Robust fast direct integral equation solver for quasi-periodic scattering problems with a large number of layers.

We present a new boundary integral formulation for time-harmonic wave diffraction from two-dimensional structures with many layers of arbitrary periodic shape, such as multilayer dielectric gratings in TM polarization. Our scheme is robust at all scattering parameters, unlike the conventional quasi-periodic Green's function method which fails whenever any of the layers approaches a Wood anomaly. We achieve this by a decomposition into near- and far-field contributions. The former uses the free-space Green's function in a second-kind integral equation on one period of the material interfaces and their immediate left and right neighbors; the latter uses proxy point sources and small least-squares solves (Schur complements) to represent the remaining contribution from distant copies. By using high-order discretization on interfaces (including those with corners), the number of unknowns per layer is kept small. We achieve overall linear complexity in the number of layers, by direct solution of the resulting block tridiagonal system. For device characterization we present an efficient method to sweep over multiple incident angles, and show a 25× speedup over solving each angle independently. We solve the scattering from a 1000-layer structure with 3 × 105 unknowns to 9-digit accuracy in 2.5 minutes on a desktop workstation.

Ensemble Reweighting Using Cryo-EM Particle Images.

Cryo-electron microscopy (cryo-EM) has recently become a leading method for obtaining high-resolution structures of biological macromolecules. However, cryo-EM is limited to biomolecular samples with low conformational heterogeneity, where most conformations can be well-sampled at various projection angles. While cryo-EM provides single-molecule data for heterogeneous molecules, most existing reconstruction tools cannot retrieve the ensemble distribution of possible molecular conformations from these data. To overcome these limitations, we build on a previous Bayesian approach and develop an ensemble refinement framework that estimates the ensemble density from a set of cryo-EM particle images by reweighting a prior conformational ensemble, e.g., from molecular dynamics simulations or structure prediction tools. Our work provides a general approach to recovering the equilibrium probability density of the biomolecule directly in conformational space from single-molecule data. To validate the framework, we study the extraction of state populations and free energies for a simple toy model and from synthetic cryo-EM particle images of a simulated protein that explores multiple folded and unfolded conformations.

A Bayesian approach to extracting free-energy profiles from cryo-electron microscopy experiments.

Cryo-electron microscopy (cryo-EM) extracts single-particle density projections of individual biomolecules. Although cryo-EM is widely used for 3D reconstruction, due to its single-particle nature it has the potential to provide information about a biomolecule's conformational variability and underlying free-energy landscape. However, treating cryo-EM as a single-molecule technique is challenging because of the low signal-to-noise ratio (SNR) in individual particles. In this work, we propose the cryo-BIFE method (cryo-EM Bayesian Inference of Free-Energy profiles), which uses a path collective variable to extract free-energy profiles and their uncertainties from cryo-EM images. We test the framework on several synthetic systems where the imaging parameters and conditions were controlled. We found that for realistic cryo-EM environments and relevant biomolecular systems, it is possible to recover the underlying free energy, with the pose accuracy and SNR as crucial determinants. We then use the method to study the conformational transitions of a calcium-activated channel with real cryo-EM particles. Interestingly, we recover not only the most probable conformation (used to generate a high-resolution reconstruction of the calcium-bound state) but also a metastable state that corresponds to the calcium-unbound conformation. As expected for turnover transitions within the same sample, the activation barriers are on the order of [Formula: see text]. We expect our tool for extracting free-energy profiles from cryo-EM images to enable more complete characterization of the thermodynamic ensemble of biomolecules.

SpikeForest, reproducible web-facing ground-truth validation of automated neural spike sorters.

Spike sorting is a crucial step in electrophysiological studies of neuronal activity. While many spike sorting packages are available, there is little consensus about which are most accurate under different experimental conditions. SpikeForest is an open-source and reproducible software suite that benchmarks the performance of automated spike sorting algorithms across an extensive, curated database of ground-truth electrophysiological recordings, displaying results interactively on a continuously-updating website. With contributions from eleven laboratories, our database currently comprises 650 recordings (1.3 TB total size) with around 35,000 ground-truth units. These data include paired intracellular/extracellular recordings and state-of-the-art simulated recordings. Ten of the most popular spike sorting codes are wrapped in a Python package and evaluated on a compute cluster using an automated pipeline. SpikeForest documents community progress in automated spike sorting, and guides neuroscientists to an optimal choice of sorter and parameters for a wide range of probes and brain regions.

High-Density, Long-Lasting, and Multi-region Electrophysiological Recordings Using Polymer Electrode Arrays.

The brain is a massive neuronal network, organized into anatomically distributed sub-circuits, with functionally relevant activity occurring at timescales ranging from milliseconds to years. Current methods to monitor neural activity, however, lack the necessary conjunction of anatomical spatial coverage, temporal resolution, and long-term stability to measure this distributed activity. Here we introduce a large-scale, multi-site, extracellular recording platform that integrates polymer electrodes with a modular stacking headstage design supporting up to 1,024 recording channels in freely behaving rats. This system can support months-long recordings from hundreds of well-isolated units across multiple brain regions. Moreover, these recordings are stable enough to track large numbers of single units for over a week. This platform enables large-scale electrophysiological interrogation of the fast dynamics and long-timescale evolution of anatomically distributed circuits, and thereby provides a new tool for understanding brain activity.

A Fully Automated Approach to Spike Sorting.

Understanding the detailed dynamics of neuronal networks will require the simultaneous measurement of spike trains from hundreds of neurons (or more). Currently, approaches to extracting spike times and labels from raw data are time consuming, lack standardization, and involve manual intervention, making it difficult to maintain data provenance and assess the quality of scientific results. Here, we describe an automated clustering approach and associated software package that addresses these problems and provides novel cluster quality metrics. We show that our approach has accuracy comparable to or exceeding that achieved using manual or semi-manual techniques with desktop central processing unit (CPU) runtimes faster than acquisition time for up to hundreds of electrodes. Moreover, a single choice of parameters in the algorithm is effective for a variety of electrode geometries and across multiple brain regions. This algorithm has the potential to enable reproducible and automated spike sorting of larger scale recordings than is currently possible.

Validation of neural spike sorting algorithms without ground-truth information.

BACKGROUND: The throughput of electrophysiological recording is growing rapidly, allowing thousands of simultaneous channels, and there is a growing variety of spike sorting algorithms designed to extract neural firing events from such data. This creates an urgent need for standardized, automatic evaluation of the quality of neural units output by such algorithms. NEW METHOD: We introduce a suite of validation metrics that assess the credibility of a given automatic spike sorting algorithm applied to a given dataset. By rerunning the spike sorter two or more times, the metrics measure stability under various perturbations consistent with variations in the data itself, making no assumptions about the internal workings of the algorithm, and minimal assumptions about the noise. RESULTS: We illustrate the new metrics on standard sorting algorithms applied to both in vivo and ex vivo recordings, including a time series with overlapping spikes. We compare the metrics to existing quality measures, and to ground-truth accuracy in simulated time series. We provide a software implementation. COMPARISON WITH EXISTING METHODS: Metrics have until now relied on ground-truth, simulated data, internal algorithm variables (e.g. cluster separation), or refractory violations. By contrast, by standardizing the interface, our metrics assess the reliability of any automatic algorithm without reference to internal variables (e.g. feature space) or physiological criteria. CONCLUSIONS: Stability is a prerequisite for reproducibility of results. Such metrics could reduce the significant human labor currently spent on validation, and should form an essential part of large-scale automated spike sorting and systematic benchmarking of algorithms.

Analytic steady-state space use patterns and rapid computations in mechanistic home range analysis.

Mechanistic home range models are important tools in modeling animal dynamics in spatially complex environments. We introduce a class of stochastic models for animal movement in a habitat of varying preference. Such models interpolate between spatially implicit resource selection analysis (RSA) and advection-diffusion models, possessing these two models as limiting cases. We find a closed-form solution for the steady-state (equilibrium) probability distribution u using a factorization of the redistribution operator into symmetric and diagonal parts. How space use is controlled by the habitat preference function w depends on the characteristic width of the animals' redistribution kernel: when the redistribution kernel is wide relative to variation in w, u proportional, variant w, whereas when it is narrow relative to variation in w, u proportional, variant w (2). In addition, we analyze the behavior at discontinuities in w which occur at habitat type boundaries, and simulate the dynamics of space use given two-dimensional prey-availability data, exploring the effect of the redistribution kernel width. Our factorization allows such numerical simulations to be done extremely fast; we expect this to aid the computationally intensive task of model parameter fitting and inverse modeling.

Quantum mushroom billiards.

We report the first large-scale statistical study of very high-lying eigenmodes (quantum states) of the mushroom billiard proposed by L. A. Bunimovich [Chaos 11, 802 (2001)]. The phase space of this mixed system is unusual in that it has a single regular region and a single chaotic region, and no KAM hierarchy. We verify Percival's conjecture to high accuracy (1.7%). We propose a model for dynamical tunneling and show that it predicts well the chaotic components of predominantly regular modes. Our model explains our observed density of such superpositions dying as E(-1/3) (E is the eigenvalue). We compare eigenvalue spacing distributions against Random Matrix Theory expectations, using 16,000 odd modes (an order of magnitude more than any existing study). We outline new variants of mesh-free boundary collocation methods which enable us to achieve high accuracy and high mode numbers (approximately 10(5)) orders of magnitude faster than with competing methods.

Effective scattering coefficient of the cerebral spinal fluid in adult head models for diffuse optical imaging.

An efficient computation of the time-dependent forward solution for photon transport in a head model is a key capability for performing accurate inversion for functional diffuse optical imaging of the brain. The diffusion approximation to photon transport is much faster to simulate than the physically correct radiative transport equation (RTE); however, it is commonly assumed that scattering lengths must be much smaller than all system dimensions and all absorption lengths for the approximation to be accurate. Neither of these conditions is satisfied in the cerebrospinal fluid (CSF). Since line-of-sight distances in the CSF are small, of the order of a few millimeters, we explore the idea that the CSF scattering coefficient may be modeled by any value from zero up to the order of the typical inverse line-of-sight distance, or approximately 0.3 mm(-1), without significantly altering the calculated detector signals or the partial path lengths relevant for functional measurements. We demonstrate this in detail by using a Monte Carlo simulation of the RTE in a three-dimensional head model based on clinical magnetic resonance imaging data, with realistic optode geometries. Our findings lead us to expect that the diffusion approximation will be valid even in the presence of the CSF, with consequences for faster solution of the inverse problem.