Do hippocampal pyramidal cells respond to nonspatial stimuli?

There are currently a number of theories of rodent hippocampal function. They fall into two major groups that differ in the role they impute to space in hippocampal information processing. On one hand, the cognitive map theory sees space as crucial and central, with other types of nonspatial information embedded in a primary spatial framework. On the other hand, most other theories see the function of the hippocampal formation as broader, treating all types of information as equivalent and concentrating on the processes carried out irrespective of the specific material being represented, stored, and manipulated. One crucial difference, therefore, is the extent to which theories see hippocampal pyramidal cells as representing nonspatial information independently of a spatial framework. Studies have reported the existence of single hippocampal unit responses to nonspatial stimuli, both to simple sensory inputs as well as to more complex stimuli such as objects, conspecifics, rewards, and time, and these findings been interpreted as evidence in favor of a broader hippocampal function. Alternatively, these nonspatial responses might actually be feature-in-place signals where the spatial nature of the response has been masked by the fact that the objects or features were only presented in one location or one spatial context. In this article, we argue that when tested in multiple locations, the hippocampal response to nonspatial stimuli is almost invariably dependent on the animal's location. Looked at collectively, the data provide strong support for the cognitive map theory.

Hippocampal place cells have goal-oriented vector fields during navigation.

The hippocampal cognitive map supports navigation towards, or away from, salient locations in familiar environments1. Although much is known about how the hippocampus encodes location in world-centred coordinates, how it supports flexible navigation is less well understood. We recorded CA1 place cells while rats navigated to a goal on the honeycomb maze2. The maze tests navigation via direct and indirect paths to the goal and allows the directionality of place cells to be assessed at each choice point. Place fields showed strong directional polarization characterized by vector fields that converged to sinks distributed throughout the environment. The distribution of these 'convergence sinks' (ConSinks) was centred near the goal location and the population vector field converged on the goal, providing a strong navigational signal. Changing the goal location led to movement of ConSinks and vector fields towards the new goal. The honeycomb maze allows independent assessment of spatial representation and spatial action in place cell activity and shows how the latter relates to the former. The results suggest that the hippocampus creates a vector-based model to support flexible navigation, allowing animals to select optimal paths to destinations from any location in the environment.

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.

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.

Minimally invasive Dorsal cheilectomy and Hallux metatarsophalangeal joint arthroscopy for the treatment of Hallux Rigidus.

BACKGROUND: Minimally invasive dorsal cheilectomy (MIDC) has become a popular alternative to an open approach for treating Hallux Rigidus (HR). To reduce some of the complications related to the MIDC approach, a first metatarsophalangeal (MTP) joint arthroscopy can be performed in addition to address the intra-articular pathology associated with Hallux Rigidus. This study aims to examine the effectiveness of MIDC with first MTP arthroscopy in patients with HR with a minimum 1-year follow-up. METHODS: This was a multicenter retrospective review for adult patients with Coughlin and Shurnass Grade 0-3 who were treated with MIDC and first MTP arthroscopy between 3/1/2020 and 8/1/2022, with at least one year of follow-up data. Demographic information, first MTP range of motion (ROM), visual analog scale (VAS), Manchester-Oxford Foot Questionnaire (MOXFQ), and EQ-5D-5 L scores were collected. Continuous data was expressed as a mean and standard deviation, categorical data was expressed as a percentage. Wilcoxon Rank Sum test was used to compare continuous variables. All P < 0.05 was considered significant. RESULTS: A total of 31 patients were included in the study. Average follow-up time was 16.5 months (range: 12 to 26.2). There was 1 (3.2%) undersurface EHL tendon tear, 2 (6.5%) conversions to an MTP fusion, and 1 (3.2%) revision cheilectomy and capsular release for MTP joint contracture. There was a significant improvement in patient's ROM in dorsiflexion (50 vs 89.6 degrees, P = 0.002), postoperative VAS pain scores (6.4 vs 2.1, P < 0.001), MOXFQ pain scores (58.1 vs 30.7, P = 0.001), MOXFQ Walking/Standing scores (56.6 vs 20.6, P = 0.001), MOXFQ Social Interaction scores (47.3 vs 19.36, P = 0.002), and MOXFQ Index scores (54.7 vs 22.4, P < 0.001). CONCLUSION: We found that MIDC with first MTP arthroscopy was effective at improving patient-reported outcomes at one year with low complication and revision rates. These results suggest that MIDC with first MTP arthroscopy is an effective treatment for early-stage HR. LEVEL OF EVIDENCE: IV.

Fully integrated silicon probes for high-density recording of neural activity.

Sensory, motor and cognitive operations involve the coordinated action of large neuronal populations across multiple brain regions in both superficial and deep structures. Existing extracellular probes record neural activity with excellent spatial and temporal (sub-millisecond) resolution, but from only a few dozen neurons per shank. Optical Ca2+ imaging offers more coverage but lacks the temporal resolution needed to distinguish individual spikes reliably and does not measure local field potentials. Until now, no technology compatible with use in unrestrained animals has combined high spatiotemporal resolution with large volume coverage. Here we design, fabricate and test a new silicon probe known as Neuropixels to meet this need. Each probe has 384 recording channels that can programmably address 960 complementary metal-oxide-semiconductor (CMOS) processing-compatible low-impedance TiN sites that tile a single 10-mm long, 70 × 20-µm cross-section shank. The 6 × 9-mm probe base is fabricated with the shank on a single chip. Voltage signals are filtered, amplified, multiplexed and digitized on the base, allowing the direct transmission of noise-free digital data from the probe. The combination of dense recording sites and high channel count yielded well-isolated spiking activity from hundreds of neurons per probe implanted in mice and rats. Using two probes, more than 700 well-isolated single neurons were recorded simultaneously from five brain structures in an awake mouse. The fully integrated functionality and small size of Neuropixels probes allowed large populations of neurons from several brain structures to be recorded in freely moving animals. This combination of high-performance electrode technology and scalable chip fabrication methods opens a path towards recording of brain-wide neural activity during behaviour.

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.

Increased flexor hallucis longus tension decreases ankle dorsiflexion.

BACKGROUND: Restricted excursion of the flexor hallucis longus (FHL) is associated with several clinical problems. An FHL excursion measurement device (EMD) was used to objectively assess differences between patients with clinically normal or tight FHL tendons. METHODS: 188 patients (356 feet) were enrolled. The EMD measured maximum ankle dorsiflexion with the great toe in 15°, 30°, and 45° of dorsiflexion. All had clinical assessment of FHL tightness by their provider independently of the EMD measurement. RESULTS: Increased hallux DF always caused decreased ankle DF. Patients with clinically tight FHLs demonstrated decreased ankle DF compared to normal subjects at all hallux positions (p<0.01). The EMD measurement was not sensitive enough for detection of FHL tightness in individuals. A clinically tight FHL was seen in almost 50% of feet. CONCLUSIONS: Tension in the FHL can limit ankle DF. Clinical tightness of the FHL is likely more common than currently recognized.

A "Seleno Effect" Differentiates the Roles of Redox Active Cysteine Residues in Plasmodium falciparum Thioredoxin Reductase.

Here, we introduce the concept of the "seleno effect" in the study of oxidoreductases that catalyze thiol/disulfide exchange reactions. In these reactions, selenium can replace sulfur as a nucleophile, electrophile, or leaving group, and the resulting change in rate (the seleno effect) is defined as kS/ kSe. In solution, selenium accelerates the rate of thiol/disulfide exchange regardless of its chemical role (e.g., nucleophile or electrophile). Here we show that this is not the case for enzyme catalyzed reactions and that the magnitude of the seleno effect can differentiate the role of each sulfur atom of a disulfide bond between that of an electrophile or leaving group. We used selenium for sulfur substitution to study the thiol/disulfide exchange step that occurs between the N-terminal redox center and the C-terminal disulfide-containing ß-hairpin motif of Plasmodium falciparum thioredoxin reductase (PfTrxR), which has the sequence Gly-Cys535-Gly-Gly-Gly-Lys-Cys540-Gly. We assayed a truncated PfTrxR enzyme missing this C-terminal tail for disulfide-reductase activity using synthetic peptide substrates in which either Cys535 or Cys540 was replaced with selenocysteine (Sec). The results show that substitution of Cys535 with Sec resulted in a nearly 9-fold decrease in the rate of reduction, while substitution of Cys540 resulted in a 1.5-fold increase in the rate of reduction. We also produced full-length, semisynthetic enzymes in which Sec replaced either of these two Cys residues and observed similar results using E. coli thioredoxin as the substrate. In this assay, the observed seleno effect ( kS/ kSe) for the C535U mutant was 7.4, and that for the C540U mutant was 0.2.

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.

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.

How vision and movement combine in the hippocampal place code.

How do external environmental and internal movement-related information combine to tell us where we are? We examined the neural representation of environmental location provided by hippocampal place cells while mice navigated a virtual reality environment in which both types of information could be manipulated. Extracellular recordings were made from region CA1 of head-fixed mice navigating a virtual linear track and running in a similar real environment. Despite the absence of vestibular motion signals, normal place cell firing and theta rhythmicity were found. Visual information alone was sufficient for localized firing in 25% of place cells and to maintain a local field potential theta rhythm (but with significantly reduced power). Additional movement-related information was required for normally localized firing by the remaining 75% of place cells. Trials in which movement and visual information were put into conflict showed that they combined nonlinearly to control firing location, and that the relative influence of movement versus visual information varied widely across place cells. However, within this heterogeneity, the behavior of fully half of the place cells conformed to a model of path integration in which the presence of visual cues at the start of each run together with subsequent movement-related updating of position was sufficient to maintain normal fields.

Can Patients Comprehend the Educational Materials that Hospitals Provide about Common IR Procedures?

PURPOSE: To assess the readability of online education materials offered by hospitals describing commonly performed interventional radiology (IR) procedures. MATERIALS AND METHODS: Online patient education materials from 402 hospitals selected from the Medicare Hospital Compare database were assessed. The presence of an IR service was determined by representation in the Society of Interventional Radiology physician finder directory. Patient online education materials about (i) uterine artery embolization for fibroid tumors, (ii) liver cancer embolization, (iii) varicose vein treatment, (iv) central venous access, (v) inferior vena cava (IVC) filter placement, (vi) nephrostomy tube insertion, (vii) gastrostomy tube placement, and (viii) vertebral augmentation were targeted and assessed by using six validated readability scoring systems. RESULTS: Of 402 hospitals sampled, 156 (39%) were presumed to offer IR services. Of these, 119 (76%) offered online patient education material for one or more of the eight service lines. The average readability scores corresponding to grade varied between the ninth- and 12th-grade levels. All were higher than the recommended seventh-grade level (P < .05) except for nephrostomy and gastrostomy tube placement. Average Flesch-Kincaid Reading Ease scores ranged from 42 to 69, corresponding with fairly difficult to difficult readability for all service lines except IVC filter and gastrostomy tube placement, which corresponded with standard readability. CONCLUSIONS: A majority of hospitals offering IR services provide at least some online patient education material. Most, however, are written significantly above the reading comprehension level of most Americans. More attention to health literacy by hospitals and IR physicians is warranted.

Grid cell firing patterns signal environmental novelty by expansion.

The hippocampal formation plays key roles in representing an animal's location and in detecting environmental novelty to create or update those representations. However, the mechanisms behind this latter function are unclear. Here, we show that environmental novelty causes the spatial firing patterns of grid cells to expand in scale and reduce in regularity, reverting to their familiar scale as the environment becomes familiar. Simultaneously recorded place cell firing fields remapped and showed a smaller, temporary expansion. Grid expansion provides a potential mechanism for novelty signaling and may enhance the formation of new hippocampal representations, whereas the subsequent slow reduction in scale provides a potential familiarity signal.

Novelty and anxiolytic drugs dissociate two components of hippocampal theta in behaving rats.

Hippocampal processing is strongly implicated in both spatial cognition and anxiety and is temporally organized by the theta rhythm. However, there has been little attempt to understand how each type of processing relates to the other in behaving animals, despite their common substrate. In freely moving rats, there is a broadly linear relationship between hippocampal theta frequency and running speed over the normal range of speeds used during foraging. A recent model predicts that spatial-translation-related and arousal/anxiety-related mechanisms of hippocampal theta generation underlie dissociable aspects of the theta frequency-running speed relationship (the slope and intercept, respectively). Here we provide the first confirmatory evidence: environmental novelty decreases slope, whereas anxiolytic drugs reduce intercept. Variation in slope predicted changes in spatial representation by CA1 place cells and novelty-responsive behavior. Variation in intercept predicted anxiety-like behavior. Our findings isolate and doubly dissociate two components of theta generation that operate in parallel in behaving animals and link them to anxiolytic drug action, novelty, and the metric for self-motion.

Representation of ethological events by basolateral amygdala neurons.

The accurate interpretation of ethologically relevant stimuli is crucial for survival. While basolateral amygdala (BLA) neuronal responses during fear conditioning are well studied, little is known about how BLA neurons respond during naturalistic events. We recorded from the rat BLA during interaction with ethological stimuli: male or female rats, a moving toy, and rice. Forty-two percent of the cells reliably respond to at least one stimulus, with over half of these exclusively identifying one of the four stimulus classes. In addition to activation during interaction with their preferred stimulus, these cells signal micro-behavioral interactions like social contact. After stimulus removal, firing activity persists in 30% of responsive cells for several minutes. At the micro-circuit level, information flows from highly tuned event-specific neurons to less specific neurons, and connection strength increases after the event. We propose that individual BLA neurons identify specific ethological events, with event-specific neurons driving circuit-wide activity during and after salient events.

Place cell firing correlates with memory deficits and amyloid plaque burden in Tg2576 Alzheimer mouse model.

Alzheimer's disease (AD) is associated with progressive memory decline. Hippocampal place cells are a well understood candidate for the neural basis of one type of memory in rodents; these cells identify the animal's location in an environment and are crucial for spatial memory and navigation. We have recorded place cells in the Tg2576 mouse model of AD, and we report that aged (16 mo) but not young (3 mo) transgenic mice show degraded neuronal representations of the environment. The level of place cell degradation correlates with the animals' (poorer) spatial memory as tested in a forced-choice spatial alternation T-maze task and with hippocampal, but not neocortical, amyloid plaque burden. Place cell recording provides a sensitive assay for measuring the amount and rate of functional deterioration in animal models of dementia as well as providing a quantifiable physiological indication of the beneficial effects of potential therapies.

Frequent callers to UK ambulance services in the COVID-19 pandemic: managing mental health, social isolation and loneliness.

OBJECTIVES: Patients who frequently call ambulance services are a vulnerable yet heterogeneous population with unmet multiple and complex physical health, mental health and/or social care needs. In this article, we report the challenges that the COVID-19 pandemic has introduced for ambulance services across the UK when managing frequent callers, and reflect on how existing systems and practices are adapting to support changing patient needs. METHODS: Data reported in this article comprise reflections from the frequent caller leads in each ambulance service in the UK. All data were provided between 23 April 2020 and 1 May 2020, shortly after the peak of the outbreak in the UK. A single anonymised case study is also reported to illustrate how the pandemic is affecting people's circumstances and contributing to frequent caller behaviour. RESULTS: Ambulance services are observing changes to the frequent caller population, with many new frequent callers due to health anxiety caused or exacerbated by the pandemic. Management of frequent callers is also changing, with multidisciplinary and multi-agency working becoming more challenging due to decreased access to external services, whether in social care or the community and voluntary sector, and the redeployment of ambulance service staff. There is also decreased face-to-face contact with frequent callers, meaning that opportunities to deliver person-centred care are reduced. However, the introduction or increased use of tele/video conferencing with other organisations has mitigated some of these challenges, and in some cases has improved engagement among external organisations. CONCLUSIONS: Health anxieties, lack of access to other health, social and community and voluntary sector services and exacerbations of social isolation and/or loneliness have reportedly contributed to changing behaviour among frequent callers. The COVID-19 pandemic has also affected how ambulance services have been able to manage frequent callers. Ambulance services should continue to engage with external organisations to aid the delivery of person-centred care, particularly organisations with experience in multiple complex needs such as mental health, social isolation and/or loneliness. Future research should examine the consequences of the pandemic for frequent users of ambulance services, and how these impact on the wider health and care community.