Effects of estrogen on spatial navigation and memory.

RATIONALE: Animal studies suggest that the so-called "female" hormone estrogen enhances spatial navigation and memory. This contradicts the observation that males generally out-perform females in spatial navigation and tasks involving spatial memory. A closer look at the vast number of studies actually reveals that performance differences are not so clear. OBJECTIVES: To help clarify the unclear performance differences between men and women and the role of estrogen, we attempted to isolate organizational from activational effects of estrogen on spatial navigation and memory. METHODS: In a double-blind, placebo-controlled study, we tested the effects of orally administered estradiol valerate (E2V) in healthy, young women in their low-hormone menstrual cycle phase, compared to healthy, young men. Participants performed several first-person, environmentally rich, 3-D computer games inspired by spatial navigation and memory paradigms in animal research. RESULTS: We found navigation behavior suggesting that sex effects dominated any E2 effects with men performing better with allocentric strategies and women with egocentric strategies. Increased E2 levels did not lead to general improvements in spatial ability in either sex but to behavioral changes reflecting navigation flexibility. CONCLUSION: Estrogen-driven differences in spatial cognition might be better characterized on a spectrum of navigation flexibility rather than by categorical performance measures or skills.

Insights into the quantification and reporting of model-related uncertainty across different disciplines.

Quantifying uncertainty associated with our models is the only way we can express how much we know about any phenomenon. Incomplete consideration of model-based uncertainties can lead to overstated conclusions with real-world impacts in diverse spheres, including conservation, epidemiology, climate science, and policy. Despite these potentially damaging consequences, we still know little about how different fields quantify and report uncertainty. We introduce the "sources of uncertainty" framework, using it to conduct a systematic audit of model-related uncertainty quantification from seven scientific fields, spanning the biological, physical, and political sciences. Our interdisciplinary audit shows no field fully considers all possible sources of uncertainty, but each has its own best practices alongside shared outstanding challenges. We make ten easy-to-implement recommendations to improve the consistency, completeness, and clarity of reporting on model-related uncertainty. These recommendations serve as a guide to best practices across scientific fields and expand our toolbox for high-quality research.

Structural connectivity-based segmentation of the human entorhinal cortex.

The medial (MEC) and lateral entorhinal cortex (LEC), widely studied in rodents, are well defined and characterized. In humans, however, the exact locations of their homologues remain uncertain. Previous functional magnetic resonance imaging (fMRI) studies have subdivided the human EC into posteromedial (pmEC) and anterolateral (alEC) parts, but uncertainty remains about the choice of imaging modality and seed regions, in particular in light of a substantial revision of the classical model of EC connectivity based on novel insights from rodent anatomy. Here, we used structural, not functional imaging, namely diffusion tensor imaging (DTI) and probabilistic tractography to segment the human EC based on differential connectivity to other brain regions known to project selectively to MEC or LEC. We defined MEC as more strongly connected with presubiculum and retrosplenial cortex (RSC), and LEC as more strongly connected with distal CA1 and proximal subiculum (dCA1pSub) and lateral orbitofrontal cortex (OFC). Although our DTI segmentation had a larger medial-lateral component than in the previous fMRI studies, our results show that the human MEC and LEC homologues have a border oriented both towards the posterior-anterior and medial-lateral axes, supporting the differentiation between pmEC and alEC.

Behavior-dependent directional tuning in the human visual-navigation network.

The brain derives cognitive maps from sensory experience that guide memory formation and behavior. Despite extensive efforts, it still remains unclear how the underlying population activity unfolds during spatial navigation and how it relates to memory performance. To examine these processes, we combined 7T-fMRI with a kernel-based encoding model of virtual navigation to map world-centered directional tuning across the human cortex. First, we present an in-depth analysis of directional tuning in visual, retrosplenial, parahippocampal and medial temporal cortices. Second, we show that tuning strength, width and topology of this directional code during memory-guided navigation depend on successful encoding of the environment. Finally, we show that participants' locomotory state influences this tuning in sensory and mnemonic regions such as the hippocampus. We demonstrate a direct link between neural population tuning and human cognition, where high-level memory processing interacts with network-wide visuospatial coding in the service of behavior.

Hippocampal theta phases organize the reactivation of large-scale electrophysiological representations during goal-directed navigation.

Humans are adept in simultaneously following multiple goals, but the neural mechanisms for maintaining specific goals and distinguishing them from other goals are incompletely understood. For short time scales, working memory studies suggest that multiple mental contents are maintained by theta-coupled reactivation, but evidence for similar mechanisms during complex behaviors such as goal-directed navigation is scarce. We examined intracranial electroencephalography recordings of epilepsy patients performing an object-location memory task in a virtual environment. We report that large-scale electrophysiological representations of objects that cue for specific goal locations are dynamically reactivated during goal-directed navigation. Reactivation of different cue representations occurred at stimulus-specific hippocampal theta phases. Locking to more distinct theta phases predicted better memory performance, identifying hippocampal theta phase coding as a mechanism for separating competing goals. Our findings suggest shared neural mechanisms between working memory and goal-directed navigation and provide new insights into the functions of the hippocampal theta rhythm.

Resting-state gamma-band power alterations in schizophrenia reveal E/I-balance abnormalities across illness-stages.

We examined alterations in E/I-balance in schizophrenia (ScZ) through measurements of resting-state gamma-band activity in participants meeting clinical high-risk (CHR) criteria (n = 88), 21 first episode (FEP) patients and 34 chronic ScZ-patients. Furthermore, MRS-data were obtained in CHR-participants and matched controls. Magnetoencephalographic (MEG) resting-state activity was examined at source level and MEG-data were correlated with neuropsychological scores and clinical symptoms. CHR-participants were characterized by increased 64-90 Hz power. In contrast, FEP- and ScZ-patients showed aberrant spectral power at both low- and high gamma-band frequencies. MRS-data showed a shift in E/I-balance toward increased excitation in CHR-participants, which correlated with increased occipital gamma-band power. Finally, neuropsychological deficits and clinical symptoms in FEP and ScZ-patients were correlated with reduced gamma band-activity, while elevated psychotic symptoms in the CHR group showed the opposite relationship. The current study suggests that resting-state gamma-band power and altered Glx/GABA ratio indicate changes in E/I-balance parameters across illness stages in ScZ.

Hexadirectional coding of visual space in human entorhinal cortex.

Entorhinal grid cells map the local environment, but their involvement beyond spatial navigation remains elusive. We examined human functional MRI responses during a highly controlled visual tracking task and show that entorhinal cortex exhibited a sixfold rotationally symmetric signal encoding gaze direction. Our results provide evidence for a grid-like entorhinal code for visual space and suggest a more general role of the entorhinal grid system in coding information along continuous dimensions.

Functional parcellation using time courses of instantaneous connectivity.

Functional neuroimaging studies have led to understanding the brain as a collection of spatially segregated functional networks. It is thought that each of these networks is in turn composed of a set of distinct sub-regions that together support each network's function. Considering the sub-regions to be an essential part of the brain's functional architecture, several strategies have been put forward that aim at identifying the functional sub-units of the brain by means of functional parcellations. Current parcellation strategies typically employ a bottom-up strategy, creating a parcellation by clustering smaller units. We propose a novel top-down parcellation strategy, using time courses of instantaneous connectivity to subdivide an initial region of interest into sub-regions. We use split-half reproducibility to choose the optimal number of sub-regions. We apply our Instantaneous Connectivity Parcellation (ICP) strategy on high-quality resting-state FMRI data, and demonstrate the ability to generate parcellations for thalamus, entorhinal cortex, motor cortex, and subcortex including brainstem and striatum. We evaluate the subdivisions against available cytoarchitecture maps to show that our parcellation strategy recovers biologically valid subdivisions that adhere to known cytoarchitectural features.

An event map of memory space in the hippocampus.

The hippocampus has long been implicated in both episodic and spatial memory, however these mnemonic functions have been traditionally investigated in separate research strands. Theoretical accounts and rodent data suggest a common mechanism for spatial and episodic memory in the hippocampus by providing an abstract and flexible representation of the external world. Here, we monitor the de novo formation of such a representation of space and time in humans using fMRI. After learning spatio-temporal trajectories in a large-scale virtual city, subject-specific neural similarity in the hippocampus scaled with the remembered proximity of events in space and time. Crucially, the structure of the entire spatio-temporal network was reflected in neural patterns. Our results provide evidence for a common coding mechanism underlying spatial and temporal aspects of episodic memory in the hippocampus and shed new light on its role in interleaving multiple episodes in a neural event map of memory space.

Grid-cell representations in mental simulation.

Anticipating the future is a key motif of the brain, possibly supported by mental simulation of upcoming events. Rodent single-cell recordings suggest the ability of spatially tuned cells to represent subsequent locations. Grid-like representations have been observed in the human entorhinal cortex during virtual and imagined navigation. However, hitherto it remains unknown if grid-like representations contribute to mental simulation in the absence of imagined movement. Participants imagined directions between building locations in a large-scale virtual-reality city while undergoing fMRI without re-exposure to the environment. Using multi-voxel pattern analysis, we provide evidence for representations of absolute imagined direction at a resolution of 30° in the parahippocampal gyrus, consistent with the head-direction system. Furthermore, we capitalize on the six-fold rotational symmetry of grid-cell firing to demonstrate a 60° periodic pattern-similarity structure in the entorhinal cortex. Our findings imply a role of the entorhinal grid-system in mental simulation and future thinking beyond spatial navigation.

Functional topography of the human entorhinal cortex.

Despite extensive research on the role of the rodent medial and lateral entorhinal cortex (MEC/LEC) in spatial navigation, memory and related disease, their human homologues remain elusive. Here, we combine high-field functional magnetic resonance imaging at 7 T with novel data-driven and model-based analyses to identify corresponding subregions in humans based on the well-known global connectivity fingerprints in rodents and sensitivity to spatial and non-spatial information. We provide evidence for a functional division primarily along the anteroposterior axis. Localising the human homologue of the rodent MEC and LEC has important implications for translating studies on the hippocampo-entorhinal memory system from rodents to humans.