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

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

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

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

Examining individual learning patterns using generalised linear mixed models.

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

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

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

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

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

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

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

The time course of systems consolidation of spatial memory from recent to remote retention: A comparison of the Immediate Early Genes Zif268, c-Fos and Arc.

Systems consolidation is a process involving the stabilisation of memory traces in the neocortex over time. The medial prefrontal cortex becomes increasingly important during the retrieval of older memories, however the timescale of its involvement is unclear, and the contribution of other neocortical brain regions to remote memory have received little attention. The Immediate Early Genes (IEGs) Zif268, c-Fos and Arc have been utilised as markers of neural activity during spatial memory retrieval, however the lack of a direct comparison between them hinders the interpretation of results. To address these questions, we examined the expression of Zif268, Arc and c-Fos protein in the medial prefrontal cortex, as well as the hippocampus, and the entorhinal, perirhinal, retrosplenial and parietal cortices of male Wistar rats following a probe trial of the Morris water maze either one day, seven days, 14 days or 30 days after acquisition. Activity of the medial prefrontal cortex during retrieval, as measured by all three IEGs, increased in correspondence with the age of the memory, reaching significance between 14 and 30 days. Similar increases in c-Fos and Arc were observed over the course of consolidation in other neocortical and parahippocampal areas, however this pattern was not observed with Zif268. Activity of the hippocampus remained largely unchanged across retention intervals. These findings suggest that systems consolidation of spatial memory takes at least two weeks, are consistent with an ongoing role for the hippocampus in the retrieval of spatial memory, and suggest that c-Fos and Arc may be a more sensitive measure of neural activity in response to behavioural tasks than Zif268.

Lipopolysaccharide-induced sepsis induces long-lasting affective changes in the mouse.

Post-septic encephalopathy is a poorly understood condition in survivors of sepsis that is characterised by cognitive and affective impairments. In this study we have sought to better understand this condition by undertaking a comprehensive behavioural and cognitive assessment of mice who had previously survived sepsis. Mice were treated with lipopolysaccharide (LPS; 5mg/kg) and one month after this assessed on a battery of tests. Post-septic animals were found to display significantly more immobility in the tail suspension test and show a significantly decreased sucrose preference. Acute fluoxetine treatment reversed the increase in immobility in the tail suspension test in post-septic animals. Post-septic animals also showed less overall exploratory behaviour in the novel object recognition task and also showed increased anxiety-like behaviour in the elevated plus maze. Post-septic mice did not show signs of cognitive impairment, as assessed in the Morris watermaze, the 8-arm radial maze or on preference for the novel object in the novel object recognition task. Immunohistochemical analysis revealed significant upregulation of the microglial marker CD-11b, F4/80 and IBA-1 in the hippocampus of post-septic animals, as well as significant downregulation of the plasticity-related immediate early gene products ARC and EGR1. We also observed a decrease in neural stem cell proliferation in the dentate gyrus of post-septic animals as judged by BrdU incorporation. Co-treatment with the NF-κB pathway inhibitor PDTC attenuated the long-lasting effects of LPS on most of the affected parameters, but not on neural stem cell proliferation. These results show that LPS-induced sepsis in the mouse is followed by long-lasting increases in depressive- and anxiety-like behaviours, as well as by changes in neuroinflammatory- and neural plasticity-associated factors, and that attenuation of the severity of sepsis by PDTC attenuates many of these effects.

Does prior sepsis alter subsequent circadian and sickness behaviour response to lipopolysaccharide treatment in mice?

Previous data has shown that prior history of immune challenge may affect central and behavioural responses to subsequent immune challenge, either leading to exaggerated responses via priming mechanisms or lessened responses via endotoxin tolerance. In this set of experiments we have examined how previously lipopolysaccharide (LPS)-induced sepsis shapes the response to subsequent treatment with lower dose LPS. After treatment with LPS (5 mg/kg) or saline mice were allowed to recover for 3-4 months before being challenged with a lower dose of LPS (100 µg/kg) for assessment of sickness behaviours. Performance on the open field test and the tail suspension test was assessed, and no evidence was found that prior sepsis altered sickness or depressive-like behaviour following LPS treatment. We then examined the responsiveness of the circadian system of mice to LPS. We found that in control animals, LPS induced a significant phase delay of the behavioural rhythm and that this was not the case in post-septic animals (4-6 weeks after sepsis), indicating that prior sepsis alters the responsivity of the circadian system to subsequent immune challenge. We further assessed the induction of the immediate early genes c-Fos and EGR1 in the hippocampus and the suprachiasmatic nucleus (SCN; the master circadian pacemaker) by LPS in control or post-septic animals, and found that post-septic animals show elevated expression in the hippocampus but not the SCN. These data suggest that previous sepsis has some effect on behavioural and molecular responses to subsequent immune challenge in mice.

An exploration of EEG features during recovery following stroke - implications for BCI-mediated neurorehabilitation therapy.

BACKGROUND: Brain-Computer Interfaces (BCI) can potentially be used to aid in the recovery of lost motor control in a limb following stroke. BCIs are typically used by subjects with no damage to the brain therefore relatively little is known about the technical requirements for the design of a rehabilitative BCI for stroke. METHODS: 32-channel electroencephalogram (EEG) was recorded during a finger-tapping task from 10 healthy subjects for one session and 5 stroke patients for two sessions approximately 6 months apart. An off-line BCI design based on Filter Bank Common Spatial Patterns (FBCSP) was implemented to test and compare the efficacy and accuracy of training a rehabilitative BCI with both stroke-affected and healthy data. RESULTS: Stroke-affected EEG datasets have lower 10-fold cross validation results than healthy EEG datasets. When training a BCI with healthy EEG, average classification accuracy of stroke-affected EEG is lower than the average for healthy EEG. Classification accuracy of the late session stroke EEG is improved by training the BCI on the corresponding early stroke EEG dataset. CONCLUSIONS: This exploratory study illustrates that stroke and the accompanying neuroplastic changes associated with the recovery process can cause significant inter-subject changes in the EEG features suitable for mapping as part of a neurofeedback therapy, even when individuals have scored largely similar with conventional behavioural measures. It appears such measures can mask this individual variability in cortical reorganization. Consequently we believe motor retraining BCI should initially be tailored to individual patients.

Hippocampal contribution to vector model hypothesis during cue-dependent navigation.

Learning to navigate toward a goal is an essential skill. Place learning is thought to rely on the ability of animals to associate the location of a goal with surrounding environmental cues. Using the Morris water maze, a task popularly used to examine place learning, we demonstrate that distal cues provide animals with distance and directional information. We show how animals use the cues in a visually dependent guidance manner to find the goal. Further, we demonstrate how hippocampal lesions disrupt this learning mechanism. Our results can be explained through the vector model of navigation built on associative learning principles rather than evoking a cognitive map.

Understanding Learning from EEG Data: Combining Machine Learning and Feature Engineering Based on Hidden Markov Models and Mixed Models.

Theta oscillations, ranging from 4-8 Hz, play a significant role in spatial learning and memory functions during navigation tasks. Frontal theta oscillations are thought to play an important role in spatial navigation and memory. Electroencephalography (EEG) datasets are very complex, making any changes in the neural signal related to behaviour difficult to interpret. However, multiple analytical methods are available to examine complex data structures, especially machine learning-based techniques. These methods have shown high classification performance, and their combination with feature engineering enhances their capability. This paper proposes using hidden Markov and linear mixed effects models to extract features from EEG data. Based on the engineered features obtained from frontal theta EEG data during a spatial navigation task in two key trials (first, last) and between two conditions (learner and non-learner), we analysed the performance of six machine learning methods on classifying learner and non-learner participants. We also analysed how different standardisation methods used to pre-process the EEG data contribute to classification performance. We compared the classification performance of each trial with data gathered from the same subjects, including solely coordinate-based features, such as idle time and average speed. We found that more machine learning methods perform better classification using coordinate-based data. However, only deep neural networks achieved an area under the ROC curve higher than 80% using the theta EEG data alone. Our findings suggest that standardising the theta EEG data and using deep neural networks enhances the classification of learner and non-learner subjects in a spatial learning task.

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

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

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

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

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

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

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

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

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

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

Imaging spatial learning in the brain using immediate early genes: insights, opportunities and limitations.

Immediate early gene (IEG) imaging offers a sophisticated approach to study the neural basis of learning in the brain. Demonstrating a high degree of spatial resolution, the activation of entire neuronal ensembles at multiple time-points can be observed. IEG imaging techniques have revealed a high level of responsiveness to spatial exploration within the hippocampus and other brain regions. The pattern of IEG activation is tightly linked with specific environments and appears to be involved in the subsequent consolidation of spatial information. This incidental learning is a potential confounding factor in studies investigating the neural correlates of spatial learning in both the radial arm maze and water maze. Although both these tasks increase hippocampal IEG expression from baseline levels, where control groups have fully explored the apparatus in the absence of task demands, or where animals are performing a non-spatial task, IEG expression in this region is comparable to spatially trained groups. However, the relationship between IEG expression and task performance, as well as the pattern of brain activation has been shown to differentiate between experimental and control groups. Inconsistencies between training protocols appear to contribute to the discrepancies between reported findings, and the role of IEG expression in the retention of spatial memory tasks remains unclear. Further investigation of the time course and dynamics of IEG expression during learning and retention is required to fully interpret observed results.

Feedback control strategies for spatial navigation revealed by dynamic modelling of learning in the Morris water maze.

The Morris water maze is an experimental procedure in which animals learn to escape swimming in a pool using environmental cues. Despite its success in neuroscience and psychology for studying spatial learning and memory, the exact mnemonic and navigational demands of the task are not well understood. Here, we provide a mathematical model of rat swimming dynamics on a behavioural level. The model consists of a random walk, a heading change and a feedback control component in which learning is reflected in parameter changes of the feedback mechanism. The simplicity of the model renders it accessible and useful for analysis of experiments in which swimming paths are recorded. Here, we used the model to analyse an experiment in which rats were trained to find the platform with either three or one extramaze cue. Results indicate that the 3-cues group employs stronger feedback relying only on the actual visual input, whereas the 1-cue group employs weaker feedback relying to some extent on memory. Because the model parameters are linked to neurological processes, identifying different parameter values suggests the activation of different neuronal pathways.

Virtual Morris water maze: opportunities and challenges.

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