Simultaneous representation of multiple time horizons by entorhinal grid cells and CA1 place cells.

Grid cells and place cells represent the spatiotemporal continuum of an animal's past, present, and future locations. However, their spatiotemporal relationship is unclear. Here, we co-record grid and place cells in freely foraging rats. We show that average time shifts in grid cells tend to be prospective and are proportional to their spatial scale, providing a nearly instantaneous readout of a spectrum of progressively increasing time horizons ranging hundreds of milliseconds. Average time shifts of place cells are generally larger compared to grid cells and also increase with place field sizes. Moreover, time horizons display nonlinear modulation by the animal's trajectories in relation to the local boundaries and locomotion cues. Finally, long and short time horizons occur at different parts of the theta cycle, which may facilitate their readout. Together, these findings suggest that population activity of grid and place cells may represent local trajectories essential for goal-directed navigation and planning.

Author Correction: The honeycomb maze provides a novel test to study hippocampal-dependent spatial navigation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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.

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 maze, 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.

Framing the grid: effect of boundaries on grid cells and navigation.

Cells in the mammalian hippocampal formation subserve neuronal representations of environmental location and support navigation in familiar environments. Grid cells constitute one of the main cell types in the hippocampal formation and are widely believed to represent a universal metric of space independent of external stimuli. Recent evidence showing that grid symmetry is distorted in non-symmetrical environments suggests that a re-examination of this hypothesis is warranted. In this review we will discuss behavioural and physiological evidence for how environmental shape and in particular enclosure boundaries influence grid cell firing properties. We propose that grid cells encode the geometric layout of enclosures.

Grid cell symmetry is shaped by environmental geometry.

Grid cells represent an animal's location by firing in multiple fields arranged in a striking hexagonal array. Such an impressive and constant regularity prompted suggestions that grid cells represent a universal and environmental-invariant metric for navigation. Originally the properties of grid patterns were believed to be independent of the shape of the environment and this notion has dominated almost all theoretical grid cell models. However, several studies indicate that environmental boundaries influence grid firing, though the strength, nature and longevity of this effect is unclear. Here we show that grid orientation, scale, symmetry and homogeneity are strongly and permanently affected by environmental geometry. We found that grid patterns orient to the walls of polarized enclosures such as squares, but not circles. Furthermore, the hexagonal grid symmetry is permanently broken in highly polarized environments such as trapezoids, the pattern being more elliptical and less homogeneous. Our results provide compelling evidence for the idea that environmental boundaries compete with the internal organization of the grid cell system to drive grid firing. Notably, grid cell activity is more local than previously thought and as a consequence cannot provide a universal spatial metric in all environments.

Nine year follow-up of a ceramic-on-ceramic bearing total hip arthroplasty utilizing a layered monoblock acetabular component.

INTRODUCTION: Early ceramic bearing systems in total hip arthoplasty (THA) sought to provide long term wear improvement over traditional metal on polyethylene systems. However, previous designs exhibited fractures of the ceramic acetabular liner, leading to the development of the Implex Hedrocel ceramic bearing THA system where the ceramic liner was supported on a layer of polyethylene intended to transition liner loads to the metal shell, a so-called "sandwich" design. Unfortunately, the device trial was stopped to further enrollment when liner fractures were reported. The current study examines nearly 10-year follow-up on 28 devices implanted by two surgeons at one institution in order to document ceramic bearing system performance over a longer time period. METHODS: Radiographic and patient reported outcomes, in the form of Harris Hip Scores (HHS) and 12-Item Short Form Health Survey (sF-12), were collected. RESULTS: During the study period two cups were replaced, one at three years and a second at seven years. At the five year follow-up HHS were similar to those reported in the literature for devices with traditional metal-on-polyethylene bearing surfaces and for other sandwich ceramic bearing designs. At the nine year follow-up, the HHS had not changed significantly and SF-12 scores measuring overall physical and mental health were higher than age matched national norms (p<0.001). There were no signs of cup migration, stem subsidence, osteolysis or cup loosening at any time up to the last follow-up in this patient cohort. The 89% survivorship rate and device revisions due to delamination of the liner observed in this group were similar to those reported earlier for this device and for other "sandwich design" ceramic bearing systems. DISCUSSION: This cohort did not exhibit new failure modes and HHS and SF-12 scores indicated high functionality for the majority of patients. These data suggest that a focus on preventing ceramic liner fracture through design and/or materials improvements may result in a device with long-term functionality.

How environment geometry affects grid cell symmetry and what we can learn from it.

The mammalian hippocampal formation provides neuronal representations of environmental location but the underlying mechanisms are unclear. The majority of cells in medial entorhinal cortex and parasubiculum show spatially periodic firing patterns. Grid cells exhibit hexagonal symmetry and form an important subset of this more general class. Occasional changes between hexagonal and non-hexagonal firing patterns imply a common underlying mechanism. Importantly, the symmetrical properties are strongly affected by the geometry of the environment. Here, we introduce a field-boundary interaction model where we demonstrate that the grid cell pattern can be formed from competing place-like and boundary inputs. We show that the modelling results can accurately capture our current experimental observations.

A modified intramedullary nail interlocking design yields improved stability for fatigue cycling in a canine femur fracture model.

Intramedullary nailing has evolved to become the standard of care for most diaphyseal femoral and tibial fractures, as well as an expanding number of metaphyseal fractures. Owing to the unstable nature of some fractures, the intramedullary device may be subjected to significant stresses owing to a lack of solid cortical contact after nailing. In such cases, excessive interfragmentary motion (due to construct toggle) has been shown to occur. Such motion increases the likelihood of a non- or delayed-union. In the current study, two versions of a modified, angle stable interlocking design were subjected to fatigue testing in a segmental defect fracture model representing a canine femur. As a control, a third group of constructs were stabilized with a traditional nail that allowed a small amount of toggle. All constructs were subjected to 50,000 fatigue cycles representing 12 weeks of cage activity at physiologic levels of combined axial-torsional loading. Torsional testing pre- and post-fatigue revealed 4.6 +/- 1.3 degrees of toggle in the traditional nail and no toggle with the angle stable nail designs. The stable nails were also significantly stiffer in axial compression and torsion before and after cycling. These data indicate that the enhanced stability of the modified interlocking designs can be maintained throughout fatigue cycling in a challenging fracture model.

Cerebral venous and sinus thrombosis associated with subcutaneous immunoglobulin injection and oral contraceptive use.

Although patients of cerebral sinus thrombosis after intravenous immunoglobulin (IVIG) has been previously reported; reports of cerebral venous thrombosis secondary to subcutaneous injection of immunoglobulin (SIG) in conjunction with oral contraceptives are nonexistent in the current literature. We describe here a patient of cerebral venous and sinus thrombosis occurring after the combination of SIG and oral contraceptive use. Furthermore, we shall explore proper clinical precautions for someone who receives IG therapy, especially in conjunction with the use of oral contraceptives.

Environmental novelty elicits a later theta phase of firing in CA1 but not subiculum.

The mechanism supporting the role of the hippocampal formation in novelty detection remains controversial. A comparator function has been variously ascribed to CA1 or subiculum, whereas the theta rhythm has been suggested to separate neural firing into encoding and retrieval phases. We investigated theta phase of firing in principal cells in subiculum and CA1 as rats foraged in familiar and novel environments. We found that the preferred theta phase of firing in CA1, but not subiculum, was shifted to a later phase of the theta cycle during environmental novelty. Furthermore, the amount of phase shift elicited by environmental change correlated with the extent of place cell remapping in CA1. Our results support a relationship between theta phase and novelty-induced plasticity in CA1.

Boundary vector cells in the subiculum of the hippocampal formation.

"Boundary vector cells" were predicted to exist by computational models of the environmental inputs underlying the spatial firing patterns of hippocampal place cells (O'Keefe and Burgess, 1996; Burgess et al., 2000; Hartley et al., 2000). Here, we report the existence of cells fulfilling this description in recordings from the subiculum of freely moving rats. These cells may contribute environmental information to place cell firing, complementing path integrative information. Their relationship to other cell types, including medial entorhinal "border cells," is discussed.

Rearing on hind legs, environmental novelty, and the hippocampal formation.

Many mammals spontaneously rear on their hind legs in response to novelty. The current paper is the first review of rearing behaviour, and is intended to collate findings from different perspectives that are not usually brought together. We suggest that rearing is a useful marker of environmental novelty, that the hippocampal formation is a crucial component of the system controlling rearing in novel environments, and that rearing is one of several ethological measures that can profitably be used to assess hippocampal learning and memory. Consideration is given to the following topics: the possible functions of rearing in information-gathering and escape behaviour; the modulation of rearing by various factors such as anxiety/ fear emotionality; comparative perspectives on rearing; neuroanatomical circuits involved in rearing with particular reference to the hippocampal formation and its afferents and efferents; and the role of the hippocampal formation in uncharted and mismatch environmental novelty. The review concludes with testable predictions about rearing, environmental novelty and the hippocampus.

The boundary vector cell model of place cell firing and spatial memory.

We review evidence for the boundary vector cell model of the environmental determinants of the firing of hippocampal place cells. Preliminary experimental results are presented concerning the effects of addition or removal of environmental boundaries on place cell firing and evidence that boundary vector cells may exist in the subiculum. We review and update computational simulations predicting the location of human search within a virtual environment of variable geometry, assuming that boundary vector cells provide one of the input representations of location used in mammalian spatial memory. Finally, we extend the model to include experience-dependent modification of connection strengths through a BCM-like learning rule - the size and sign of strength change is influenced by historic activity of the postsynaptic cell. Simulations are compared to experimental data on the firing of place cells under geometrical manipulations to their environment. The relationship between neurophysiological results in rats and spatial behaviour in humans is discussed.

Preserved performance in a hippocampal-dependent spatial task despite complete place cell remapping.

The spatially localized firing of hippocampal place cells is thought to underlie the navigational function of the hippocampus. Performance on a spatial task learned using a particular place cell map should therefore deteriorate if the map is disrupted. To test this prediction, we trained rats on a hippocampal-dependent spatial task in a black box and tested them in a white box. Although the change from black to white induced remapping of most place cells, navigational performance remained essentially intact. Furthermore, place cell activity was also unrelated to specific aspects of the task such as tone onset, response, or goal location. Together, these results imply that the spatial information needed to solve this navigation task is represented outside the hippocampus and suggest that the place cells encode some other aspect, such as the spatial context.