challenges. The rats were randomly assigned as Sham, Lesion - 4-vessel occlusion (4VO) i.e., transient global cerebral ischemia (tGCI), 4VO + F50mg/kg, 4VO + EE, and 4VO + F50mg/kg + EE. At the end of the study periods, the rats were exposed to the Novel object task, T-maze, and the Morris water maze. The profile of hippocampal pyramidal neurons and their dendrites was assessed through the CFV, and Golgi cox stained brain sections. Neuroinflammatory markers (IL-1β, IL-6, NF-κB, TNF-α) and synaptogenic markers (BDNF, SYP, PSD-95) were evaluated through western blot analysis. The levels of oxidative stress marker (LPO) and antioxidants (SOD, CAT, GSH, GST, GPX) in the hippocampus were quantified through biochemical assay. The findings revealed that the cognitive deficits were significantly reduced in both the 4VO + F50mg/kg and 4VO + F50mg/kg + EE treatment groups and inflammatory markers were reduced with increased antioxidant levels and synaptogenic markers when compared with the lesion group. However, through this study, the combination therapy involving fucoidan and exposure to an EE was proven effective in preserving neural integrity and restoring cognitive function against the damage caused by oxidative stress and inflammation following tGCI., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Guilu Erxian Jiao (GLEXJ) is a renowned traditional Chinese herbal formula used to tonify the kidney. It is employed to treat psychiatric disorders, and alleviate memory impairment, cognitive dysfunction, and behavioral disorders. Modern pharmacological studies have demonstrated GLEXJ's ability to significantly inhibit the fear response in post-traumatic stress disorder (PTSD) and facilitate the extinction of fear memory. However, the underlying pharmacological mechanisms remain elusive., Aim of the Study: Fear memory generalization, a fundamental characteristic of PTSD, remains poorly understood, and optimal pharmacological treatments are lacking. This study aimed to investigate GLEXJ's inhibitory effects on fear memory generalization in PTSD rats and elucidate its underlying mechanisms., Materials and Methods: PTSD rats were induced using the single prolonged stress and electrical stimulation (SPS&S) protocol and treated with GLEXJ or paroxetine (PRX). Fear memory generalization was assessed using a contextual fear memory test. Hippocampal dendritic spine morphology was analyzed using Golgi-Cox staining. The chemical composition of GLEXJ was determined using ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Network pharmacology was employed to predict GLEXJ's therapeutic mechanism in PTSD treatment. Western blotting and immunofluorescence were used to measure indicators of the transient receptor potential channel 6 (TRPC6)-mediated calcium/calmodulin-dependent protein kinase IV-cAMP response element-binding protein (CaMKIV-CREB) signaling pathway. In vitro, TRPC6 was suppressed in rat adrenal pheochromocytoma (PC12) cells using lentiviral vectors, and phalloidin staining was employed to examine changes in Fibros actin (F-actin), elucidating the mechanistic effects of GLEXJ-containing serum., Results: GLEXJ significantly mitigated fear memory generalization in PTSD rats, even with repeated stress exposure. It also alleviated abnormal hippocampal dendritic spine morphology. Network pharmacology analysis confirmed that GLEXJ was closely related to the Ca 2+ signaling pathway in PTSD treatment. PTSD rats exhibited disrupted TRPC6-mediated CaMKIV-CREB signaling and impaired synaptic plasticity. GLEXJ upregulated TRPC6 expression, reactivated the CaMKIV-CREB pathway, and promoted synaptic remodeling. In vitro studies confirmed that TRPC6 suppression reduced F-actin levels while GLEXJ-containing serum increased TRPC6 expression and F-actin content., Conclusions: GLEXJ activates CaMKIV-CREB signaling by upregulating TRPC6 in the hippocampus of PTSD rats, leading to the positive modulation of dendritic spine morphology and synaptic remodeling. This mechanism contributes to the attenuation of fear memory generalization. Given the limitations of current PTSD treatments, these findings offer potential avenues for developing more effective therapeutic strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Transient receptor vanillin 1 (TRPV1) is widely expressed in the neural axis and surrounding tissues, and is easily activated by harmful stimuli such as pain and inflammatory responses. Previous studies have shown that activated TRPV1 channels regulate all levels of nervous system activity by improving calcium influx and modulating nervous system excitability. Recent studies have suggested that TRPV1 activation in the peripheral nervous system may induce sleep disorders, while activation in the central nervous system may ameliorate sleep disorders and assist memory consolidation processes. Here, we summarize the risk factors for inducing sleep disorders, the alteration of these risk factors by TRPV1 receptor activation, and the driving effect of TRPV1 receptor activity on memory consolidation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Neonicotinoid pesticide use has increased around the world despite accumulating evidence of their potential detrimental sub-lethal effects on the behaviour and physiology of bees, and its contribution to the global decline in bee health. Whilst flower colour is considered as one of the most important signals for foraging honey bees (Apis mellifera), the effects of pesticides on colour vision and memory retention in a natural setting remain unknown. We trained free flying honey bee foragers by presenting artificial yellow flower feeder, to an unscented artificial flower patch with 6 different flower colours to investigate if sub-lethal levels of imidacloprid would disrupt the acquired association made between the yellow flower colour from the feeder and food reward. We found that for doses higher than 4 % of LD 50 value, the foraging honey bees no longer preferentially visited the yellow flowers within the flower patch and instead, we suspect, reverted back to baseline foraging preferences, with a complete loss of the yellow preference. Our honey bee colour vision modelling indicates that discriminating the yellow colour from the rest should have been easy cognitive task. Pesticide exposure also resulted in a significant increase in Lop1, UVop, and Blop, and a decrease in CaMKII and CREB gene expression. Our results suggest that memory loss is the most plausible mechanism to explain the alteration of bee foraging colour preference. Across bees, colour vision is highly conserved and is essential for efficient pollination services. Therefore, our findings have important implications for ecosystem health and agricultural services world-wide., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

The canonical size phenomenon refers to the mental representation of real-object size information: the objects larger in the physical world are represented as larger in mental spatial representations. This study tested this phenomenon in a drawing-from-memory task among children aged 5, 7, and 9 years. The participants were asked to draw objects whose actual sizes varied at eight size rank levels. Drawings were made on regular paper sheets or special foils to produce embossed drawings. When drawing from memory, the participants were either sighted or blindfolded (to prevent visual feedback). We predicted that the drawn size of objects would increase with increasing size rank of objects. The findings supported the hypothesis concerning the canonical size effect among all age groups tested. This means that children aged 5 to 9 represent real-world size information about everyday objects and are sensitive to their size subtleties. Moreover, the drawn size increased with increasing size ranks both within sighted and blindfolded perceptual conditions (however, the slope of functions that best explain the relation between size rank and drawn size varied between the perceptual conditions). This finding further supports the recent evidence of the spatial character of the canonical size phenomenon., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Diabetes, characterized by elevated blood glucose levels and associated organ damage, is reportedly correlated with adecline in cognitive functions with a potential involvement of oxidative stress mechanisms. Mitochondria-induced oxidative stress reported to cause hyperglycemia is believed to impair hippocampal neural plasticity, affecting long-term potentiation, and isconsidered crucial for maintaining memory functions. In this study, the neuroprotective effect of Pentoxifylline (PTX) for four weeks, an agent known for antioxidant and anti-inflammatory properties, was examined in an animal model of diabetes. In a streptozotocin (STZ) diabetic model, rats received intraperitoneal PTX (100 mg/kg), and learning and memory functions were tested using the radial arm water maze. STZ-treated diabetic rats exhibited impaired learning and memory functions (short/long-term, P < 0.05), whereas PTX treatment prevented these deficits. PTX treatment normalized diabetes-induced reduction in the protein expression levels of two enzymes of antioxidant defense superoxide dismutase and glutathione peroxidase (P < 0.05) in the hippocampal brain tissues. PTX treatment also mitigated STZ-induced increase in lipid peroxidation (TBARS, P < 0.05). Furthermore, reduced/oxidized glutathione (GSH/GSSG) ratios were enhanced in PTX-treated diabetic rats (P < 0.05), emphasizing the importance of redox balance restoration. However, PTX treatment did not significantly affect theantioxidant defense enzyme catalase activity. In conclusion, STZ-induced diabetes resulted in learning and memory impairment in rats, while PTX treatment prevented these effects, most likely via enhancement of antioxidant defense in the brain. This study highlights PTX's potential neuroprotective benefits, providing translational insights into the issue of diabetes-related cognitive complications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Luffa cylindrica (L.), is a medicinal plant aimed to investigate the efficacy of the alkaloid-rich fraction (ARF) extracted from L. cylindrica. The study employed behavioural analysis of rat using Morris water maze (MWM), biochemical analysis of apoptotic proteins, Immunohistochemistry of caspase 3 protein and network pharmacology approach. The ozone-induced group exhibited complex behavioral changes. Western blot analysis revealed altered expression of SOD2, Caspase 3, and Cytochrome C which play integral roles in oxidative stress, apoptosis, and mitochondrial function. Histopathological analysis of the hippocampus further supported the neuroprotective potential of L. cylindrica, demonstrating a reduction in neuropathological lesions and improved memory processes. Network Pharmacology showed the implication of GSK3β in neuronal damage. ARF showed promise in preventing further neuronal damage. In summary, this comprehensive study sheds light on its potential in neuroprotective applications by in vivo behavioral and molecular analyses. It provides a holistic understanding of the medicinal properties of ARF, encouraging further exploration for potential therapeutic interventions in neurological diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

This penultimate chapter is based on a single paper published in Nature in 2022. I have used it specifically as an exemplar, in this case to show that memory improvement in old age may be regulated by a multiplicity of electrical forces. However, I include it because I believe that one could pick almost any other substantial single paper and show that a completely disparate set of biological mechanisms similarly depend crucially on multiple electrical forces., (© 2025. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

This study aimed to evaluate the relationship between autonomic nervous function (ANF) and cognitive abilities, such as memory and attention, using the Kana pick-out test (KPT). The participants were 11 female college students aged 21 years old. Each participant completed the KPT ten times, during which their ANF was assessed via heart rate variability analysis. During the KPT, participants circled Japanese vowels in a 400-character story written in hiragana. We measured attention using the KPT score and assessed memory using a memory score based on ten descriptive questions about the story. Statistical analysis revealed a significant positive correlation between higher KPT and memory scores, indicating a link between memory and attention. The parasympathetic sinus modulation marker, high-frequency component power (HF), decreased during the kana-picking task (Interval B) and recovered during the subsequent content verification task (Interval C). In Interval A (before the kana-picking task), the HF showed a positive correlation with both the KPT and memory scores. Additionally, a positive correlation was observed between HF and memory scores during interval B. Other autonomic nervous indices, including low-frequency component power (LF), total power (TP), and LF/HF ratio, also showed significant correlations with KPT and memory scores. Our findings strongly suggest that ANF is intricately connected to cognitive functions, such as memory and attention. This indicates that monitoring ANF could provide a novel methodology for assessing learning and occupational efficiency., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hirohiko Kuratsune reports financial support was provided by Government of Japan Ministry of Education Culture Sports Science and Technology. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

When I began my career, I had no idea that much of it would center around the hippocampus. Here I discuss some of the history of how this happened. I briefly mention my early undergraduate life and the problems it posed for getting into graduate school. I describe the unique circumstances that led me to Allan Wagner's laboratory and changed my career trajectory. My path to the hippocampus began with a decision to study memory development. This led to a collaboration with Rob Sutherland that produced the configural theory of the hippocampus. The idea was that the hippocampus facilitated the construction of representations of the co-occurring stimulus elements currently experienced by the organism. Thus, if two elements, A and B, occurred together, a representation, AB, could be constructed that could be discriminated from its elements, A and B. This idea was partially correct, but we missed an important property of the hippocampal system that was recognized by O'Keefe and Nadel, 1978 that is, that the hippocampus is an unmotivated, rapid learning system. Randy O'Reilly and I addressed this issue in what we called conjunctive representation theory and put forth a detailed cortical-hippocampus computational theory to explain how this could work I later realized that our ideas were remarkably like Tim Teyler's indexing theory of how the hippocampal system supports memory. At a Park City meeting, a chance encounter with Tim (whom I had never met) resulted in the opportunity to write a paper with Tim updating the indexing theory, It is my favorite theoretical paper., (© 2024 Wiley Periodicals LLC.)

Alzheimer's disease (AD) is a representative neurodegenerative disease that is characterized by the overaccumulation of amyloid beta (Aβ) proteins. Since AD is accompanied by excessive oxidative stress, which aggravates neurological pathologies, the use of antioxidants has been considered to prevent disease development. NXP031, a combination of vitamin C (VitC) and an optimized aptamer that binds to VitC and stabilizes the reactivity of VitC, was designed. This study aimed to evaluate the effects of NXP031 on AD pathology, including Aβ accumulation, Aβ-induced oxidative stress, neuronal damage, and neuroinflammation. When NXP031 was administered to 5xFAD transgenic mice, NXP031 exerted a strong inhibitory action on Aβ accumulation, superior to that of VitC, by inducing an increase in Aβ-degrading endopeptidase expression. NXP031 diminished lipid peroxidation levels, activated Nrf2-mediated antioxidant pathways, and suppressed overactivated neuroinflammation. An in vitro study using Neuro2a cells revealed that NXP031 protects the cells against oxidative stress by regulating the MAPK signaling pathway-mediated apoptosis. Additionally, the neuroprotective effects of NXP031 were confirmed in a dose-dependent manner when administered to intrahippocampal Aβ-injected mice, as NXP031 attenuated memory decline, neuronal apoptosis, synaptic degeneration, and excessive glial activation, and reduced NOX-2 expression in the hippocampus. Taken together, NXP031 reduced the Aβ burden by regulating Aβ-degeneration and attenuated memory impairment, neuronal death, synaptic degeneration, and neuroinflammation induced by Aβ toxicity. These results suggest the potential of NXP031 as a therapeutic agent for AD., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In 1978, Mort Mishkin published a landmark paper describing a monkey model of H.M.'s dense, global amnesia. It depended on a combined removal of the amygdala and hippocampus (the A + H lesion) and a memory test called delayed nonmatching-to-sample (DNMS). My first project examined whether the impairment Mishkin had found in visual memory generalized to tactual stimuli. However, to gain access to the hippocampus and amygdala with 1980s surgical methods, we had to remove the underlying cortex. When we were able to test the effects of bilateral removal of that underlying cortex (the entorhinal and perirhinal cortex, or "rhinal cortex" for short) we obtained a dramatic result. This so-called "control" lesion caused a profound impairment on the DNMS task. A few years later, excitotoxic A + H lesions, which left the rhinal cortex intact, confirmed that removal of the cortical "impediments" had caused the entire memory impairment that Mishkin had observed. These results: (1) forced a reconsideration of the monkey model of global anterograde amnesia; (2) spurred study of the independent contributions of the amygdala, hippocampus, and perirhinal cortex to cognition; and (3) led to the realization that the DNMS task did not test the kinds of memory that H.M. lost after his surgery., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Hippocampus published by Wiley Periodicals LLC.)

Per- and Polyfluoroalkyl Substances (PFAS) are a group of water-soluble chemicals used for decades with important industrial and commercial applications. Due to their chemical and thermal stability, persistence in the environment, and widespread human exposure, PFAS become an important concern for public health. In this study, eleven highly prevalent PFAS and a reference mixture were selected according to various drinking water sources. The nematode, Caenorhabditis elegans, were exposed to PFAS at 0.1, 1, 10, 100, and 200 μM, and the toxic effects on learning & memory along with the bioaccumulation were investigated using a high-throughput screening (HTS) platform. Our results showed that perfluorooctanesulfonic acid (PFOS) and perfluorobutanesulfonic acid (PFBS) exhibited significant inhibitory effects (p < 0.05) on learning and memory in both time points at concentrations between 100 and 200 μmol/L. After 48 h of exposure, every PFAS resulted in an inhibition of learning and memory with a concentration of 200 μmol/L. Furthermore, the PFOS and PFBS had the highest bioaccumulation levels after 48 h of exposure. These findings provide valuable insight into the developmental adverse effects associated with exposure and the bioaccumulation of both individual and mixtures of PFAS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Studies on memory engram have demonstrated how experience and learning can be allocated at a neuronal level for centuries. Recently emerging evidence narrowed down further to the synaptic connections and their patterned allocation on dendrites. Notably, groups of synapses within a specific range within dendrites known as 'synaptic clusters' have been revealed in association with learning and memory. Previous investigations have shown that a variety of factors mediated by both presynaptic inputs and postsynaptic dendrites contribute to clustering. Here, we review the neural mechanism of synaptic clustering and its correlation with memory. We highlight the recent findings about the clustering of synaptic engrams and memory formation and discuss future directions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Mitochondria are classically viewed as 'on demand' energy suppliers to neurons in support of their activity. In order to adapt to a wide range of demands, mitochondria need to be highly dynamic and capable of adjusting their metabolic activity, shape, and localization. Although these plastic properties give them a central support role in basal neuronal physiology, recent lines of evidence point toward a role for mitochondria in the regulation of high-order cognitive functions such as memory formation. In this review, we discuss the interplay between mitochondrial function and neural plasticity in sustaining memory formation at the molecular and cellular levels. First, we explore the global significance of mitochondria in memory formation. Then, we will detail the memory-relevant cellular and molecular mechanisms of mitochondrial plasticity. Finally, we focus on those mitochondrial functions, including but not limited to ATP production, that give mitochondria their pivotal role in memory formation. Altogether, this review highlights the central role of mitochondrial structural and functional plasticity in supporting and regulating neuronal plasticity and memory., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Growing evidence suggests nutritional intervention may influence the development and progression of Alzheimer's Disease (AD). Choline, an essential dietary nutrient plays a critical role in neurological development and brain function, however, its effects on AD in humans is unclear. The research aims to investigate mechanistic links between dietary choline intake and cognitive functioning, focusing on the role of phosphatidylcholine (PC) in neuroplasticity and its interaction with amyloid beta (Aβ) peptides in neuron membranes. Additionally, human evidence on the potential benefits of PC interventions on AD, cognition, and proposed mechanisms are evaluated., Methods: A reproducible systematic literature search was performed using a three-tranche strategy, consisting of a review, mechanism, and intervention search. Using PubMed as the main database, 1254 titles and abstracts were screened, 149 papers were read in full and 65 peer-reviewed papers were accepted, critically appraised, and analysed in a narrative review., Results: Predominantly preclinical evidence demonstrated that PC enhances neuroplasticity, a key biological substrate for cognition, by activating intracellular neuronal signalling pathways or through neuron membrane function. Molecular dynamic simulation methods provided a mechanistic understanding of the interconnection between neuronal PC content and the potential behaviour and trajectory of Aβ peptide aggregation. The results indicate that the neuronal membrane composition of PC is critical to inhibiting Aβ aggregation and neuronal damage, protecting the neuron from Aβ toxicity. This might provide a foundation for optimising cellular PC which may prove beneficial in the treatment or prevention of neurodegenerative disease. Altered PC metabolism in AD was evidenced in observational studies; however, whether this relationship represents a cause or consequence of AD remains to be determined. Human intervention studies did not produce conclusive evidence supporting its effectiveness in enhancing cognitive function. This lack of consistency primarily stems from methodological constraints within the conducted studies. Human observational research provided the most compelling evidence linking a higher dietary PC intake to a reduced risk of dementia and significant improvements in cognitive testing., Conclusion: Despite the lack of randomised control trials (RCTs) assessing the efficacy of lecithin/PC to improve cognition in AD patients, there exists promising evidence supporting its neuroprotective and neurotrophic role. This review establishes an evidence-based framework through chains of mechanistic evidence, that may provide potential strategies for enhanced neuroprotection and reduced neurodegeneration caused by AD. Considering the escalating global burden of AD and the current shortcomings in effective treatments, this review together with the limitations and gaps identified in the existing research presents valuable insights that emphasise the urgency of more comprehensive research into the relationship between PC and AD., Competing Interests: Declaration of competing interest There are no conflicts of interest., (Copyright © 2024 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)