Spatial Navigation Research Articles

Distinguishing Doors and Floors on All Fours: Landmarks as Tools for Vertical Navigation Learning in Domestic Dogs (Canis familiaris)

Spatial navigation allows animals to understand their environment position and is crucial to survival. An animal’s primary mode of spatial navigation (horizontal or vertical) is dependent on how they naturally move in space. Observations of the domestic dog (Canis familiaris) have shown that they, like other terrestrial animals, navigate poorly in vertical space. This deficit is visible in their use of multi-story buildings. To date, no research has been conducted to determine if dogs can learn how to navigate in an anthropogenic vertical environment with the help of a landmark. As such, we herein investigate the effect of the addition of a visual or olfactory landmark on dogs’ ability to identify when they are on their home floor. Subject behaviors toward their home door and a contrasting floor door were compared before and after exposure to a landmark outside of their home door. While subjects initially showed no difference in latency to approach an apartment door on their home or a wrong floor, we found a significant difference in latency to approach the doors in the test trials for subjects who approached the doors in every trial. Other findings are equivocal, but this result is consistent with the hypothesis that dogs can learn to navigate in vertical space.

Navigating space: how fine and gross motor expertise influence spatial abilities at different scales.

Spatial ability, essential for navigating and interacting with the environment, comprises small-scale (e.g., mental rotation) and large-scale (e.g., spatial navigation) skills. Previous research underscores the influence of motor expertise on these abilities, yet comparative studies among different types of movement experts are limited, especially regarding the impact of gross motor skills on large-scale spatial abilities. This case-control study compared small-scale and large-scale spatial abilities among fine movement experts, gross movement experts, and non-movement experts. Ninety participants (30 per group) were assessed through computer-based spatial ability tests, including the Revised Purdue Spatial Visualization Test (PSVT: R), Mental Rotation Test, a navigation task developed in Unity 3D, and Triangle Completion Test (TCT). Fine movement experts excelled in small-scale spatial tasks compared to non-movement experts. Gross movement experts demonstrated superior large-scale spatial abilities, evidenced by lower errors in TCT and higher navigation scores, distinguishing their performance in spatial navigation and orientation from both fine movement experts and non-movement experts. The study highlights the distinct impacts of fine and gross motor expertise on spatial abilities, with gross motor skills particularly benefiting large-scale spatial navigation. These findings suggest potential clinical applications of gross motor training for improving spatial abilities in neurological populations, advocating for further research in immersive virtual environments and exploring lateral dominance effects on spatial performance.

Wide-angle simulated artificial vision enhances spatial navigation and object interaction in a naturalistic environment

Objective. Vision restoration approaches, such as prosthetics and optogenetics, provide visual perception to blind individuals in clinical settings. Yet their effectiveness in daily life remains a challenge. Stereotyped quantitative tests used in clinical trials often fail to translate into practical, everyday applications. On the one hand, assessing real-life benefits during clinical trials is complicated by environmental complexity, reproducibility issues, and safety concerns. On the other hand, predicting behavioral benefits of restorative therapies in naturalistic environments may be a crucial step before starting clinical trials to minimize patient discomfort and unmet expectations.Approach. To address this, we leverage advancements in virtual reality technology to conduct a fully immersive and ecologically valid task within a physical artificial street environment. As a case study, we assess the impact of the visual field size in simulated artificial vision for common outdoor tasks.Main results. We show that a wide visual angle (45°) enhances participants' ability to navigate and solve tasks more effectively, safely, and efficiently. Moreover, it promotes their learning and generalization capability. Concurrently, it changes the visual exploration behavior and facilitates a more accurate mental representation of the environment. Further increasing the visual angle beyond this value does not yield significant additional improvements in most metrics.Significance. We present a methodology combining augmented reality with a naturalistic environment, enabling participants to perceive the world as patients with retinal implants would and to interact physically with it. Combining augmented reality in naturalistic environments is a valuable framework for low vision and vision restoration research.

Community-based reconstruction and simulation of a full-scale model of the rat hippocampus CA1 region.

The CA1 region of the hippocampus is one of the most studied regions of the rodent brain, thought to play an important role in cognitive functions such as memory and spatial navigation. Despite a wealth of experimental data on its structure and function, it has been challenging to integrate information obtained from diverse experimental approaches. To address this challenge, we present a community-based, full-scale in silico model of the rat CA1 that integrates a broad range of experimental data, from synapse to network, including the reconstruction of its principal afferents, the Schaffer collaterals, and a model of the effects that acetylcholine has on the system. We tested and validated each model component and the final network model, and made input data, assumptions, and strategies explicit and transparent. The unique flexibility of the model allows scientists to potentially address a range of scientific questions. In this article, we describe the methods used to set up simulations to reproduce in vitro and in vivo experiments. Among several applications in the article, we focus on theta rhythm, a prominent hippocampal oscillation associated with various behavioral correlates and use our computer model to reproduce experimental findings. Finally, we make data, code, and model available through the hippocampushub.eu portal, which also provides an extensive set of analyses of the model and a user-friendly interface to facilitate adoption and usage. This community-based model represents a valuable tool for integrating diverse experimental data and provides a foundation for further research into the complex workings of the hippocampal CA1 region.

Acute glyphosate and aminomethylphosphonic acid (AMPA), its major metabolite, impaired spatial orientation, navigation, learning and/or memory in female rats

Human exposure to glyphosate-based herbicides (GBH) has been associated with a range of toxicological effects involving the central nervous system (CNS) such as alterations in learning and memory. Nevertheless, the effects of aminomethylphosphonic acid (AMPA), the main metabolite of glyphosate, remain essentially obscure. Previous preclinical reports suggest that acute intoxication with AMPA and glyphosate exerts decrease on hippocampal acetylcholinesterase activity and produces more metabolomic alterations in the female brain over the male one. Therefore, this work explored the effects of acute AMPA and glyphosate on spatial learning, memory and navigation in female rats. Sprague Dawley rats received a single injection (i.p.) of: (i) vehicle; (ii) 10 or 100mg/kg of AMPA; or (iii) 10 or 100mg/kg of glyphosate; subsequently, the Barnes maze paradigm was performance. Animals from the control group decreased latency and the attempts to solve the Barnes maze; and increased the degree of orientation when compared first training sessions (S1) vs. the last one (S4; p < 0.05). In contrast, both 10 and 100mg/kg of glyphosate and 100mg/kg of AMPA prevented the decrease in latency and attempts; and the increase of orientation (p>0.05 S1 vs. S4). Both treatments decreased the use of the spatial navigation strategy (p < 0.05). Besides, glyphosate at the higher dose but not AMPA impaired the spatial memory during the test. Our findings suggest that acute exposure to glyphosate and AMPA similarly affected spatial orientation, navigations, learning and/or memory.

Heliconius butterflies use wide-field landscape features, but not individual local landmarks, during spatial learning.

Spatial learning is vital in foraging ecology. Many hymenopteran insects are adept spatial foragers that rely on visual cues contained within broader wide-field scenes for central place foraging from a central nest. By contrast, for butterflies, which lack central nest sites, visual cue use during spatial foraging is less understood. Heliconius butterflies, however, exhibit stable nocturnal roosts, strong site fidelity and a sophisticated capacity for spatial navigation. This study furthers our understanding of Heliconius spatial learning by testing whether H. erato can associate a spatially informative visual cue with artificial feeders. We explored the relative importance of a visual local landmark compared with broader, wide-field visual cues, through experiments with (i) a fixed rewarded feeder with a local landmark; (ii) a mobile rewarded feeder with the landmark as the sole reliable cue; (iii) the same setup while blocking visual access to external landscape features. Our data suggest that Heliconius butterflies learn static feeder locations without relying on a local individual landmark. Instead, we suggest they integrate broader landscape and celestial cues. This suggests that Heliconius butterflies and central place foraging hymenopterans likely share similar visual navigation strategies, using wide-field, low-resolution views rather than focusing on specific individual landmarks.

The Wolf Spider Tigrosa helluo Uses Visual Associative and Beacon Landmarks During Water Maze Navigation Tasks

ABSTRACTWolf spiders can learn simple spatial navigation tasks. Previous studies have shown that the wolf spider Tigrosa helluo can use environmental edge features (reference frame landmarks) to learn the location of a dry target in flooded T‐mazes; however, the relative importance of different types or numbers of landmark cues to spatial learning remains unknown. We used a modified open arena water maze and recorded the ability of adult female T. helluo to find a target reward (a dark and dry cup) among cups that were identical to the target but flooded. We measured variation in spatial learning by measuring time to target with no landmark (control), with a beacon (a landmark that is part of the target), with an associative cue (a landmark associated with a specific navigational action), and with both a beacon and an associative cue (N = 92 subjects, n = 23 per landmark cue treatment). For each treatment, we tested females for five trials each on four consecutive days, with the last trial on the fourth day having an altered target location, totaling 19 training trials and one reversal trial (1840 trials). We found that spiders took significantly less time to find the target over subsequent trials within a day and learned more quickly when landmark cues were present, but we found no difference in the type or number of landmark features in the meantime to target entrance. After learning a target location, moving the landmark significantly increased the mean time to target entrance in the combined beacon and associative cue treatment relative to other treatments. Our results indicate that wolf spiders use visual beacons and associative cue landmarks alone or in combination and that performance improves across trials when landmarks are present and deteriorates more when multiple landmarks are moved.

Architectural styles of curiosity in global Wikipedia mobile app readership.

Intrinsically motivated information seeking is an expression of curiosity believed to be central to human nature. However, most curiosity research relies on small, Western convenience samples. Here, we analyze a naturalistic population of 482,760 readers using Wikipedia's mobile app in 14 languages from 50 countries or territories. By measuring the structure of knowledge networks constructed by readers weaving a thread through articles in Wikipedia, we replicate two styles of curiosity previously identified in laboratory studies: the nomadic "busybody" and the targeted "hunter." Further, we find evidence for another style-the "dancer"-which was previously predicted by a historico-philosophical examination of texts over two millennia and is characterized by creative modes of knowledge production. We identify associations, globally, between the structure of knowledge networks and population-level indicators of spatial navigation, education, mood, well-being, and inequality. These results advance our understanding of Wikipedia's global readership and demonstrate how cultural and geographical properties of the digital environment relate to different styles of curiosity.

Cortex-wide characterization of decision-making neural dynamics during spatial navigation.

Decision-making during freely moving behaviors involves complex interactions among many cortical and subcortical regions. However, the spatiotemporal coordination across regions to generate a decision is less understood. Using a head-mounted widefield microscope, cortex-wide calcium dynamics were recorded in mice expressing GCaMP7f as they navigated an 8-maze using two paradigms. The first was an alternating pattern that required short term memory of the previous trial to make the correct decision and the second after a rule change to a fixed path in which rewards were delivered only on the left side. Identification of cortex-wide activation states revealed differences between the two paradigms. There was a higher probability for a visual/retrosplenial cortical state during the alternating paradigm and higher probability of a secondary motor and posterior parietal state during left-only. Three state sequences (motifs) illustrated both anterior and posterior activity propagations across the cortex. The anterior propagating motifs had the highest probability around the decision and propagating motifs peaked following the decision. The latter, likely reflecting internal feedback to influence future actions, were more common in the left-only paradigm. Therefore, the probabilities and sequences of cortical states differ when working memory is required versus a fixed trajectory reward paradigm.

Repulsion of CA3 / dentate gyrus representations is driven by distinct internal beliefs in the face of ambiguous sensory input.

Recent human neuroimaging studies of episodic memory have revealed a counterintuitive phenomenon in the hippocampus: when events are highly similar, corresponding hippocampal activity patterns are sometimes less correlated than activity patterns associated with unrelated events. This phenomenon- repulsion- is not accounted for by most theories of the hippocampus, and the conditions that trigger repulsion remain poorly understood. Here, we used a spatial route-learning task and high-resolution fMRI in humans to test whether hippocampal repulsion is fundamentally driven by internal beliefs about the environment. By precisely measuring participants' internal beliefs and actively manipulating them, we show that repulsion selectively occurred in hippocampal subfields CA3 and dentate gyrus when visual input was ambiguous-or even identical -but internal beliefs were distinct. These findings firmly establish conditions that elicit repulsion and have broad relevance to theories of hippocampal function and to the fields of human episodic memory and rodent spatial navigation.

A framework for a low-cost system of automated gate control in assays of spatial cognition in fishes.

Automation of experimental setups is a promising direction in behavioral research because it can facilitate the acquisition of data while increasing its repeatability and reliability. For example, research in spatial cognition can benefit from automated control by systematic manipulation of sensory cues and more efficient execution of training procedures. However, commercial solutions are often costly, restricted to specific platforms, and mainly focused on the automation of data acquisition, stimulus presentation, and reward delivery. Animal welfare considerations as well as experimental demands may require automating the access of an animal or animals to the experimental arena. Here, we provide and test a low-cost, versatile Raspberry Pi-based solution for such use cases. We provide four application scenarios of varying complexities, based on our research of spatial orientation and navigation in weakly electric fish, with step-by-step protocols for the control of gates in the experimental setups. This easy-to-implement, platform-independent approach can be adapted to various experimental needs, including closed-loop as well as field experiments. As such, it can contribute to the optimization and standardization of experiments in a variety of species, thereby enhancing the comparability of data.

Food intake enhances hippocampal sharp wave-ripples.

Effective regulation of energy metabolism is critical for survival. Metabolic control involves various nuclei within the hypothalamus, which receive information about the body's energy state and coordinate appropriate responses to maintain homeostasis, such as thermogenesis, pancreatic insulin secretion, and food-seeking behaviors. It has recently been found that the hippocampus, a brain region traditionally associated with memory and spatial navigation, is also involved in metabolic regulation. Specifically, hippocampal sharp wave ripples (SWRs), which are high-frequency neural oscillations supporting memory consolidation and foraging decisions, have been shown to influence peripheral glucose metabolism. However, whether SWRs are enhanced by recent feeding-when the need for glucose metabolism increases, and if so, whether feeding-dependent modulation of SWRs is communicated to other brain regions involved in metabolic regulation, remains unknown. To address these gaps, we recorded SWRs from the dorsal CA1 region of the hippocampus of mice during sleep sessions before and after consumption of meals of varying caloric values. We found that SWRs occurring during sleep are significantly enhanced following food intake, with the magnitude of enhancement being dependent on the caloric content of the meal. This pattern occurred under both food-deprived and ad libitum feeding conditions. Moreover, we demonstrate that neuronal populations in the lateral hypothalamus, which regulates food intake, exhibit robust SWR-triggered increase in activity. These findings identify the satiety state as a factor modulating SWRs and suggest that hippocampal-lateral hypothalamic communication is a potential mechanism by which SWRs could modulate peripheral metabolism and food intake.

Regulation of the NF-κB/NLRP3 signalling pathway by Shenghui Yizhi decoction reduces neuroinflammation in mice with Alzheimer’s disease

Background Shenghui Yizhi Decoction (SHYZD) has exhibited the capacity to enhance cognitive function and learning abilities in individuals diagnosed with Alzheimer’s disease (AD) while ameliorating pre-existing neuroinflammation. Nevertheless, the precise mechanism underlying its therapeutic effects on AD remains to be elucidated. Methods Twenty-four male SAMP8 mice were randomly divided into three groups, and eight male SAMR1 mice were used as a blank control, to examine their learning and spatial memory abilities. The expression of amyloid β1-42 (Aβ1-42) was detected by immunohistochemical staining of hippocampal tissue. ELISA was used to detect the interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) expressions. Real time PCR was used to detect NOD-like receptor thermal protein domain associated protein 3 (NLRP3), cysteine protease-1 (Caspase-1), and IL-1β mRNA expression. Western blot was used to detect nuclear factor kappa-B (NF-κB), inhibitor of NF-κB α (IκBα), IκB kinase α (IKKα), NLRP3, Caspase-1, and IL-1β protein expression. Results In this study, SAMP8 mice, employed as an AD model, displayed markedly diminished abilities in terms of spatial localization, navigation, and spatial exploration when compared to the blank control group. Additionally, there was a substantial upregulation of Aβ1-42 expression in the hippocampus of these mice, along with a significant increase in the levels of inflammation-associated factors, including IL-1β, IL-6, TNF-α, NLRP3, Caspase-1, as well as the NF-κB pathway-related proteins, namely, NF-κB, IκBα, and IKKα. Moreover, after treatment with positive drugs (donepezil hydrochloride) and SHYZD, the learning abilities of the mice exhibited significant improvements. Furthermore, the hallmark AD protein Aβ1-42, inflammatory factors, and NF-κB/NLRP3 signalling pathway proteins were significantly reduced. These findings collectively suggest that SHYZD exerts a therapeutic effect on AD. Conclusion In summary, the specific molecular mechanisms through which SHYZD alleviates AD and the potential role for SHYZD in the NF-κB/NLRP3 signalling pathway are identified in this study.

Integration of auditory and visual cues in spatial navigation under normal and impaired viewing conditions.

Auditory landmarks can contribute to spatial updating during navigation with vision. Whereas large inter-individual differences have been identified in how navigators combine auditory and visual landmarks, it is still unclear under what circumstances audition is used. Further, whether or not individuals optimally combine auditory cues with visual cues to decrease the amount of perceptual uncertainty, or variability, has not been well-documented. Here, we test audiovisual integration during spatial updating in a virtual navigation task. In Experiment 1, 24 individuals with normal sensory acuity completed a triangular homing task with either visual landmarks, auditory landmarks, or both. In addition, participants experienced a fourth condition with a covert spatial conflict where auditory landmarks were rotated relative to visual landmarks. Participants generally relied more on visual landmarks than auditory landmarks and were no more accurate with multisensory cues than with vision alone. In Experiment 2, a new group of 24 individuals completed the same task, but with simulated low vision in the form of a blur filter to increase visual uncertainty. Again, participants relied more on visual landmarks than auditory ones and no multisensory benefit occurred. Participants navigating with blur did not rely more on their hearing compared with the group that navigated with normal vision. These results support previous research showing that one sensory modality at a time may be sufficient for spatial updating, even under impaired viewing conditions. Future research could investigate task- and participant-specific factors that lead to different strategies of multisensory cue combination with auditory and visual cues.

Distinct effects of slow and fast theta tACS in enhancing temporal memory

Abstract Temporal memory plays a crucial role in organizing real-life events into meaningful segments. Previous research suggests that the clustering of temporally related information builds on the neural correlates of associative memory, including theta oscillations. Transcranial alternating current stimulation (tACS) provides a means of modulating theta oscillations within associative memory networks, possibly including hippocampal modulation when targeting parietal cortex. Theta oscillations are not limited to a single frequency range, but instead, exhibit functional specialization, with slow theta (3 Hz) implicated in short-term episodic memory formation and fast theta (8 Hz) involved in spatial navigation. This study aimed to investigate the distinct effects of slow and fast theta stimulation on temporal memory. Participants encoded visual objects paired with frame color while receiving tACS stimulation at 8 Hz, 3 Hz, or sham targeting the left parietal cortex. The frame color would change for every eight objects, establishing a context boundary with each color change. Subsequently, participants performed a timeline task to assess temporal memory performance. Results showed that slow, but not fast, theta stimulation led to an enhancement in temporal accuracy (absolute temporal error) compared to sham tACS, in support of our main hypothesis. Under sham stimulation, participants consistently underestimated the temporal position of items presented further away from boundary, compared to those presented at boundary. This finding resembled temporal compression observed during event segmentation. Interestingly, fast, but not slow, theta stimulation reduced this temporal bias (rated position— actual position). This study represents the first tACS evidence for differential contributions of slow versus fast theta to temporal memory formation in humans. We speculate that parietal theta tACS may modulate the hippocampus and facilitate temporal memory formation.

Neuronal Vulnerability of the Entorhinal Cortex to Tau Pathology in Alzheimer's Disease.

This review delves into the entorhinal cortex (EC) as a central player in the pathogenesis of Alzheimer's Disease (AD), emphasizing its role in the accumulation and propagation of tau pathology. It elucidates the multifaceted functions of the EC, encompassing memory formation, spatial navigation, and olfactory processing, while exploring how disruptions in these processes contribute to cognitive decline in AD. The review discusses the intricate interplay between tau pathology and EC vulnerability, highlighting how alterations in neuronal firing patterns and synaptic function within the EC exacerbate cognitive impairments. Furthermore, it elucidates how specific neuronal subtypes within the EC exhibit differential susceptibility to tau-induced damage, contributing to disease progression. Early detection methods, such as imaging techniques and assessments of EC blood flow, are examined as potential tools for identifying tau pathology in the preclinical stages of AD. These approaches offer promise for improving diagnostic accuracy and enabling timely intervention. Therapeutic strategies targeting tau pathology within the EC are explored, including the clearance of pathological tau aggregates and the inhibition of tau aggregation processes. By understanding the molecular and cellular mechanisms underlying EC vulnerability, researchers can develop more targeted and effective interventions to slow disease progression. The review underscores the importance of reliable biomarkers to assess disease progression and therapeutic efficacy in clinical trials targeting the EC. Ultimately, it aims to contribute to the development of more effective management strategies for AD, emphasizing the translation of research findings into clinical practice to address the growing societal burden of the disease.

Identifying older adults at risk for dementia based on smartphone data obtained during a wayfinding task in the real world.

Alzheimer's disease (AD), as the most common form of dementia and leading cause for disability and death in old age, represents a major burden to healthcare systems worldwide. For the development of disease-modifying interventions and treatments, the detection of cognitive changes at the earliest disease stages is crucial. Recent advancements in mobile consumer technologies provide new opportunities to collect multi-dimensional data in real-life settings to identify and monitor at-risk individuals. Based on evidence showing that deficits in spatial navigation are a common hallmark of dementia, we assessed whether a memory clinic sample of patients with subjective cognitive decline (SCD) who still scored normally on neuropsychological assessments show differences in smartphone-assisted wayfinding behavior compared with cognitively healthy older and younger adults. Guided by a mobile application, participants had to find locations along a short route on the medical campus of the Magdeburg university. We show that performance measures that were extracted from GPS and user input data distinguish between the groups. In particular, the number of orientation stops was predictive of the SCD status in older participants. Our data suggest that subtle cognitive changes in patients with SCD, whose risk to develop dementia in the future is elevated, can be inferred from smartphone data, collected during a brief wayfinding task in the real world.

Transcriptomic Signature of Spatial Navigation in Brains ofDesert Ants.

Navigation is crucial for central-place foragers to locate food and return to the nest. Cataglyphis ants are renowned for their advanced navigation abilities, relying on landmark cues and path integration. This study aims to uncover the transcriptomic basis of exceptional spatial learning in the central nervous system of Cataglyphis niger. Ants navigated a maze with a food reward, and we examined expression changes linked to correct decisions in subsequent runs. Correct decisions correlated with expression changes in the optic lobes, but not the central brain, showing a downregulation of genes associated with sucrose response and Creb3l1. The latter gene is homologous to Drosophila crebA, which is essential for long-term memory formation. To understand how ants use distance information during path integration, we analyzed expression shifts associated with the last distance traveled. We uncovered a transcriptomic footprint in the central brain, but not in the optic lobes, with genes enriched for energy consumption and neurological functions, including neuronal projection development, synaptic target inhibition, and recognition processes. This suggests that transcriptional activity in the central brain is necessary for estimating distance traveled, which is crucial for path integration. Our study supports the distinct roles of different brain parts for navigation in Cataglyphis ants.

Natural- and redirected walking in virtual reality: Spatial performance and user experience

AbstractImmersive virtual reality offers a range of unique possibilities. One of these is the realistic exploration of virtual worlds using natural walking. This however becomes difficult when the size of the virtual world exceeds that of the available physical space. Redirected walking in virtual reality presents a novel solution to this problem by typically making its users think to be walking in a straight line while they are in fact walking in a curve, thus allowing them to physically walk long distances in confined physical spaces. Yet, few studies have examined the effects of redirected walking on variables such as spatial memory, navigation and user experience as compared to other immersive and non-immersive locomotion methods. In a maze task we examined 1) redirected- and 2) natural walking in immersive virtual reality conditions, and 3) artificial locomotion on a non-immersive desktop monitor. Walked path lengths became shorter and distance estimates, object location memory and user experience improved using natural walking compared to a monitor condition. However, redirected walking yielded similar performance to natural walking while requiring less physical space, opening up possibilities for more pervasive use of real locomotion in virtual environments.

Investigating Transcutaneous Vagus Nerve Stimulation in Amnestic Mild Cognitive Impairment

Abstract Background New treatments are urgently needed for individuals with Mild Cognitive Impairment (MCI) - in particular for those with amnestic MCI, of whom a high proportion have underlying Alzheimer's Disease (AD). Transcutaneous Vagus Nerve Stimulation (tVNS) is a non-invasive neuro-modulatory treatment which has not been extensively examined in older adults with amnestic MCI. Methods A single site, single-blind, randomised three-arm crossover pilot trial of acute (60 minutes) tVNS (baseline, sham or active stimulation) was conducted a Regional Specialist Memory Service. Forty participants (age 71.7 ±6.9; 22/40 male) with diagnosed amnestic MCI were recruited. Given the links between AD and neuro-cardiovascular instability, potential adverse effects of active tVNS were assessed using beat-to-beat peripheral (Blood Pressure (BP) and Heart Rate [HR]) and central (via Near Infra-red Spectroscopy) haemodynamic responses to Active Stand (AS). Cognition was assessed between 21.3 ±4.9 and 60.5 ±4.4 minutes using a domain-specific cognitive performance battery with results analysed using mixed-effects linear regression. Results In older adults with amnestic MCI, tVNS was safe, tolerable and acceptable with 98% of participants stating they would use the device again. There was no significant effect on BP, or HR responses to AS and cerebral oxygenation remained stable during AS. After tVNS stimulation, performance on tests of spatial navigation were significantly improved compared to both baseline (ß= -8.76; [-14.91, -2.56]; p=0.01) and sham (ß= -4.15; [-7.32, -0.99]; p=0.01) conditions. Conclusion tVNS is a safe and tolerable treatment modality in older adults with amnestic MCI. Future studies should explore sustained effects and feasibility of domiciliary use.