Toroidal topology of population activity in grid cells.

The medial entorhinal cortex is part of a neural system for mapping the position of an individual within a physical environment1. Grid cells, a key component of this system, fire in a characteristic hexagonal pattern of locations2, and are organized in modules3 that collectively form a population code for the animal's allocentric position1. The invariance of the correlation structure of this population code across environments4,5 and behavioural states6,7, independent of specific sensory inputs, has pointed to intrinsic, recurrently connected continuous attractor networks (CANs) as a possible substrate of the grid pattern1,8-11. However, whether grid cell networks show continuous attractor dynamics, and how they interface with inputs from the environment, has remained unclear owing to the small samples of cells obtained so far. Here, using simultaneous recordings from many hundreds of grid cells and subsequent topological data analysis, we show that the joint activity of grid cells from an individual module resides on a toroidal manifold, as expected in a two-dimensional CAN. Positions on the torus correspond to positions of the moving animal in the environment. Individual cells are preferentially active at singular positions on the torus. Their positions are maintained between environments and from wakefulness to sleep, as predicted by CAN models for grid cells but not by alternative feedforward models12. This demonstration of network dynamics on a toroidal manifold provides a population-level visualization of CAN dynamics in grid cells.

Review of human supraspinatus tendon mechanics. Part II: tendon healing response and characterization of tendon health.

Overuse injuries of the rotator cuff, particularly of the supraspinatus tendon (SST), are highly prevalent and debilitating in work, sport, and daily activities. Despite the clinical significance of these injuries, there remains a large degree of uncertainty regarding the pathophysiology of injury, optimal methods of nonoperative and operative repair, and how to adequately assess tendon injury and healing. The tendon response to fatigue damage resulting from overuse is different from that of acute rupture and results in either an adaptive (healing) or a maladaptive (degenerative) response. Factors associated with the degenerative response include increasing age, smoking, hypercholesterolemia, biological sex (variable by tendon), diabetes mellitus, and excessive load post fatigue damage. After injury, the average healing rate of tendon is approximately 1% per day and may be significantly influenced by biologic sex (females have lower collagen synthesis rates) and excessive load after damage. Although magnetic resonance imaging (MRI) is considered the gold standard in assessing acute tears as well as tendinopathic change in the SST, ultrasonography has proven to be a valuable tool to measure tendinopathic change in real time. Ultrasonography can determine multiple mechanical and structural parameters of the SST that are altered in fatigue loading. Thus, ultrasonography may be utilized to understand how these parameters change in response to SST overuse, and may aid in determining the activity level that places the SST at greater risk of rupture.

Review of human supraspinatus tendon mechanics. Part I: fatigue damage accumulation and failure.

Repetitive stress injuries to the rotator cuff, and particularly the supraspinatus tendon (SST), are highly prevalent and debilitating. These injuries typically occur through the application of cyclic load below the threshold necessary to cause acute tears, leading to accumulation of incremental damage that exceeds the body's ability to heal, resulting in decreased mechanical strength and increased risk of frank rupture at lower loads. Consistent progression of fatigue damage across multiple model systems suggests a generalized tendon response to overuse. This finding may allow for interventions before gross injury of the SST occurs. Further research into the human SST response to fatigue loading is necessary to characterize the fatigue life of the tendon, which will help determine the frequency, duration, and magnitude of load spectra the SST may experience before injury. Future studies may allow in vivo SST strain analysis during specific activities, generation of a human SST stress-cycle curve, and characterization of damage and repair related to repetitive tasks.

Differential spike timing and phase dynamics of reticular thalamic and prefrontal cortical neuronal populations during sleep spindles.

The 8-15 Hz thalamocortical oscillations known as sleep spindles are a universal feature of mammalian non-REM sleep, during which they are presumed to shape activity-dependent plasticity in neocortical networks. The cortex is hypothesized to contribute to initiation and termination of spindles, but the mechanisms by which it implements these roles are unknown. We used dual-site local field potential and multiple single-unit recordings in the thalamic reticular nucleus (TRN) and medial prefrontal cortex (mPFC) of freely behaving rats at rest to investigate thalamocortical network dynamics during natural sleep spindles. During each spindle epoch, oscillatory activity in mPFC and TRN increased in frequency from onset to offset, accompanied by a consistent phase precession of TRN spike times relative to the cortical oscillation. In mPFC, the firing probability of putative pyramidal cells was highest at spindle initiation and termination times. We thus identified "early" and "late" cell subpopulations and found that they had distinct properties: early cells generally fired in synchrony with TRN spikes, whereas late cells fired in antiphase to TRN activity and also had higher firing rates than early cells. The accelerating and highly structured temporal pattern of thalamocortical network activity over the course of spindles therefore reflects the engagement of distinct subnetworks at specific times across spindle epochs. We propose that early cortical cells serve a synchronizing role in the initiation and propagation of spindle activity, whereas the subsequent recruitment of late cells actively antagonizes the thalamic spindle generator by providing asynchronous feedback.

Neural oscillations during non-rapid eye movement sleep as biomarkers of circuit dysfunction in schizophrenia.

The neurophysiology of non-rapid eye movement sleep is characterized by the occurrence of neural network oscillations with distinct origins and frequencies, which act in concert to support sleep-dependent information processing. Thalamocortical circuits generate slow (0.25-4 Hz) oscillations reflecting synchronized temporal windows of cortical activity, whereas concurrent waxing and waning spindle oscillations (8-15 Hz) act to facilitate cortical plasticity. Meanwhile, fast (140-200 Hz) and brief (< 200 ms) hippocampal ripple oscillations are associated with the reactivation of neural assemblies recruited during prior wakefulness. The extent of the forebrain areas engaged by these oscillations, and the variety of cellular and synaptic mechanisms involved, make them sensitive assays of distributed network function. Each of these three oscillations makes crucial contributions to the offline memory consolidation processes supported by non-rapid eye movement sleep. Slow, spindle and ripple oscillations are therefore potential surrogates of cognitive function and may be used as diagnostic measures in a range of brain diseases. We review the evidence for disrupted slow, spindle and ripple oscillations in schizophrenia, linking pathophysiological mechanisms to the functional impact of these neurophysiological changes and drawing links with the cognitive symptoms that accompany this condition. Finally, we discuss potential therapies that may normalize the coordinated activity of these three oscillations in order to restore healthy cognitive function.

Grid-cell modules remain coordinated when neural activity is dissociated from external sensory cues.

The representation of an animal's position in the medial entorhinal cortex (MEC) is distributed across several modules of grid cells, each characterized by a distinct spatial scale. The population activity within each module is tightly coordinated and preserved across environments and behavioral states. Little is known, however, about the coordination of activity patterns across modules. We analyzed the joint activity patterns of hundreds of grid cells simultaneously recorded in animals that were foraging either in the light, when sensory cues could stabilize the representation, or in darkness, when such stabilization was disrupted. We found that the states of different modules are tightly coordinated, even in darkness, when the internal representation of position within the MEC deviates substantially from the true position of the animal. These findings suggest that internal brain mechanisms dynamically coordinate the representation of position in different modules, ensuring that they jointly encode a coherent and smooth trajectory.

Task-dependent mixed selectivity in the subiculum.

CA1 and subiculum (SUB) connect the hippocampus to numerous output regions. Cells in both areas have place-specific firing fields, although they are more dispersed in SUB. Weak responses to head direction and running speed have been reported in both regions. However, how such information is encoded in CA1 and SUB and the resulting impact on downstream targets are poorly understood. Here, we estimate the tuning of simultaneously recorded CA1 and SUB cells to position, head direction, and speed. Individual neurons respond conjunctively to these covariates in both regions, but the degree of mixed representation is stronger in SUB, and more so during goal-directed spatial navigation than free foraging. Each navigational variable could be decoded with higher precision, from a similar number of neurons, in SUB than CA1. The findings point to a possible contribution of mixed-selective coding in SUB to efficient transmission of hippocampal representations to widespread brain regions.

Neuropixels 2.0: A miniaturized high-density probe for stable, long-term brain recordings.

Measuring the dynamics of neural processing across time scales requires following the spiking of thousands of individual neurons over milliseconds and months. To address this need, we introduce the Neuropixels 2.0 probe together with newly designed analysis algorithms. The probe has more than 5000 sites and is miniaturized to facilitate chronic implants in small mammals and recording during unrestrained behavior. High-quality recordings over long time scales were reliably obtained in mice and rats in six laboratories. Improved site density and arrangement combined with newly created data processing methods enable automatic post hoc correction for brain movements, allowing recording from the same neurons for more than 2 months. These probes and algorithms enable stable recordings from thousands of sites during free behavior, even in small animals such as mice.

D-cycloserine potentiates the reconsolidation of cocaine-associated memories.

Conditioned cue-induced relapse to drug seeking is a major challenge to the treatment of drug addiction. It has been proposed that D-cycloserine might be useful in the prevention of relapse by reducing the conditioned reinforcing properties of drug-associated stimuli through facilitation of extinction. Here we show that intrabasolateral amygdala infusions of D-cycloserine in fact potentiate the reconsolidation of stimulus-cocaine memories to increase cue-induced relapse to drug seeking in rats with an extensive drug self-administration history. This elevation of cocaine seeking was correlated with an increase in the expression of the reconsolidation-associated gene zif268.

A new algorithm for 3D reconstruction from support functions.

We introduce a new algorithm for reconstructing an unknown shape from a finite number of noisy measurements of its support function. The algorithm, based on a least squares procedure, is very easy to program in standard software such as Matlab, and it works for both 2D and 3D reconstructions (in fact, in principle, in any dimension). Reconstructions may be obtained without any pre- or post-processing steps and with no restriction on the sets of measurement directions except their number, a limitation dictated only by computing time. An algorithm due to Prince and Willsky was implemented earlier for 2D reconstructions, and we compare the performance of their algorithm and ours. But our algorithm is the first that works for 3D reconstructions with the freedom stated in the previous paragraph. Moreover, under mild conditions, theory guarantees that outputs of the new algorithm will converge to the input shape as the number of measurements increases. In addition we offer a linear program version of the new algorithm that is much faster and better, or at least comparable, in performance at low levels of noise and reasonably small numbers of measurements. Another modification of the algorithm, suitable for use in a "focus of attention" scheme, is also described.

Correlation structure of grid cells is preserved during sleep.

The network of grid cells in the medial entorhinal cortex (MEC) forms a fixed reference frame for mapping physical space. The mechanistic origin of the grid representation is unknown, but continuous attractor network models explain multiple fundamental features of grid cell activity. An untested prediction of these models is that the grid cell network should exhibit an activity correlation structure that transcends behavioral states. By recording from MEC cell ensembles during navigation and sleep, we found that spatial phase offsets of grid cells predict arousal-state-independent spike rate correlations. Similarly, state-invariant correlations between conjunctive grid-head direction and pure head direction cells were predicted by their head direction tuning offsets during awake behavior. Grid cells were only weakly correlated across grid modules, and module scale relationships disintegrated during slow-wave sleep, suggesting that grid modules function as independent attractor networks. Collectively, our observations imply that network states in MEC are expressed universally across brain and behavior states.

Efficacy of Articaine versus Lidocaine in Supplemental Infiltration for Mandibular First versus Second Molars with Irreversible Pulpitis: A Prospective, Randomized, Double-blind Clinical Trial.

INTRODUCTION: Profound pulpal anesthesia is difficult to achieve in mandibular molars with irreversible pulpitis (IP). However, there are no published randomized controlled clinical trials comparing the success of supplemental buccal infiltration (BI) in mandibular first versus second molars with IP. The purpose of this prospective, randomized, double-blind study was to compare the efficacy of 4% articaine with 2% lidocaine for supplemental BIs in mandibular first versus second molars with IP after a failed inferior alveolar nerve block (IANB). This study's sample was combined with data from a previous trial. METHODS: One hundred ninety-nine emergency subjects diagnosed with IP of a mandibular molar were selected and received an IANB with 4% articaine. Subjects who failed to achieve profound pulpal anesthesia, determined by a positive response to cold or pain upon access, randomly received 4% articaine or 2% lidocaine as a supplemental BI. Endodontic access was begun 5 minutes after infiltration. Success was defined as less than mild pain during endodontic access and instrumentation on the Heft-Parker visual analog scale. RESULTS: There was a 25% IANB success rate with 4% articaine. The success rate for articaine supplemental BI in first molars was 61% versus 63% for second molars (P > .05). The success of lidocaine in first molars was 66%, but for second molars it was 32% (P = .004). CONCLUSIONS: The success rate for IANB with 4% articaine was 25%. Articaine and lidocaine had similar success rates for supplemental infiltration in first molars, whereas articaine was significantly more successful for second molars. However, because BI often did not provide profound pulpal anesthesia, additional techniques including intraosseous anesthesia may still be required.

Efficacy of articaine versus lidocaine as a supplemental buccal infiltration in mandibular molars with irreversible pulpitis: a prospective, randomized, double-blind study.

INTRODUCTION: Profound pulpal anesthesia in mandibular molars with irreversible pulpitis (IP) is often difficult to obtain and often requires supplemental injections after an ineffective inferior alveolar nerve block (IANB). The purpose of this prospective, randomized, double-blind study was to compare the efficacy of 4% articaine with 2% lidocaine for supplemental buccal infiltrations (BIs) after an ineffective IANB in mandibular molars with IP. In addition, the use of articaine for IANB and intraosseous injections was investigated. METHODS: One hundred emergency patients diagnosed with IP of a mandibular molar were selected and received an IANB with 4% articaine. All injections were 1.7 mL with 1:100,000 epinephrine. All patients reported profound lip numbness after IANB. Patients with ineffective IANB (positive pulpal response to cold or pain on access) randomly received 4% articaine or 2% lidocaine as a supplemental BI. Endodontic access was initiated 5 minutes after deposition of the infiltration solution. Success was defined as no pain or no more than mild pain during endodontic access and instrumentation as measured on a visual analogue scale. RESULTS: Seventy-four patients failed to achieve pulpal anesthesia after IANB with 4% articaine, resulting in IANB success rate of 26%. Success rates for supplemental BIs were 62% for articaine and 37% for lidocaine (P < .05). This effect was most pronounced in second molars (P < .05). CONCLUSIONS: Supplemental BI with articaine was significantly more effective than lidocaine. The IANB success rate of 4% articaine confirmed published data.

Geometric reconstruction methods for electron tomography.

Electron tomography is becoming an increasingly important tool in materials science for studying the three-dimensional morphologies and chemical compositions of nanostructures. The image quality obtained by many current algorithms is seriously affected by the problems of missing wedge artefacts and non-linear projection intensities due to diffraction effects. The former refers to the fact that data cannot be acquired over the full 180° tilt range; the latter implies that for some orientations, crystalline structures can show strong contrast changes. To overcome these problems we introduce and discuss several algorithms from the mathematical fields of geometric and discrete tomography. The algorithms incorporate geometric prior knowledge (mainly convexity and homogeneity), which also in principle considerably reduces the number of tilt angles required. Results are discussed for the reconstruction of an InAs nanowire.