The grid code for ordered experience.

Entorhinal cortical grid cells fire in a periodic pattern that tiles space, which is suggestive of a spatial coordinate system. However, irregularities in the grid pattern as well as responses of grid cells in contexts other than spatial navigation have presented a challenge to existing models of entorhinal function. In this Perspective, we propose that hippocampal input provides a key informative drive to the grid network in both spatial and non-spatial circumstances, particularly around salient events. We build on previous models in which neural activity propagates through the entorhinal-hippocampal network in time. This temporal contiguity in network activity points to temporal order as a necessary characteristic of representations generated by the hippocampal formation. We advocate that interactions in the entorhinal-hippocampal loop build a topological representation that is rooted in the temporal order of experience. In this way, the structure of grid cell firing supports a learned topology rather than a rigid coordinate frame that is bound to measurements of the physical world.

A comparison of rapid rule-learning strategies in humans and monkeys.

Inter-species comparisons are key to deriving an understanding of the behavioral and neural correlates of human cognition from animal models. We perform a detailed comparison of the strategies of female macaque monkeys to male and female humans on a variant of the Wisconsin Card Sort Test (WCST), a widely studied and applied task that provides a multi-attribute measure of cognitive function and depends on the frontal lobe. WCST performance requires the inference of a rule change given ambiguous feedback. We found that well-trained monkeys infer new rules three times more slowly than minimally instructed humans. Input-dependent Hidden Markov Model-Generalized Linear Models were fit to their choices, revealing hidden states akin to feature-based attention in both species. Decision processes resembled a Win-Stay Lose-Shift strategy with inter-species similarities as well as key differences. Monkeys and humans both test multiple rule hypotheses over a series of rule-search trials and perform inference-like computations to exclude candidate choice options. We quantitatively show that perseveration, random exploration and poor sensitivity to negative feedback account for the slower task-switching performance in monkeys.Significance Statement Advances in training and recording from animal models support the study of increasingly complex behaviors in non-humans. Before interpreting their neural computations as human-like, we must first ascertain whether their computational algorithms are human-like. We compared rapid rule-learning strategies of macaque monkeys and humans on a Wisconsin Card Sorting Test variant and found that monkeys are 3-4 times slower than humans at learning new rules. Model fits to choice behavior revealed that both species use qualitatively similar exploration strategies with different decision criteria. These differences produced distinct errors in monkeys that are similar to those observed in humans with prefrontal deficits. Our results generate detailed neural hypotheses and highlight the need for systematic inter-species behavioral and neural comparisons.

Multiple memory systems for efficient temporal order memory.

We report distinct contributions of multiple memory systems to the retrieval of the temporal order of events. The neural dynamics related to the retrieval of movie scenes revealed that recalling the temporal order of close events elevates hippocampal theta power, like that observed for recalling close spatial relationships. In contrast, recalling far events increases beta power in the orbitofrontal cortex, reflecting recall based on the overall movie structure.

A temporal record of the past with a spectrum of time constants in the monkey entorhinal cortex.

Episodic memory is believed to be intimately related to our experience of the passage of time. Indeed, neurons in the hippocampus and other brain regions critical to episodic memory code for the passage of time at a range of timescales. The origin of this temporal signal, however, remains unclear. Here, we examined temporal responses in the entorhinal cortex of macaque monkeys as they viewed complex images. Many neurons in the entorhinal cortex were responsive to image onset, showing large deviations from baseline firing shortly after image onset but relaxing back to baseline at different rates. This range of relaxation rates allowed for the time since image onset to be decoded on the scale of seconds. Further, these neurons carried information about image content, suggesting that neurons in the entorhinal cortex carry information about not only when an event took place but also, the identity of that event. Taken together, these findings suggest that the primate entorhinal cortex uses a spectrum of time constants to construct a temporal record of the past in support of episodic memory.

Improving rigor and reproducibility in nonhuman primate research.

Nonhuman primates (NHPs) are a critical component of translational/preclinical biomedical research due to the strong similarities between NHP and human physiology and disease pathology. In some cases, NHPs represent the most appropriate, or even the only, animal model for complex metabolic, neurological, and infectious diseases. The increased demand for and limited availability of these valuable research subjects requires that rigor and reproducibility be a prime consideration to ensure the maximal utility of this scarce resource. Here, we discuss a number of approaches that collectively can contribute to enhanced rigor and reproducibility in NHP research.

Device-Embedded Cameras for Eye Tracking-Based Cognitive Assessment: Implications for Teleneuropsychology.

Introduction:Widespread screening for cognitive decline is an important challenge to address as the aging population grows, but there is currently a shortage of clinical infrastructure to meet the demand for in-person evaluation. Remotely delivered assessments that utilize eye-tracking data from webcams, such as visual paired comparison (VPC) tasks, could increase access to remote, asynchronous neuropsychological screening for cognitive decline but further validation against clinical-grade eye trackers is required.Methods:To demonstrate equivalence between a novel automated scoring system for eye-tracking metrics acquired through a laptop-embedded camera and a gold-standard eye tracker, we analyzed VPC data from 18 subjects aged 50+ with normal cognitive function across three visits. The eye tracker data were scored by the manufacturer's software, and the webcam data were scored by a novel algorithm.Results:Automated scoring of webcam-based VPC data revealed strong correlations with the clinical-grade eye-tracking camera. Correlation of mean VPC performance across all time points was robust: r = 0.95 (T1 r = 0.97; T2 r = 0.88; T3 r = 0.97; p's < 0.001). Correlation of per-trial performance across time points was also robust: r = 0.88 (T1 r = 0.85; T2 r = 0.89; T3 r = 0.92; p's < 0.001). Mean differences between performance data acquired by each device were 0.00.Conclusion:These results suggest that device-embedded cameras are a valid and scalable alternative to traditional laboratory-based equipment for gaze-based tasks measuring cognitive function. The validation of this technique represents an important technical advance for the field of teleneuropsychology.

Neurons in Primate Entorhinal Cortex Represent Gaze Position in Multiple Spatial Reference Frames.

Primates rely predominantly on vision to gather information from the environment and neurons representing visual space and gaze position are found in many brain areas. Within the medial temporal lobe, a brain region critical for memory, neurons in the entorhinal cortex of macaque monkeys exhibit spatial selectivity for gaze position. Specifically, the firing rate of single neurons reflects fixation location within a visual image (Killian et al., 2012). In the rodents, entorhinal cells such as grid cells, border cells, and head direction cells show spatial representations aligned to visual environmental features instead of the body (Hafting et al., 2005; Sargolini et al., 2006; Solstad et al., 2008; Diehl et al., 2017). However, it is not known whether similar allocentric representations exist in primate entorhinal cortex. Here, we recorded neural activity in the entorhinal cortex in two male rhesus monkeys during a naturalistic, free-viewing task. Our data reveal that a majority of entorhinal neurons represent gaze position and that simultaneously recorded neurons represent gaze position relative to distinct spatial reference frames, with some neurons aligned to the visual image and others aligned to the monkey's head position. Our results also show that entorhinal neural activity can be used to predict gaze position with a high degree of accuracy. These findings demonstrate that visuospatial representation is a fundamental property of entorhinal neurons in primates and suggest that entorhinal cortex may support relational memory and motor planning by coding attentional locus in distinct, behaviorally relevant frames of reference.SIGNIFICANCE STATEMENT The entorhinal cortex, a brain area important for memory, shows striking spatial activity in rodents through grid cells, border cells, head direction cells, and nongrid spatial cells. The majority of entorhinal neurons signal the location of a rodent relative to visual environmental cues, representing the location of the animal relative to space in the world instead of the body. Recently, we found that entorhinal neurons can signal location of gaze while a monkey explores images visually. Here, we report that spatial entorhinal neurons are widespread in the monkey and these neurons are capable of showing a world-based spatial reference frame locked to the bounds of explored images. These results help connect the extensive findings in rodents to the primate.

Recognition Memory in Marmoset and Macaque Monkeys: A Comparison of Active Vision.

The core functional organization of the primate brain is remarkably conserved across the order, but behavioral differences evident between species likely reflect derived modifications in the underlying neural processes. Here, we performed the first study to directly compare visual recognition memory in two primate species-rhesus macaques and marmoset monkeys-on the same visual preferential looking task as a first step toward identifying similarities and differences in this cognitive process across the primate phylogeny. Preferences in looking behavior on the task were broadly similar between the species, with greater looking times for novel images compared with repeated images as well as a similarly strong preference for faces compared with other categories. Unexpectedly, we found large behavioral differences among the two species in looking behavior independent of image familiarity. Marmosets exhibited longer looking times, with greater variability compared with macaques, regardless of image content or familiarity. Perhaps most strikingly, marmosets shifted their gaze across the images more quickly, suggesting a different behavioral strategy when viewing images. Although such differences limit the comparison of recognition memory across these closely related species, they point to interesting differences in the mechanisms underlying active vision that have significant implications for future neurobiological investigations with these two nonhuman primate species. Elucidating whether these patterns are reflective of species or broader phylogenetic differences (e.g., between New World and Old World monkeys) necessitates a broader sample of primate taxa from across the Order.

A map of visual space in the primate entorhinal cortex.

Place-modulated activity among neurons in the hippocampal formation presents a means to organize contextual information in the service of memory formation and recall. One particular spatial representation, that of grid cells, has been observed in the entorhinal cortex (EC) of rats and bats, but has yet to be described in single units in primates. Here we examined spatial representations in the EC of head-fixed monkeys performing a free-viewing visual memory task. Individual neurons were identified in the primate EC that emitted action potentials when the monkey fixated multiple discrete locations in the visual field in each of many sequentially presented complex images. These firing fields possessed spatial periodicity similar to a triangular tiling with a corresponding well-defined hexagonal structure in the spatial autocorrelation. Further, these neurons showed theta-band oscillatory activity and changing spatial scale as a function of distance from the rhinal sulcus, which is consistent with previous findings in rodents. These spatial representations may provide a framework to anchor the encoding of stimulus content in a complex visual scene. Together, our results provide a direct demonstration of grid cells in the primate and suggest that EC neurons encode space during visual exploration, even without locomotion.

Differential Contribution of Low- and High-level Image Content to Eye Movements in Monkeys and Humans.

Oculomotor selection exerts a fundamental impact on our experience of the environment. To better understand the underlying principles, researchers typically rely on behavioral data from humans, and electrophysiological recordings in macaque monkeys. This approach rests on the assumption that the same selection processes are at play in both species. To test this assumption, we compared the viewing behavior of 106 humans and 11 macaques in an unconstrained free-viewing task. Our data-driven clustering analyses revealed distinct human and macaque clusters, indicating species-specific selection strategies. Yet, cross-species predictions were found to be above chance, indicating some level of shared behavior. Analyses relying on computational models of visual saliency indicate that such cross-species commonalities in free viewing are largely due to similar low-level selection mechanisms, with only a small contribution by shared higher level selection mechanisms and with consistent viewing behavior of monkeys being a subset of the consistent viewing behavior of humans.

Saccade direction encoding in the primate entorhinal cortex during visual exploration.

We recently demonstrated that position in visual space is represented by grid cells in the primate entorhinal cortex (EC), suggesting that visual exploration of complex scenes in primates may employ signaling mechanisms similar to those used during exploration of physical space via movement in rodents. Here, we describe a group of saccade direction (SD) cells that encode eye movement information in the monkey EC during free-viewing of complex images. Significant saccade direction encoding was found in 20% of the cells recorded in the posterior EC. SD cells were generally broadly tuned and two largely separate populations of SD cells encoded future and previous saccade direction. Some properties of these cells resemble those of head-direction cells in rodent EC, suggesting that the same neural circuitry may be capable of performing homologous spatial computations under different exploratory contexts.

Device-Embedded Cameras for Eye Tracking-Based Cognitive Assessment: Validation With Paper-Pencil and Computerized Cognitive Composites.

BACKGROUND: As eye tracking-based assessment of cognition becomes more widely used in older adults, particularly those at risk for dementia, reliable and scalable methods to collect high-quality data are required. Eye tracking-based cognitive tests that utilize device-embedded cameras have the potential to reach large numbers of people as a screening tool for preclinical cognitive decline. However, to fully validate this approach, more empirical evidence about the comparability of eyetracking-based paradigms to existing cognitive batteries is needed. OBJECTIVE: Using a population of clinically normal older adults, we examined the relationship between a 30-minute Visual Paired Comparison (VPC) recognition memory task and cognitive composite indices sensitive to a subtle decline in domains associated with Alzheimer disease. Additionally, the scoring accuracy between software used with a commercial grade eye tracking camera at 60 frames per second (FPS) and a manually scored procedure used with a laptop-embedded web camera (3 FPS) on the VPC task was compared, as well as the relationship between VPC task performance and domain-specific cognitive function. METHODS: A group of 49 clinically normal older adults completed a 30-min VPC recognition memory task with simultaneous recording of eye movements by a commercial-grade eye-tracking camera and a laptop-embedded camera. Relationships between webcam VPC performance and the Preclinical Alzheimer Cognitive Composite (PACC) and National Institutes of Health Toolbox Cognitive Battery (NIHTB-CB) were examined. Inter-rater reliability for manually scored tests was analyzed using Krippendorff's kappa formula, and we used Spearman's Rho correlations to investigate the relationship between VPC performance scores with both cameras. We also examined the relationship between VPC performance with the device-embedded camera and domain-specific cognitive performance. RESULTS: Modest relationships were seen between mean VPC novelty preference and the PACC (r=.39, P=.007) and NIHTB-CB (r=.35, P=.03) composite scores, and additional individual neurocognitive task scores including letter fluency (r=.33, P=.02), category fluency (r=.36, P=.01), and Trail Making Test A (-.40, P=.006). Robust relationships were observed between the 60 FPS eye tracker and 3 FPS webcam on both trial-level VPC novelty preference (r=.82, P<.001) and overall mean VPC novelty preference (r=.92 P<.001). Inter-rater agreement of manually scored web camera data was high (kappa=.84). CONCLUSIONS: In a sample of clinically normal older adults, performance on a 30-minute VPC task correlated modestly with computerized and paper-pencil based cognitive composites that serve as preclinical Alzheimer disease cognitive indices. The strength of these relationships did not differ between camera devices. We suggest that using a device-embedded camera is a reliable and valid way to assess performance on VPC tasks accurately and that these tasks correlate with existing cognitive composites.

Memory and Space: Towards an Understanding of the Cognitive Map.

More than 50 years of research have led to the general agreement that the hippocampus contributes to memory, but there has been a major schism among theories of hippocampal function over this time. Some researchers argue that the hippocampus plays a broad role in episodic and declarative memory, whereas others argue for a specific role in the creation of spatial cognitive maps and navigation. Although both views have merit, neither provides a complete account of hippocampal function. Guided by recent reviews that attempt to bridge between these views, here we suggest that reconciliation can be accomplished by exploring hippocampal function from the perspective of Tolman's (1948) original conception of a cognitive map as organizing experience and guiding behavior across all domains of cognition. We emphasize recent studies in animals and humans showing that hippocampal networks support a broad range of domains of cognitive maps, that these networks organize specific experiences within the contextually relevant map, and that network activity patterns reflect behavior guided through cognitive maps. These results are consistent with a framework that bridges theories of hippocampal function by conceptualizing the hippocampus as organizing incoming information within the context of a multidimensional cognitive map of spatial, temporal, and associational context. SIGNIFICANCE STATEMENT: Research of hippocampal function is dominated by two major views. The spatial view argues that the hippocampus tracks routes through space, whereas the memory view suggests a broad role in declarative memory. Both views rely on considerable evidence, but neither provides a complete account of hippocampal function. Here we review evidence that, in addition to spatial context, the hippocampus encodes a wide variety of information about temporal and situational context, about the systematic organization of events in abstract space, and about routes through maps of cognition and space. We argue that these findings cross the boundaries of the memory and spatial views and offer new insights into hippocampal function as a system supporting a broad range of cognitive maps.

Hippocampus at 25.

The journal Hippocampus has passed the milestone of 25 years of publications on the topic of a highly studied brain structure, and its closely associated brain areas. In a recent celebration of this event, a Boston memory group invited 16 speakers to address the question of progress in understanding the hippocampus that has been achieved. Here we present a summary of these talks organized as progress on four main themes: (1) Understanding the hippocampus in terms of its interactions with multiple cortical areas within the medial temporal lobe memory system, (2) understanding the relationship between memory and spatial information processing functions of the hippocampal region, (3) understanding the role of temporal organization in spatial and memory processing by the hippocampus, and (4) understanding how the hippocampus integrates related events into networks of memories. © 2016 Wiley Periodicals, Inc.

Getting directions from the hippocampus: The neural connection between looking and memory.

Investigations into the neural basis of memory in human and non-human primates have focused on the hippocampus and associated medial temporal lobe (MTL) structures. However, how memory signals from the hippocampus affect motor actions is unknown. We propose that approaching this question through eye movement, especially by assessing the changes in looking behavior that occur with experience, is a promising method for exposing neural computations within the hippocampus. Here, we review how looking behavior is guided by memory in several ways, some of which have been shown to depend on the hippocampus, and how hippocampal neural signals are modulated by eye movements. Taken together, these findings highlight the need for future research on how MTL structures interact with the oculomotor system. Probing how the hippocampus reflects and impacts motor output during looking behavior renders a practical path to advance our understanding of the hippocampal memory system.

Oscillatory activity in the monkey hippocampus during visual exploration and memory formation.

Primates explore the visual world through the use of saccadic eye movements. Neuronal activity in the hippocampus, a structure known to be essential for memory, is modulated by this saccadic activity, but the relationship between visual exploration through saccades and memory formation is not well understood. Here, we identify a link between theta-band (3-12 Hz) oscillatory activity in the hippocampus and saccadic activity in monkeys performing a recognition memory task. As monkeys freely explored novel images, saccades produced a theta-band phase reset, and the reliability of this phase reset was predictive of subsequent recognition. In addition, enhanced theta-band power before stimulus onset predicted stronger stimulus encoding. Together, these data suggest that hippocampal theta-band oscillations act in concert with active exploration in the primate and possibly serve to establish the optimal conditions for stimulus encoding.

Bridging the gap between spatial and mnemonic views of the hippocampal formation.

While it has long been recognized that medial temporal lobe structures are important for memory formation, studies in rodents have also identified exquisite spatial representations in these regions in the form of place cells in the hippocampus and grid cells in the entorhinal cortex. Spatial representations entail neural activity that is observed when the rat is in a given physical location, and these representations are thought to form the basis of navigation via path integration. Recent studies in nonhuman primates have suggested that similar kinds of spatial representations can be identified, even in the absence of physical movement through an environment. Here, I will highlight some recent work that addresses similarities and differences between spatial responses as identified in rodents and primates. I will also discuss areas of opportunity for future research to further our understanding of the function of the hippocampal formation.

Oscillatory correlates of memory in non-human primates.

The ability to navigate through our environment, explore with our senses, track the passage of time, and integrate these various components to form the experiences which make up our lives is shared among humans and animals. The use of animal models to study memory, coupled with electrophysiological techniques that permit the direct measurement of neural activity as memories are formed and retrieved, has provided a wealth of knowledge about these mechanisms. Here, we discuss current knowledge regarding the specific role of neural oscillations in memory, with particular emphasis on findings derived from non-human primates. Some of these findings provide evidence for the existence in the primate brain of mechanisms previously identified only in rodents and other lower mammals, while other findings suggest parallels between memory-related activity and processes observed in other cognitive modalities, including attention and sensory perception. Taken together, these results provide insight into how network activity may be organized to promote memory formation, and suggest that key aspects of this activity are similar across species, providing important information about the organization of human memory.