Facilitating the Sharing of Electrophysiology Data Analysis Results Through In-Depth Provenance Capture.

Scientific research demands reproducibility and transparency, particularly in data-intensive fields like electrophysiology. Electrophysiology data are typically analyzed using scripts that generate output files, including figures. Handling these results poses several challenges due to the complexity and iterative nature of the analysis process. These stem from the difficulty to discern the analysis steps, parameters, and data flow from the results, making knowledge transfer and findability challenging in collaborative settings. Provenance information tracks data lineage and processes applied to it, and provenance capture during the execution of an analysis script can address those challenges. We present Alpaca (Automated Lightweight Provenance Capture), a tool that captures fine-grained provenance information with minimal user intervention when running data analysis pipelines implemented in Python scripts. Alpaca records inputs, outputs, and function parameters and structures information according to the W3C PROV standard. We demonstrate the tool using a realistic use case involving multichannel local field potential recordings of a neurophysiological experiment, highlighting how the tool makes result details known in a standardized manner in order to address the challenges of the analysis process. Ultimately, using Alpaca will help to represent results according to the FAIR principles, which will improve research reproducibility and facilitate sharing the results of data analyses.

A modular and adaptable analysis pipeline to compare slow cerebral rhythms across heterogeneous datasets.

Neuroscience is moving toward a more integrative discipline where understanding brain function requires consolidating the accumulated evidence seen across experiments, species, and measurement techniques. A remaining challenge on that path is integrating such heterogeneous data into analysis workflows such that consistent and comparable conclusions can be distilled as an experimental basis for models and theories. Here, we propose a solution in the context of slow-wave activity (<1 Hz), which occurs during unconscious brain states like sleep and general anesthesia and is observed across diverse experimental approaches. We address the issue of integrating and comparing heterogeneous data by conceptualizing a general pipeline design that is adaptable to a variety of inputs and applications. Furthermore, we present the Collaborative Brain Wave Analysis Pipeline (Cobrawap) as a concrete, reusable software implementation to perform broad, detailed, and rigorous comparisons of slow-wave characteristics across multiple, openly available electrocorticography (ECoG) and calcium imaging datasets.

Simulations approaching data: cortical slow waves in inferred models of the whole hemisphere of mouse.

The development of novel techniques to record wide-field brain activity enables estimation of data-driven models from thousands of recording channels and hence across large regions of cortex. These in turn improve our understanding of the modulation of brain states and the richness of traveling waves dynamics. Here, we infer data-driven models from high-resolution in-vivo recordings of mouse brain obtained from wide-field calcium imaging. We then assimilate experimental and simulated data through the characterization of the spatio-temporal features of cortical waves in experimental recordings. Inference is built in two steps: an inner loop that optimizes a mean-field model by likelihood maximization, and an outer loop that optimizes a periodic neuro-modulation via direct comparison of observables that characterize cortical slow waves. The model reproduces most of the features of the non-stationary and non-linear dynamics present in the high-resolution in-vivo recordings of the mouse brain. The proposed approach offers new methods of characterizing and understanding cortical waves for experimental and computational neuroscientists.

Research Data Management and Data Sharing for Reproducible Research-Results of a Community Survey of the German National Research Data Infrastructure Initiative Neuroscience.

Science is changing: the volume and complexity of data are increasing, the number of studies is growing and the goal of achieving reproducible results requires new solutions for scientific data management. In the field of neuroscience, the German National Research Data Infrastructure (NFDI-Neuro) initiative aims to develop sustainable solutions for research data management (RDM). To obtain an understanding of the present RDM situation in the neuroscience community, NFDI-Neuro conducted a comprehensive survey among the neuroscience community. Here, we report and analyze the results of the survey. We focused the survey and our analysis on current needs, challenges, and opinions about RDM. The German neuroscience community perceives barriers with respect to RDM and data sharing mainly linked to (1) lack of data and metadata standards, (2) lack of community adopted provenance tracking methods, (3) lack of secure and privacy preserving research infrastructure for sensitive data, (4) lack of RDM literacy, and (5) lack of resources (time, personnel, money) for proper RDM. However, an overwhelming majority of community members (91%) indicated that they would be willing to share their data with other researchers and are interested to increase their RDM skills. Taking advantage of this willingness and overcoming the existing barriers requires the systematic development of standards, tools, and infrastructure, the provision of training, education, and support, as well as additional resources for RDM to the research community and a constant dialogue with relevant stakeholders including policy makers to leverage of a culture change through adapted incentivization and regulation.

Evaluating the statistical similarity of neural network activity and connectivity via eigenvector angles.

Neural systems are networks, and strategic comparisons between multiple networks are a prevalent task in many research scenarios. In this study, we construct a statistical test for the comparison of matrices representing pairwise aspects of neural networks, in particular, the correlation between spiking activity and connectivity. The "eigenangle test" quantifies the similarity of two matrices by the angles between their ranked eigenvectors. We calibrate the behavior of the test for use with correlation matrices using stochastic models of correlated spiking activity and demonstrate how it compares to classical two-sample tests, such as the Kolmogorov-Smirnov distance, in the sense that it is able to evaluate also structural aspects of pairwise measures. Furthermore, the principle of the eigenangle test can be applied to compare the similarity of adjacency matrices of certain types of networks. Thus, the approach can be used to quantitatively explore the relationship between connectivity and activity with the same metric. By applying the eigenangle test to the comparison of connectivity matrices and correlation matrices of a random balanced network model before and after a specific synaptic rewiring intervention, we gauge the influence of connectivity features on the correlated activity. Potential applications of the eigenangle test include simulation experiments, model validation, and data analysis.

Acceleration of the SPADE Method Using a Custom-Tailored FP-Growth Implementation.

The SPADE (spatio-temporal Spike PAttern Detection and Evaluation) method was developed to find reoccurring spatio-temporal patterns in neuronal spike activity (parallel spike trains). However, depending on the number of spike trains and the length of recording, this method can exhibit long runtimes. Based on a realistic benchmark data set, we identified that the combination of pattern mining (using the FP-Growth algorithm) and the result filtering account for 85-90% of the method's total runtime. Therefore, in this paper, we propose a customized FP-Growth implementation tailored to the requirements of SPADE, which significantly accelerates pattern mining and result filtering. Our version allows for parallel and distributed execution, and due to the improvements made, an execution on heterogeneous and low-power embedded devices is now also possible. The implementation has been evaluated using a traditional workstation based on an Intel Broadwell Xeon E5-1650 v4 as a baseline. Furthermore, the heterogeneous microserver platform RECS|Box has been used for evaluating the implementation on two HiSilicon Hi1616 (Kunpeng 916), an Intel Coffee Lake-ER Xeon E-2276ME, an Intel Broadwell Xeon D-D1577, and three NVIDIA Tegra devices (Jetson AGX Xavier, Jetson Xavier NX, and Jetson TX2). Depending on the platform, our implementation is between 27 and 200 times faster than the original implementation. At the same time, the energy consumption was reduced by up to two orders of magnitude.

odMLtables: A User-Friendly Approach for Managing Metadata of Neurophysiological Experiments.

An essential aspect of scientific reproducibility is a coherent and complete acquisition of metadata along with the actual data of an experiment. The high degree of complexity and heterogeneity of neuroscience experiments requires a rigorous management of the associated metadata. The odML framework represents a solution to organize and store complex metadata digitally in a hierarchical format that is both human and machine readable. However, this hierarchical representation of metadata is difficult to handle when metadata entries need to be collected and edited manually during the daily routines of a laboratory. With odMLtables, we present an open-source software solution that enables users to collect, manipulate, visualize, and store metadata in tabular representations (in xls or csv format) by providing functionality to convert these tabular collections to the hierarchically structured metadata format odML, and to either extract or merge subsets of a complex metadata collection. With this, odMLtables bridges the gap between handling metadata in an intuitive way that integrates well with daily lab routines and commonly used software products on the one hand, and the implementation of a complete, well-defined metadata collection for the experiment in a standardized format on the other hand. We demonstrate usage scenarios of the odMLtables tools in common lab routines in the context of metadata acquisition and management, and show how the tool can assist in exploring published datasets that provide metadata in the odML format.

Evaluation of Spike Sorting Algorithms: Application to Human Subthalamic Nucleus Recordings and Simulations.

An important prerequisite for the analysis of spike synchrony in extracellular recordings is the extraction of single-unit activity from the multi-unit signal. To identify single units, potential spikes are separated with respect to their potential neuronal origins ('spike sorting'). However, different sorting algorithms yield inconsistent unit assignments, which seriously influences subsequent spike train analyses. We aim to identify the best sorting algorithm for subthalamic nucleus recordings of patients with Parkinson's disease (experimental data ED). Therefore, we apply various prevalent algorithms offered by the 'Plexon Offline Sorter' and evaluate the sorting results. Since this evaluation leaves us unsure about the best algorithm, we apply all methods again to artificial data (AD) with known ground truth. AD consists of pairs of single units with different shape similarity embedded in the background noise of the ED. The sorting evaluation depicts a significant influence of the respective methods on the single unit assignments. We find a high variability in the sortings obtained by different algorithms that increases with single units shape similarity. We also find significant differences in the resulting firing characteristics. We conclude that Valley-Seeking algorithms produce the most accurate result if the exclusion of artifacts as unsorted events is important. If the latter is less important ('clean' data) the K-Means algorithm is a better option. Our results strongly argue for the need of standardized validation procedures based on ground truth data. The recipe suggested here is simple enough to become a standard procedure.

Rigorous Neural Network Simulations: A Model Substantiation Methodology for Increasing the Correctness of Simulation Results in the Absence of Experimental Validation Data.

The reproduction and replication of scientific results is an indispensable aspect of good scientific practice, enabling previous studies to be built upon and increasing our level of confidence in them. However, reproducibility and replicability are not sufficient: an incorrect result will be accurately reproduced if the same incorrect methods are used. For the field of simulations of complex neural networks, the causes of incorrect results vary from insufficient model implementations and data analysis methods, deficiencies in workmanship (e.g., simulation planning, setup, and execution) to errors induced by hardware constraints (e.g., limitations in numerical precision). In order to build credibility, methods such as verification and validation have been developed, but they are not yet well-established in the field of neural network modeling and simulation, partly due to ambiguity concerning the terminology. In this manuscript, we propose a terminology for model verification and validation in the field of neural network modeling and simulation. We outline a rigorous workflow derived from model verification and validation methodologies for increasing model credibility when it is not possible to validate against experimental data. We compare a published minimal spiking network model capable of exhibiting the development of polychronous groups, to its reproduction on the SpiNNaker neuromorphic system, where we consider the dynamics of several selected network states. As a result, by following a formalized process, we show that numerical accuracy is critically important, and even small deviations in the dynamics of individual neurons are expressed in the dynamics at network level.

Massively parallel recordings in macaque motor cortex during an instructed delayed reach-to-grasp task.

We publish two electrophysiological datasets recorded in motor cortex of two macaque monkeys during an instructed delayed reach-to-grasp task, using chronically implanted 10-by-10 Utah electrode arrays. We provide a) raw neural signals (sampled at 30 kHz), b) time stamps and spike waveforms of offline sorted single and multi units (93/49 and 156/19 SUA/MUA for the two monkeys, respectively), c) trial events and the monkey's behavior, and d) extensive metadata hierarchically structured via the odML metadata framework (including quality assessment post-processing steps, such as trial rejections). The dataset of one monkey contains a simultaneously saved record of the local field potential (LFP) sampled at 1 kHz. To load the datasets in Python, we provide code based on the Neo data framework that produces a data structure which is annotated with relevant metadata. We complement this loading routine with an example code demonstrating how to access the data objects (e.g., raw signals) contained in such structures. For Matlab users, we provide the annotated data structures as mat files.

LFP beta amplitude is linked to mesoscopic spatio-temporal phase patterns.

Beta oscillations observed in motor cortical local field potentials (LFPs) recorded on separate electrodes of a multi-electrode array have been shown to exhibit non-zero phase shifts that organize into planar waves. Here, we generalize this concept to additional classes of salient patterns that fully describe the spatial organization of beta oscillations. During a delayed reach-to-grasp task we distinguish planar, synchronized, random, circular, and radial phase patterns in monkey primary motor and dorsal premotor cortices. We observe that patterns correlate with the beta amplitude (envelope): Coherent planar/radial wave propagation accelerates with growing amplitude, and synchronized patterns are observed at largest amplitudes. In contrast, incoherent random or circular patterns are observed almost exclusively when beta is strongly attenuated. The occurrence probability of a particular pattern modulates with behavioral epochs in the same way as beta amplitude: Coherent patterns are more present during movement preparation where amplitudes are large, while incoherent phase patterns are dominant during movement execution where amplitudes are small. Thus, we uncover a trigonal link between the spatial arrangement of beta phases, beta amplitude, and behavior. Together with previous findings, we discuss predictions on the spatio-temporal organization of precisely coordinated spiking on the mesoscopic scale as a function of beta power.

Reproducible Neural Network Simulations: Statistical Methods for Model Validation on the Level of Network Activity Data.

Computational neuroscience relies on simulations of neural network models to bridge the gap between the theory of neural networks and the experimentally observed activity dynamics in the brain. The rigorous validation of simulation results against reference data is thus an indispensable part of any simulation workflow. Moreover, the availability of different simulation environments and levels of model description require also validation of model implementations against each other to evaluate their equivalence. Despite rapid advances in the formalized description of models, data, and analysis workflows, there is no accepted consensus regarding the terminology and practical implementation of validation workflows in the context of neural simulations. This situation prevents the generic, unbiased comparison between published models, which is a key element of enhancing reproducibility of computational research in neuroscience. In this study, we argue for the establishment of standardized statistical test metrics that enable the quantitative validation of network models on the level of the population dynamics. Despite the importance of validating the elementary components of a simulation, such as single cell dynamics, building networks from validated building blocks does not entail the validity of the simulation on the network scale. Therefore, we introduce a corresponding set of validation tests and present an example workflow that practically demonstrates the iterative model validation of a spiking neural network model against its reproduction on the SpiNNaker neuromorphic hardware system. We formally implement the workflow using a generic Python library that we introduce for validation tests on neural network activity data. Together with the companion study (Trensch et al., 2018), the work presents a consistent definition, formalization, and implementation of the verification and validation process for neural network simulations.

High-Performance Computing in Neuroscience for Data-Driven Discovery, Integration, and Dissemination.

Opportunities offered by new neuro-technologies are threatened by lack of coherent plans to analyze, manage, and understand the data. High-performance computing will allow exploratory analysis of massive datasets stored in standardized formats, hosted in open repositories, and integrated with simulations.

Handling Metadata in a Neurophysiology Laboratory.

To date, non-reproducibility of neurophysiological research is a matter of intense discussion in the scientific community. A crucial component to enhance reproducibility is to comprehensively collect and store metadata, that is, all information about the experiment, the data, and the applied preprocessing steps on the data, such that they can be accessed and shared in a consistent and simple manner. However, the complexity of experiments, the highly specialized analysis workflows and a lack of knowledge on how to make use of supporting software tools often overburden researchers to perform such a detailed documentation. For this reason, the collected metadata are often incomplete, incomprehensible for outsiders or ambiguous. Based on our research experience in dealing with diverse datasets, we here provide conceptual and technical guidance to overcome the challenges associated with the collection, organization, and storage of metadata in a neurophysiology laboratory. Through the concrete example of managing the metadata of a complex experiment that yields multi-channel recordings from monkeys performing a behavioral motor task, we practically demonstrate the implementation of these approaches and solutions with the intention that they may be generalized to other projects. Moreover, we detail five use cases that demonstrate the resulting benefits of constructing a well-organized metadata collection when processing or analyzing the recorded data, in particular when these are shared between laboratories in a modern scientific collaboration. Finally, we suggest an adaptable workflow to accumulate, structure and store metadata from different sources using, by way of example, the odML metadata framework.

Synchronous Spike Patterns in Macaque Motor Cortex during an Instructed-Delay Reach-to-Grasp Task.

UNLABELLED: The computational role of spike time synchronization at millisecond precision among neurons in the cerebral cortex is hotly debated. Studies performed on data of limited size provided experimental evidence that low-order correlations occur in relation to behavior. Advances in electrophysiological technology to record from hundreds of neurons simultaneously provide the opportunity to observe coordinated spiking activity of larger populations of cells. We recently published a method that combines data mining and statistical evaluation to search for significant patterns of synchronous spikes in massively parallel spike trains (Torre et al., 2013). The method solves the computational and multiple testing problems raised by the high dimensionality of the data. In the current study, we used our method on simultaneous recordings from two macaque monkeys engaged in an instructed-delay reach-to-grasp task to determine the emergence of spike synchronization in relation to behavior. We found a multitude of synchronous spike patterns aligned in both monkeys along a preferential mediolateral orientation in brain space. The occurrence of the patterns is highly specific to behavior, indicating that different behaviors are associated with the synchronization of different groups of neurons ("cell assemblies"). However, pooled patterns that overlap in neuronal composition exhibit no specificity, suggesting that exclusive cell assemblies become active during different behaviors, but can recruit partly identical neurons. These findings are consistent across multiple recording sessions analyzed across the two monkeys. SIGNIFICANCE STATEMENT: Neurons in the brain communicate via electrical impulses called spikes. How spikes are coordinated to process information is still largely unknown. Synchronous spikes are effective in triggering a spike emission in receiving neurons and have been shown to occur in relation to behavior in a number of studies on simultaneous recordings of few neurons. We recently published a method to extend this type of investigation to larger data. Here, we apply it to simultaneous recordings of hundreds of neurons from the motor cortex of macaque monkeys performing a motor task. Our analysis reveals groups of neurons selectively synchronizing their activity in relation to behavior, which sheds new light on the role of synchrony in information processing in the cerebral cortex.

ASSET: Analysis of Sequences of Synchronous Events in Massively Parallel Spike Trains.

With the ability to observe the activity from large numbers of neurons simultaneously using modern recording technologies, the chance to identify sub-networks involved in coordinated processing increases. Sequences of synchronous spike events (SSEs) constitute one type of such coordinated spiking that propagates activity in a temporally precise manner. The synfire chain was proposed as one potential model for such network processing. Previous work introduced a method for visualization of SSEs in massively parallel spike trains, based on an intersection matrix that contains in each entry the degree of overlap of active neurons in two corresponding time bins. Repeated SSEs are reflected in the matrix as diagonal structures of high overlap values. The method as such, however, leaves the task of identifying these diagonal structures to visual inspection rather than to a quantitative analysis. Here we present ASSET (Analysis of Sequences of Synchronous EvenTs), an improved, fully automated method which determines diagonal structures in the intersection matrix by a robust mathematical procedure. The method consists of a sequence of steps that i) assess which entries in the matrix potentially belong to a diagonal structure, ii) cluster these entries into individual diagonal structures and iii) determine the neurons composing the associated SSEs. We employ parallel point processes generated by stochastic simulations as test data to demonstrate the performance of the method under a wide range of realistic scenarios, including different types of non-stationarity of the spiking activity and different correlation structures. Finally, the ability of the method to discover SSEs is demonstrated on complex data from large network simulations with embedded synfire chains. Thus, ASSET represents an effective and efficient tool to analyze massively parallel spike data for temporal sequences of synchronous activity.

Unsupervised classification of neocortical activity patterns in neonatal and pre-juvenile rodents.

Flexible communication within the brain, which relies on oscillatory activity, is not confined to adult neuronal networks. Experimental evidence has documented the presence of discontinuous patterns of oscillatory activity already during early development. Their highly variable spatial and time-frequency organization has been related to region specificity. However, it might be equally due to the absence of unitary criteria for classifying the early activity patterns, since they have been mainly characterized by visual inspection. Therefore, robust and unbiased methods for categorizing these discontinuous oscillations are needed for increasingly complex data sets from different labs. Here, we introduce an unsupervised detection and classification algorithm for the discontinuous activity patterns of rodents during early development. For this, in a first step time windows with discontinuous oscillations vs. epochs of network "silence" were identified. In a second step, the major features of detected events were identified and processed by principal component analysis for deciding on their contribution to the classification of different oscillatory patterns. Finally, these patterns were categorized using an unsupervised cluster algorithm. The results were validated on manually characterized neonatal spindle bursts (SB), which ubiquitously entrain neocortical areas of rats and mice, and prelimbic nested gamma spindle bursts (NG). Moreover, the algorithm led to satisfactory results for oscillatory events that, due to increased similarity of their features, were more difficult to classify, e.g., during the pre-juvenile developmental period. Based on a linear classification, the optimal number of features to consider increased with the difficulty of detection. This algorithm allows the comparison of neonatal and pre-juvenile oscillatory patterns in their spatial and temporal organization. It might represent a first step for the unbiased elucidation of activity patterns during development.

Statistical evaluation of synchronous spike patterns extracted by frequent item set mining.

We recently proposed frequent itemset mining (FIM) as a method to perform an optimized search for patterns of synchronous spikes (item sets) in massively parallel spike trains. This search outputs the occurrence count (support) of individual patterns that are not trivially explained by the counts of any superset (closed frequent item sets). The number of patterns found by FIM makes direct statistical tests infeasible due to severe multiple testing. To overcome this issue, we proposed to test the significance not of individual patterns, but instead of their signatures, defined as the pairs of pattern size z and support c. Here, we derive in detail a statistical test for the significance of the signatures under the null hypothesis of full independence (pattern spectrum filtering, PSF) by means of surrogate data. As a result, injected spike patterns that mimic assembly activity are well detected, yielding a low false negative rate. However, this approach is prone to additionally classify patterns resulting from chance overlap of real assembly activity and background spiking as significant. These patterns represent false positives with respect to the null hypothesis of having one assembly of given signature embedded in otherwise independent spiking activity. We propose the additional method of pattern set reduction (PSR) to remove these false positives by conditional filtering. By employing stochastic simulations of parallel spike trains with correlated activity in form of injected spike synchrony in subsets of the neurons, we demonstrate for a range of parameter settings that the analysis scheme composed of FIM, PSF and PSR allows to reliably detect active assemblies in massively parallel spike trains.

The local field potential reflects surplus spike synchrony.

While oscillations of the local field potential (LFP) are commonly attributed to the synchronization of neuronal firing rate on the same time scale, their relationship to coincident spiking in the millisecond range is unknown. Here, we present experimental evidence to reconcile the notions of synchrony at the level of spiking and at the mesoscopic scale. We demonstrate that only in time intervals of significant spike synchrony that cannot be explained on the basis of firing rates, coincident spikes are better phase locked to the LFP than predicted by the locking of the individual spikes. This effect is enhanced in periods of large LFP amplitudes. A quantitative model explains the LFP dynamics by the orchestrated spiking activity in neuronal groups that contribute the observed surplus synchrony. From the correlation analysis, we infer that neurons participate in different constellations but contribute only a fraction of their spikes to temporally precise spike configurations. This finding provides direct evidence for the hypothesized relation that precise spike synchrony constitutes a major temporally and spatially organized component of the LFP.

Estimating the contribution of assembly activity to cortical dynamics from spike and population measures.

The hypothesis that cortical networks employ the coordinated activity of groups of neurons, termed assemblies, to process information is debated. Results from multiple single-unit recordings are not conclusive because of the dramatic undersampling of the system. However, the local field potential (LFP) is a mesoscopic signal reflecting synchronized network activity. This raises the question whether the LFP can be employed to overcome the problem of undersampling. In a recent study in the motor cortex of the awake behaving monkey based on the locking of coincidences to the LFP we determined a lower bound for the fraction of spike coincidences originating from assembly activation. This quantity together with the locking of single spikes leads to a lower bound for the fraction of spikes originating from any assembly activity. Here we derive a statistical method to estimate the fraction of spike synchrony caused by assemblies-not its lower bound-from the spike data alone. A joint spike and LFP surrogate data model demonstrates consistency of results and the sensitivity of the method. Combining spike and LFP signals, we obtain an estimate of the fraction of spikes resulting from assemblies in the experimental data.