Unsupervised, frequent and remote: A novel platform for personalised digital phenotyping of long-term memory in humans

Long-term memory tests are commonly used to facilitate the diagnosis of hippocampal-related neurological disorders such as Alzheimer's disease due to their relatively high specificity and sensitivity to damage to the medial temporal lobes compared to standard commonly used clinical tests. Pathological changes in Alzheimer's disease start years before the formal diagnosis is made, partially due to testing too late. This proof-of-concept exploratory study aimed to assess the feasibility of introducing an unsupervised digital platform for continuous testing of long-term memory over long periods outside the laboratory environment. To address this challenge, we developed a novel digital platform, hAge ('healthy Age'), which integrates double spatial alternation, image recognition and visuospatial tasks for frequent remote unsupervised assessment of spatial and non-spatial long-term memory carried out continuously over eight week period. To demonstrate the feasibility of our approach, we tested whether we could achieve sufficient levels of adherence and whether the performance on hAge tasks is comparable to the performance observed in the analogous standard tests measured in the controlled laboratory environments.191 healthy adults (67% females, 18-81 years old) participated in the study. We report an estimated 42.4% adherence level with minimal inclusion criteria. In line with findings using standard laboratory tests, we showed that performance on the spatial alternation task negatively correlated with inter-trial periods and the performance levels on image recognition and visuospatial tasks could be controlled by varying image similarity. Importantly, we demonstrated that frequent engagement with the double spatial alternation task leads to a strong practice effect, previously identified as a potential measure of cognitive decline in MCI patients. Finally, we discuss how lifestyle and motivation confounds may present a serious challenge for cognitive assessment in real-world uncontrolled environments

Local transformations of the hippocampal cognitive map.

Grid cells are neurons active in multiple fields arranged in a hexagonal lattice and are thought to represent the "universal metric for space." However, they become nonhomogeneously distorted in polarized enclosures, which challenges this view. We found that local changes to the configuration of the enclosure induce individual grid fields to shift in a manner inversely related to their distance from the reconfigured boundary. The grid remained primarily anchored to the unchanged stable walls and showed a nonuniform rescaling. Shifts in simultaneously recorded colocalized grid fields were strongly correlated, which suggests that the readout of the animal's position might still be intact. Similar field shifts were also observed in place and boundary cells-albeit of greater magnitude and more pronounced closer to the reconfigured boundary-which suggests that there is no simple one-to-one relationship between these three different cell types

Variational log-Gaussian point-process methods for grid cells

We present practical solutions to applying Gaussian‐process (GP) methods to calculate spatial statistics for grid cells in large environments. GPs are a data efficient approach to inferring neural tuning as a function of time, space, and other variables. We discuss how to design appropriate kernels for grid cells, and show that a variational Bayesian approach to log‐Gaussian Poisson models can be calculated quickly. This class of models has closed‐form expressions for the evidence lower‐bound, and can be estimated rapidly for certain parameterizations of the posterior covariance. We provide an implementation that operates in a low‐rank spatial frequency subspace for further acceleration, and demonstrate these methods on experimental data

The honeycomb maze provides a novel test to study hippocampal-dependent spatial navigation

Here we describe the honeycomb maze, a behavioural paradigm for the study of spatial navigation in rats. The maze consists of 37 platforms that can be raised or lowered independently. Place navigation requires an animal to go to a goal platform from any of several start platforms via a series of sequential choices. For each, the animal is confined to a raised platform and allowed to choose between two of the six adjacent platforms, the correct one being the platform with the smallest angle to the goal-heading direction. Rats learn rapidly and their choices are influenced by three factors: the angle between the two choice platforms, the distance from the goal, and the angle between the correct platform and the direction of the goal. Rats with hippocampal damage are impaired in learning and their performance is affected by all three factors. The honeycomb maze represents a marked improvement over current spatial navigation tests, such as the Morris water maze1,2,3, because it controls the choices of the animal at each point in the maze, provides the ability to assess knowledge of the goal direction from any location, enables the identification of factors influencing task performance and provides the possibility for concomitant single-cell recording.This work was supported by grants from the Wellcome Trust and the Gatsby Charitable Foundation to J.O. R.A.W. is an MRC Clinical Research Training Fellow, J.K. is a Wellcome Trust/Royal Society Sir Henry Dale Fellow and is supported by the Kavli Foundation Dream Team project and the Isaac Newton Trust. D.C. is funded by the Cambridge NIHR Biomedical Research Centre and by the Wellcome Trust

Unsupervised, frequent and remote: A novel platform for personalised digital phenotyping of long-term memory in humans.

Long-term memory tests are commonly used to facilitate the diagnosis of hippocampal-related neurological disorders such as Alzheimer's disease due to their relatively high specificity and sensitivity to damage to the medial temporal lobes compared to standard commonly used clinical tests. Pathological changes in Alzheimer's disease start years before the formal diagnosis is made, partially due to testing too late. This proof-of-concept exploratory study aimed to assess the feasibility of introducing an unsupervised digital platform for continuous testing of long-term memory over long periods outside the laboratory environment. To address this challenge, we developed a novel digital platform, hAge ('healthy Age'), which integrates double spatial alternation, image recognition and visuospatial tasks for frequent remote unsupervised assessment of spatial and non-spatial long-term memory carried out continuously over eight week period. To demonstrate the feasibility of our approach, we tested whether we could achieve sufficient levels of adherence and whether the performance on hAge tasks is comparable to the performance observed in the analogous standard tests measured in the controlled laboratory environments.191 healthy adults (67% females, 18-81 years old) participated in the study. We report an estimated 42.4% adherence level with minimal inclusion criteria. In line with findings using standard laboratory tests, we showed that performance on the spatial alternation task negatively correlated with inter-trial periods and the performance levels on image recognition and visuospatial tasks could be controlled by varying image similarity. Importantly, we demonstrated that frequent engagement with the double spatial alternation task leads to a strong practice effect, previously identified as a potential measure of cognitive decline in MCI patients. Finally, we discuss how lifestyle and motivation confounds may present a serious challenge for cognitive assessment in real-world uncontrolled environments

Unsupervised, frequent and remote: A novel platform for personalised digital phenotyping of long-term memory in humans.

Funder: Isaac Newton Trust/Wellcome Trust ISSF/University of Cambridge Joint Research GrantFunder: BBSRC DTP at University of CambridgeFunder: NVIDIA CorporationFunder: Wellcome Trust/Royal Society Sir Henry Dale FellowLong-term memory tests are commonly used to facilitate the diagnosis of hippocampal-related neurological disorders such as Alzheimer's disease due to their relatively high specificity and sensitivity to damage to the medial temporal lobes compared to standard commonly used clinical tests. Pathological changes in Alzheimer's disease start years before the formal diagnosis is made, partially due to testing too late. This proof-of-concept exploratory study aimed to assess the feasibility of introducing an unsupervised digital platform for continuous testing of long-term memory over long periods outside the laboratory environment. To address this challenge, we developed a novel digital platform, hAge ('healthy Age'), which integrates double spatial alternation, image recognition and visuospatial tasks for frequent remote unsupervised assessment of spatial and non-spatial long-term memory carried out continuously over eight week period. To demonstrate the feasibility of our approach, we tested whether we could achieve sufficient levels of adherence and whether the performance on hAge tasks is comparable to the performance observed in the analogous standard tests measured in the controlled laboratory environments.191 healthy adults (67% females, 18-81 years old) participated in the study. We report an estimated 42.4% adherence level with minimal inclusion criteria. In line with findings using standard laboratory tests, we showed that performance on the spatial alternation task negatively correlated with inter-trial periods and the performance levels on image recognition and visuospatial tasks could be controlled by varying image similarity. Importantly, we demonstrated that frequent engagement with the double spatial alternation task leads to a strong practice effect, previously identified as a potential measure of cognitive decline in MCI patients. Finally, we discuss how lifestyle and motivation confounds may present a serious challenge for cognitive assessment in real-world uncontrolled environments

Unsupervised, frequent and remote: A novel platform for personalised digital phenotyping of long-term memory in humans.

Acknowledgements: We thank all the Participants for their participation in this study. We also thank Profs. Rik Henson, Dennis Chan and John O’Keefe for their comments on the early version of the manuscript. We thank the anonymous reviewers for their many insightful comments and suggestions.Funder: BBSRC DTP at University of CambridgeFunder: Wellcome Trust/Royal Society Sir Henry Dale FellowFunder: Isaac Newton Trust/Wellcome Trust ISSF/University of Cambridge Joint Research GrantFunder: NVIDIA CorporationLong-term memory tests are commonly used to facilitate the diagnosis of hippocampal-related neurological disorders such as Alzheimer's disease due to their relatively high specificity and sensitivity to damage to the medial temporal lobes compared to standard commonly used clinical tests. Pathological changes in Alzheimer's disease start years before the formal diagnosis is made, partially due to testing too late. This proof-of-concept exploratory study aimed to assess the feasibility of introducing an unsupervised digital platform for continuous testing of long-term memory over long periods outside the laboratory environment. To address this challenge, we developed a novel digital platform, hAge ('healthy Age'), which integrates double spatial alternation, image recognition and visuospatial tasks for frequent remote unsupervised assessment of spatial and non-spatial long-term memory carried out continuously over eight week period. To demonstrate the feasibility of our approach, we tested whether we could achieve sufficient levels of adherence and whether the performance on hAge tasks is comparable to the performance observed in the analogous standard tests measured in the controlled laboratory environments.191 healthy adults (67% females, 18-81 years old) participated in the study. We report an estimated 42.4% adherence level with minimal inclusion criteria. In line with findings using standard laboratory tests, we showed that performance on the spatial alternation task negatively correlated with inter-trial periods and the performance levels on image recognition and visuospatial tasks could be controlled by varying image similarity. Importantly, we demonstrated that frequent engagement with the double spatial alternation task leads to a strong practice effect, previously identified as a potential measure of cognitive decline in MCI patients. Finally, we discuss how lifestyle and motivation confounds may present a serious challenge for cognitive assessment in real-world uncontrolled environments

Unsupervised, frequent and remote: A novel platform for personalised digital phenotyping of long-term memory in humans

Long-term memory tests are commonly used to facilitate the diagnosis of hippocampal-related neurological disorders such as Alzheimer’s disease due to their relatively high specificity and sensitivity to damage to the medial temporal lobes compared to standard commonly used clinical tests. Pathological changes in Alzheimer’s disease start years before the formal diagnosis is made, partially due to testing too late. This proof-of-concept exploratory study aimed to assess the feasibility of introducing an unsupervised digital platform for continuous testing of long-term memory over long periods outside the laboratory environment. To address this challenge, we developed a novel digital platform, hAge (‘healthy Age’), which integrates double spatial alternation, image recognition and visuospatial tasks for frequent remote unsupervised assessment of spatial and non-spatial long-term memory carried out continuously over eight week period. To demonstrate the feasibility of our approach, we tested whether we could achieve sufficient levels of adherence and whether the performance on hAge tasks is comparable to the performance observed in the analogous standard tests measured in the controlled laboratory environments.191 healthy adults (67% females, 18-81 years old) participated in the study. We report an estimated 42.4% adherence level with minimal inclusion criteria. In line with findings using standard laboratory tests, we showed that performance on the spatial alternation task negatively correlated with inter-trial periods and the performance levels on image recognition and visuospatial tasks could be controlled by varying image similarity. Importantly, we demonstrated that frequent engagement with the double spatial alternation task leads to a strong practice effect, previously identified as a potential measure of cognitive decline in MCI patients. Finally, we discuss how lifestyle and motivation confounds may present a serious challenge for cognitive assessment in real-world uncontrolled environments

Performance on Phase 2 IR and VS tasks.

A: An example of the left l-IR (top inset) and VS (bottom inset) tasks. All of the images were drawn from the same ‘planes’ category. B: Performance on Phase 2 IR and VS tasks was lower than Phase 1. C: The type of errors on IR and VS tasks for each age group. ‘Missing change’ errors occurred significantly more often than other errors in younger and middle age groups (P−5 after Bonferroni correction, top left). The Participants tended to significantly overreact to no change (fucking-diameter-sign) by incorrectly pressing left (L), right (R) or both (LR) buttons (P−5 after Bonferroni correction, top right). E: The performance on different IR and VS tasks did not noticeably improve with experience: the first half of total engagements are shown in the dark, and the latter half in light colours for each age group.</p

Performance on Phase 2 hAge program.

A: Phase 2 hAge was significantly more challenging compared to Phase 1. The SA task was changed to a double spatial alternation (dSA) task where Participants had to alternate on every second choice to pick the correct side (LLRRLLRR). Simultaneously presented images on IR and VS tasks were drawn from the same categories. B: Female (left) and male (right) distribution by age. C: Daily engagement levels throughout the study. Zone of rewarded participation is shown in orange. D: The adherence levels at different durations and daily participation in Phase 1 (black) and Phase 2 (red) programs. The x-axis corresponds to the number of weeks of engagement. Solid lines show the minimum daily engagement level equal to 10 used in the analysis. Dashed lines correspond to minimum daily engagement levels set to 4, 6, 8 (above solid lines) and 12, 14, 16, 18, and 20 (below solid lines). As expected, the adherence levels fall with the increased daily engagement and the total required duration of the engagement. E: As in the Phase 1 SA task, the performance on the dSA task was negatively correlated with the inter-trial period in all age groups. There was no significant difference in performance between different age groups.</p