The 3D Structural Architecture of the Human Hand Area Is Nontopographic.

The functional topography of the human primary somatosensory cortex hand area is a widely studied model system to understand sensory organization and plasticity. It is so far unclear whether the underlying 3D structural architecture also shows a topographic organization. We used 7 Tesla (7T) magnetic resonance imaging (MRI) data to quantify layer-specific myelin, iron, and mineralization in relation to population receptive field maps of individual finger representations in Brodman area 3b (BA 3b) of human S1 in female and male younger adults. This 3D description allowed us to identify a characteristic profile of layer-specific myelin and iron deposition in the BA 3b hand area, but revealed an absence of structural differences, an absence of low-myelin borders, and high similarity of 3D microstructure profiles between individual fingers. However, structural differences and borders were detected between the hand and face areas. We conclude that the 3D structural architecture of the human hand area is nontopographic, unlike in some monkey species, which suggests a high degree of flexibility for functional finger organization and a new perspective on human topographic plasticity.SIGNIFICANCE STATEMENT Using ultra-high-field MRI, we provide the first comprehensive in vivo description of the 3D structural architecture of the human BA 3b hand area in relation to functional population receptive field maps. High similarity of precise finger-specific 3D profiles, together with an absence of structural differences and an absence of low-myelin borders between individual fingers, reveals the 3D structural architecture of the human hand area to be nontopographic. This suggests reduced structural limitations to cortical plasticity and reorganization and allows for shared representational features across fingers.

Memory traces of duration and location in the right intraparietal sulcus.

Time and space form an integral part of every human experience, and for the neuronal representation of these perceptual dimensions, previous studies point to the involvement of the right-hemispheric intraparietal sulcus and structures in the medial temporal lobe. Here we used multi-voxel pattern analysis (MVPA) to investigate long-term memory traces for temporal and spatial stimulus features in those areas. Participants were trained on four images associated with short versus long durations and with left versus right locations. Our results demonstrate stable representations of both temporal and spatial information in the right posterior intraparietal sulcus. Building upon previous findings of stable neuronal codes for directly perceived durations and locations, these results show that the reactivation of long-term memory traces for temporal and spatial features can be decoded from neuronal activation patterns in the right parietal cortex.

Entorhinal-based path integration selectively predicts midlife risk of Alzheimer's disease.

INTRODUCTION: Entorhinal cortex (EC) is the first cortical region to exhibit neurodegeneration in Alzheimer's disease (AD), associated with EC grid cell dysfunction. Given the role of grid cells in path integration (PI)-based spatial behaviors, we predicted that PI impairment would represent the first behavioral change in adults at risk of AD. METHODS: We compared immersive virtual reality (VR) PI ability to other cognitive domains in 100 asymptomatic midlife adults stratified by hereditary and physiological AD risk factors. In some participants, behavioral data were compared to 7T magnetic resonance imaging (MRI) measures of brain structure and function. RESULTS: Midlife PI impairments predicted both hereditary and physiological AD risk, with no corresponding multi-risk impairment in episodic memory or other spatial behaviors. Impairments associated with altered functional MRI signal in the posterior-medial EC. DISCUSSION: Altered PI may represent the transition point from at-risk state to disease manifestation in AD, prior to impairment in other cognitive domains.

Increased Hippocampal Excitability and Altered Learning Dynamics Mediate Cognitive Mapping Deficits in Human Aging.

Learning the spatial layout of a novel environment is associated with dynamic activity changes in the hippocampus and in medial parietal areas. With advancing age, the ability to learn spatial environments deteriorates substantially but the underlying neural mechanisms are not well understood. Here, we report findings from a behavioral and a fMRI experiment where healthy human older and younger adults of either sex performed a spatial learning task in a photorealistic virtual environment (VE). We modeled individual learning states using a Bayesian state-space model and found that activity in retrosplenial cortex (RSC)/parieto-occipital sulcus (POS) and anterior hippocampus did not change systematically as a function learning in older compared with younger adults across repeated episodes in the environment. Moreover, effective connectivity analyses revealed that the age-related learning deficits were linked to an increase in hippocampal excitability. Together, these results provide novel insights into how human aging affects computations in the brain's navigation system, highlighting the critical role of the hippocampus.SIGNIFICANCE STATEMENT Key structures of the brain's navigation circuit are particularly vulnerable to the deleterious consequences of aging, and declines in spatial navigation are among the earliest indicators for a progression from healthy aging to neurodegenerative diseases. Our study is among the first to provide a mechanistic account about how physiological changes in the aging brain affect the formation of spatial knowledge. We show that neural activity in the aging hippocampus and medial parietal areas is decoupled from individual learning states across repeated episodes in a novel spatial environment. Importantly, we find that increased excitability of the anterior hippocampus might constitute a potential neural mechanism for cognitive mapping deficits in old age.

Cross-dimensional interference between time and distance during spatial navigation is mediated by speed representations in intraparietal sulcus and area hMT.

When navigating a straight path, perceived travel time and perceived traveled distance are linked via movement speed. Behavioral studies have revealed systematic interferences between the perception of travel time and distance, but the role of neuronal representations of movement speed for these effects has not been addressed to date. Using a combined fMRI-behavioral paradigm, we investigate the neuronal representations that underlie cross-dimensional interferences between travel time and traveled distance. Participants underwent fMRI while experiencing visual forward movements for either a short or a long duration, and covering either a short or a long distance. At the behavioral level, we found bi-directional interference effects between time and distance perception, which was correlated with greater representational similarity in speed-sensitive brain regions. The strength of the distance-on-time effect scaled with representational similarity in the left human middle temporal complex (hMT+), and the strength of the time-on-distance effect scaled with representational similarity in the right intraparietal sulcus (IPS). In accordance with the idea that the interference is mediated by the perception of speed, distance-on-time and time-on-distance effects were of opposing directions. Increases in traveled distance led to increases in perceived travel time, while increases in travel time led to decreases in perceived traveled distance. Together, these findings support the view that cross-dimensional interference effects between travel time and traveled distance are mediated by neuronal representations of movement speed.

Temporal context effects are associated with cognitive status in advanced age.

The perception of temporal intervals changes during the life-span, and especially older adults demonstrate specific impairments of timing abilities. Recently, we demonstrated that timing performance and cognitive status are correlated in older adults, suggesting that timing tasks can serve as a behavioral marker for the development of dementia. Easy-to-administer and retest-capable timing tasks therefore have potential as diagnostic tools for tracking cognitive decline. However, before being tested in a clinical cohort study, a further validation and specification of the original findings is warranted. Here we introduce several modifications of the original task and investigated the effects of temporal context on time perception in older adults (> 65 years) with low versus high scores in the Montreal Cognitive Assessment survey (MoCA) and a test of memory functioning. In line with our previous work, we found that temporal context effects were more pronounced with increasing memory deficits, but also that these effects are stronger for realistic compared to abstract visual stimuli. Furthermore, we show that two distinct temporal contexts influence timing behavior in separate experimental blocks, as well as in a mixed block in which both contexts are presented together. These results replicate and extend our previous findings. They demonstrate the stability of the effect for different stimulus material and show that timing tasks can reveal valuable information about the cognitive status of older adults. In the future, these findings could serve as a basis for the development of a diagnostic tool for pathological cognitive decline at an early, pre-clinical stage.

Negative errors in time reproduction tasks.

In time reproduction tasks, the reaction time of motor responses is intrinsically linked to the measure of perceptual timing. Decisions are based on a continuous comparison between elapsed time and a memory trace of the to-be-reproduced interval. Here, we investigate the possibility that negative reproduction errors can be explained by the tendency to prefer earlier over later response times, or whether the whole range of possible response times is shifted. In experiment 1, we directly compared point reproduction (participants indicate the exact time point of equality) and range reproduction (participants bracket an interval containing this time point). In experiment 2, participants indicated, in three separate tasks, the exact time point at which the reproduction phase was equal to the standard duration (point reproduction), the earliest (start reproduction), or the latest moment (stop reproduction) at which the exact time point of equality might have been reached. The results demonstrate that the bias towards earlier responses not only affects reproduction of the exact time point of equality. Rather, even if the decision threshold is changed in favor of late responses, they exhibit a continuous shift towards negative errors that increases with the length of the standard duration. The findings are discussed in the context of the hypothesis that systematic errors in time reproduction tasks reflect a dimension-unspecific tendency towards earlier responses caused by the psychophysical method rather than by a time-specific perceptual distortion.

A novel virtual-reality-based route-learning test suite: Assessing the effects of cognitive aging on navigation.

Most research groups studying human navigational behavior with virtual environment (VE) technology develop their own tasks and protocols. This makes it difficult to compare results between groups and to create normative data sets for any specific navigational task. Such norms, however, are prerequisites for the use of navigation assessments as diagnostic tools-for example, to support the early and differential diagnosis of atypical aging. Here we start addressing these problems by presenting and evaluating a new navigation test suite that we make freely available to other researchers (https://osf.io/mx52y/). Specifically, we designed three navigational tasks, which are adaptations of earlier published tasks used to study the effects of typical and atypical aging on navigation: a route-repetition task that can be solved using egocentric navigation strategies, and route-retracing and directional-approach tasks that both require allocentric spatial processing. Despite introducing a number of changes to the original tasks to make them look more realistic and ecologically valid, and therefore easy to explain to people unfamiliar with a VE or who have cognitive impairments, we replicated the findings from the original studies. Specifically, we found general age-related declines in navigation performance and additional specific difficulties in tasks that required allocentric processes. These findings demonstrate that our new tasks have task demands similar to those of the original tasks, and are thus suited to be used more widely.

Computing distance information from landmarks and self-motion cues - Differential contributions of anterior-lateral vs. posterior-medial entorhinal cortex in humans.

Landmarks and path integration cues are two important sources of spatial information for navigation. For example, both can be used to compute positional information, which, in rodents, has been related to computations in the entorhinal cortex. In humans, however, if and how the entorhinal cortex supports landmark-based navigation and path integration is poorly understood. To address this important question, we developed a novel spatial navigation task in which participants learned a target location and judged relative positions of test locations in relation to the target. Landmarks and path integration cues were dissociated, and their reliability levels were manipulated. Using fMRI adaptation, we investigated whether spatial distances among the test locations were encoded in the BOLD responses, separately for landmarks and self-motion cues. The results showed that the anterior-lateral entorhinal cortex adapted to the distance between successively visited test locations when landmarks were used for localization, meaning that its activation decreased as the distance between the currently occupied location and the preceding location decreased. In contrast, the posterior-medial entorhinal cortex adapted to between-location distance when path integration cues were used for localization. In addition, along with the hippocampus and the precuneus, both entorhinal subregions showed stronger activation in correct trials than incorrect trials, regardless of cue type and reliability level. Together, these findings suggest that subdivisions of entorhinal cortex encode fine-grained spatial information for different spatial cues, which provides important insights into how the entorhinal cortex supports different modes of spatial navigation.

Rapid improvement of cognitive maps in the awake state.

Post-navigation awake quiescence, relative to task engagement, benefits the accuracy of a new "cognitive map". This effect is hypothesized to reflect awake quiescence, like sleep, being conducive to the consolidation and integration of new spatial memories. Sleep has been shown to improve cognitive map accuracy over time. It remained unknown whether awake quiescence can induce similar time-related improvements in new cognitive maps, or whether it simply counteracts their decay. We examined this question via two experiments. In Experiment 1, using an established cognitive mapping paradigm, we reveal that map accuracy for a virtual town was significantly better in people whose memory was probed after 10 min of post-navigation awake quiescence or ongoing cognitive engagement, relative to those whose memory was probed shortly after initial navigation. In Experiment 2, using a newly developed cognitive mapping task that involved a more complex and real-life virtual town, we again found that map accuracy was superior in those whose memory was probed after 10 min of awake quiescence than those who were tested soon after navigation. These findings indicate that actual improvements in human memories are not restricted to sleep. Thus, contrary to conventional wisdom and theories, the passage of (day)time need not always result in forgetting.

Memory Image Completion: Establishing a task to behaviorally assess pattern completion in humans.

For memory retrieval, pattern completion is a crucial process that restores memories from partial or degraded cues. Neurocognitive aging models suggest that the aged memory system is biased toward pattern completion, resulting in a behavioral preference for retrieval over encoding of memories. Here, we built on our previously developed behavioral recognition memory paradigm-the Memory Image Completion (MIC) task-a task to specifically target pattern completion. First, we used the original design with concurrent eye-tracking in order to rule out perceptual confounds that could interact with recognition performance. Second, we developed parallel versions of the task to accommodate test settings in clinical environments or longitudinal studies. The results show that older adults have a deficit in pattern completion ability with a concurrent bias toward pattern completion. Importantly, eye-tracking data during encoding could not account for age-related performance differences. At retrieval, spatial viewing patterns for both age groups were more driven by stimulus identity than by response choice, but compared to young adults, older adults' fixation patterns overlapped more between stimuli that they (wrongly) thought had the same identity. This supports the observation that older adults choose responses perceived as similar to a learned stimulus, indicating a bias toward pattern completion. Additionally, two shorter versions of the task yielded comparable results, and no general learning effects were observed for repeated testing. Together, we present evidence that the MIC is a reliable behavioral task that targets pattern completion, that is easily and repeatedly applicable, and that is made freely available online.

The potential of virtual reality for spatial navigation research across the adult lifespan.

Older adults often experience serious problems in spatial navigation, and alterations in underlying brain structures are among the first indicators for a progression to neurodegenerative diseases. Studies investigating the neural mechanisms of spatial navigation and its changes across the adult lifespan are increasingly using virtual reality (VR) paradigms. VR offers major benefits in terms of ecological validity, experimental control and options to track behavioral responses. However, navigation in the real world differs from navigation in VR in several aspects. In addition, the importance of body-based or visual cues for navigation varies between animal species. Incongruences between sensory and motor input in VR might consequently affect their performance to a different degree. After discussing the specifics of using VR in spatial navigation research across species, we outline several challenges when investigating age-related deficits in spatial navigation with the help of VR. In addition, we discuss ways to reduce their impact, together with the possibilities VR offers for improving navigational abilities in older adults.

On the (a)symmetry between the perception of time and space in large-scale environments.

Cross-dimensional interference between spatial and temporal processing is well documented in humans, but the direction of these interactions remains unclear. The theory of metaphoric structuring states that space is the dominant concept influencing time perception, whereas time has little effect upon the perception of space. In contrast, theories proposing a common neuronal mechanism representing magnitudes argue for a symmetric interaction between space and time perception. Here, we investigated space-time interactions in realistic, large-scale virtual environments. Our results demonstrate a symmetric relationship between the perception of temporal intervals in the supra-second range and room size (experiment 1), but an asymmetric relationship between the perception of travel time and traveled distance (experiment 2). While the perception of time was influenced by the size of virtual rooms and by the distance traveled within these rooms, time itself affected only the perception of room size, but had no influence on the perception of traveled distance. These results are discussed in the context of recent evidence from rodent studies suggesting that subsets of hippocampal place and entorhinal grid cells can simultaneously code for space and time, providing a potential neuronal basis for the interactions between these domains.

Social targets improve body-based and environment-based strategies during spatial navigation.

Encoding the position of another person in space is vital for everyday life. Nevertheless, little is known about the specific navigational strategies associated with encoding the position of another person in the wider spatial environment. We asked two groups of participants to learn the location of a target (person or object) during active navigation, while optic flow information, a landmark, or both optic flow information and a landmark were available in a virtual environment. Whereas optic flow information is used for body-based encoding, such as the simulation of motor movements, landmarks are used to form an abstract, disembodied representation of the environment. During testing, we passively moved participants through virtual space, and compared their abilities to correctly decide whether the non-visible target was before or behind them. Using psychometric functions and the Bayes Theorem, we show that both groups assigned similar weights to body-based and environment-based cues in the condition, where both cue types were available. However, the group who was provided with a person as target showed generally reduced position errors compared to the group who was provided with an object as target. We replicated this effect in a second study with novel participants. This indicates a social advantage in spatial encoding, with facilitated processing of both body-based and environment-based cues during spatial navigation when the position of a person is encoded. This may underlie our critical ability to make accurate distance judgments during social interactions, for example, during fight or flight responses.

The Human Retrosplenial Cortex and Thalamus Code Head Direction in a Global Reference Frame.

UNLABELLED: Spatial navigation is a multisensory process involving integration of visual and body-based cues. In rodents, head direction (HD) cells, which are most abundant in the thalamus, integrate these cues to code facing direction. Human fMRI studies examining HD coding in virtual environments (VE) have reported effects in retrosplenial complex and (pre-)subiculum, but not the thalamus. Furthermore, HD coding appeared insensitive to global landmarks. These tasks, however, provided only visual cues for orientation, and attending to global landmarks did not benefit task performance. In the present study, participants explored a VE comprising four separate locales, surrounded by four global landmarks. To provide body-based cues, participants wore a head-mounted display so that physical rotations changed facing direction in the VE. During subsequent MRI scanning, subjects saw stationary views of the environment and judged whether their orientation was the same as in the preceding trial. Parameter estimates extracted from retrosplenial cortex and the thalamus revealed significantly reduced BOLD responses when HD was repeated. Moreover, consistent with rodent findings, the signal did not continue to adapt over repetitions of the same HD. These results were supported by a whole-brain analysis showing additional repetition suppression in the precuneus. Together, our findings suggest that: (1) consistent with the rodent literature, the human thalamus may integrate visual and body-based, orientation cues; (2) global reference frame cues can be used to integrate HD across separate individual locales; and (3) immersive training procedures providing full body-based cues may help to elucidate the neural mechanisms supporting spatial navigation. SIGNIFICANCE STATEMENT: In rodents, head direction (HD) cells signal facing direction in the environment via increased firing when the animal assumes a certain orientation. Distinct brain regions, the retrosplenial cortex (RSC) and thalamus, code for visual and vestibular cues of orientation, respectively. Putative HD signals have been observed in human RSC but not the thalamus, potentially because body-based cues were not provided. Here, participants encoded HD in a novel virtual environment while wearing a head-mounted display to provide body-based cues for orientation. In subsequent fMRI scanning, we found evidence of an HD signal in RSC, thalamus, and precuneus. These findings harmonize rodent and human data, and suggest that immersive training procedures provide a viable way to examine the neural basis of navigation.

Cue combination in human spatial navigation.

This project investigated the ways in which visual cues and bodily cues from self-motion are combined in spatial navigation. Participants completed a homing task in an immersive virtual environment. In Experiments 1A and 1B, the reliability of visual cues and self-motion cues was manipulated independently and within-participants. Results showed that participants weighted visual cues and self-motion cues based on their relative reliability and integrated these two cue types optimally or near-optimally according to Bayesian principles under most conditions. In Experiment 2, the stability of visual cues was manipulated across trials. Results indicated that cue instability affected cue weights indirectly by influencing cue reliability. Experiment 3 was designed to mislead participants about cue reliability by providing distorted feedback on the accuracy of their performance. Participants received feedback that their performance with visual cues was better and that their performance with self-motion cues was worse than it actually was or received the inverse feedback. Positive feedback on the accuracy of performance with a given cue improved the relative precision of performance with that cue. Bayesian principles still held for the most part. Experiment 4 examined the relations among the variability of performance, rated confidence in performance, cue weights, and spatial abilities. Participants took part in the homing task over two days and rated confidence in their performance after every trial. Cue relative confidence and cue relative reliability had unique contributions to observed cue weights. The variability of performance was less stable than rated confidence over time. Participants with higher mental rotation scores performed relatively better with self-motion cues than visual cues. Across all four experiments, consistent correlations were found between observed weights assigned to cues and relative reliability of cues, demonstrating that the cue-weighting process followed Bayesian principles. Results also pointed to the important role of subjective evaluation of performance in the cue-weighting process and led to a new conceptualization of cue reliability in human spatial navigation.

Space, time, and numbers in the right posterior parietal cortex: Differences between response code associations and congruency effects.

The mental representations of space, time, and number magnitude are inherently linked. The right posterior parietal cortex (PPC) has been suggested to contain a general magnitude system that underlies the overlap between various perceptual dimensions. However, comparative studies including spatial, temporal, and numerical dimensions are missing. In a unified paradigm, we compared the impact of right PPC inhibition on associations with spatial response codes (i.e., Simon, SNARC, and STARC effects) and on congruency effects between space, time, and numbers. Prolonged cortical inhibition was induced by continuous theta-burst stimulation (cTBS), a protocol for transcranial magnetic stimulation (TMS), at the right intraparietal sulcus (IPS). Our results show that congruency effects, but not response code associations, are affected by right PPC inhibition, indicating different neuronal mechanisms underlying these effects. Furthermore, the results demonstrate that interactions between space and time perception are reflected in congruency effects, but not in an association between time and spatial response codes. Taken together, these results implicate that the congruency between purely perceptual dimensions is processed in PPC areas along the IPS, while the congruency between percepts and behavioral responses is independent of this region.

Wakeful rest promotes the integration of spatial memories into accurate cognitive maps.

Flexible spatial navigation, e.g. the ability to take novel shortcuts, is contingent upon accurate mental representations of environments-cognitive maps. These cognitive maps critically depend on hippocampal place cells. In rodents, place cells replay recently travelled routes, especially during periods of behavioural inactivity (sleep/wakeful rest). This neural replay is hypothesised to promote not only the consolidation of specific experiences, but also their wider integration, e.g. into accurate cognitive maps. In humans, rest promotes the consolidation of specific experiences, but the effect of rest on the wider integration of memories remained unknown. In the present study, we examined the hypothesis that cognitive map formation is supported by rest-related integration of new spatial memories. We predicted that if wakeful rest supports cognitive map formation, then rest should enhance knowledge of overarching spatial relations that were never experienced directly during recent navigation. Forty young participants learned a route through a virtual environment before either resting wakefully or engaging in an unrelated perceptual task for 10 min. Participants in the wakeful rest condition performed more accurately in a delayed cognitive map test, requiring the pointing to landmarks from a range of locations. Importantly, the benefit of rest could not be explained by active rehearsal, but can be attributed to the promotion of consolidation-related activity. These findings (i) resonate with the demonstration of hippocampal replay in rodents, and (ii) provide the first evidence that wakeful rest can improve the integration of new spatial memories in humans, a function that has, hitherto, been associated with sleep.

Systematic Underreproduction of Time Is Independent of Judgment Certainty.

We recently proposed that systematic underreproduction of time is caused by a general judgment bias towards earlier responses, instead of reflecting a genuine misperception of temporal intervals. Here we tested whether this bias can be explained by the uncertainty associated with temporal judgments. We applied transcranial magnetic stimulation (TMS) to inhibit neuronal processes in the right posterior parietal cortex (PPC) and tested its effects on time discrimination and reproduction tasks. The results show increased certainty for discriminative time judgments after PPC inhibition. They suggest that the right PPC plays an inhibitory role for time perception, possibly by mediating the multisensory integration between temporal stimuli and other quantities. Importantly, this increased judgment certainty had no influence on the degree of temporal underreproduction. We conclude that the systematic underreproduction of time is not caused by uncertainty for temporal judgments.

Representation of spatial information in key areas of the descending pain modulatory system.

Behavioral studies have demonstrated that descending pain modulation can be spatially specific, as is evident in placebo analgesia, which can be limited to the location at which pain relief is expected. This suggests that higher-order cortical structures of the descending pain modulatory system carry spatial information about the site of stimulation. Here, we used functional magnetic resonance imaging and multivariate pattern analysis in 15 healthy human volunteers to test whether spatial information of painful stimuli is represented in areas of the descending pain modulatory system. We show that the site of nociceptive stimulation (arm or leg) can be successfully decoded from local patterns of brain activity during the anticipation and receipt of painful stimulation in the rostral anterior cingulate cortex, the dorsolateral prefrontal cortices, and the contralateral parietal operculum. These results demonstrate that information regarding the site of nociceptive stimulation is represented in these brain regions. Attempts to predict arm and leg stimulation from the periaqueductal gray, control regions (e.g., white matter) or the control time interval in the intertrial phase did not allow for classifications above chance level. This finding represents an important conceptual advance in the understanding of endogenous pain control mechanisms by bridging the gap between previous behavioral and neuroimaging studies, suggesting a spatial specificity of endogenous pain control.