Trial-to-trial variability of spiking delay activity in prefrontal cortex constrains burst-coding models of working memory

A hallmark neuronal correlate of working memory (WM) is stimulus-selective spiking activity of neurons in prefrontal cortex (PFC) during mnemonic delays. These observations have motivated an influential computational modeling framework in which WM is supported by persistent activity. Recently this framework has been challenged by arguments that observed persistent activity may be an artifact of trial-averaging, which potentially masks high variability of delay activity at the single-trial level. In an alternative scenario, WM delay activity could be encoded in bursts of selective neuronal firing which occur intermittently across trials. However, this alternative proposal has not been tested on single-neuron spike-train data. Here, we developed a framework for addressing this issue by characterizing the trial-to-trial variability of neuronal spiking quantified by Fano factor (FF). By building a doubly stochastic Poisson spiking model, we first demonstrated that the burst-coding proposal implies a significant increase in FF positively correlated with firing rate, and thus loss of stability across trials during the delay. Simulation of spiking cortical circuit WM models further confirmed that FF is a sensitive measure that can well dissociate distinct WM mechanisms. We then tested these predictions on datasets of single-neuron recordings from macaque prefrontal cortex during three WM tasks. In sharp contrast to the burst-coding model predictions, we only found a small fraction of neurons showing increased WM-dependent burstiness, and stability across trials during delay was strengthened in empirical data. Therefore, reduced trial-to-trial variability during delay provides strong constraints on the contribution of single-neuron intermittent bursting to WM maintenance.Significance StatementThere are diverging classes of theoretical models explaining how information is maintained in working memory by cortical circuits. In an influential model class, neurons fire exhibit persistent elevated memorandum-selective firing, whereas a recently developed class of burst-coding models suggests that persistent activity is an artifact of trial-averaging, and spiking is sparse in each single trial, subserved by brief intermittent bursts. However, this alternative picture has not been characterized or tested on empirical spike-train data. Here we combine mathematical analysis, computational model simulation and experimental data analysis to test empirically theses two classes of models and show that the trial-to-trial variability of empirical spike trains is not consistent with burst coding. These findings provide constraints for theoretical models of working memory.

The problem of perfect predictors in statistical spike train models

Generalized Linear Models (GLMs) have been used extensively in statistical models of spike train data. However, the IRLS algorithm, which is often used to fit such models, can fail to converge in situations where response and non-response can be separated by a single predictor or a linear combination of multiple predictors. Such situations are likely to arise in many neural systems due to properties such as refractoriness and incomplete sampling of the signals that influence spiking. In this paper, we describe multiple classes of approaches to address this problem: Standard IRLS with a fixed iteration limit, computing the maximum likelihood solution in the limit, Bayesian estimation, regularization, change of basis, and modifying the search parameters. We demonstrate a specific application of each of these methods to spiking data from rat somatosensory cortex and discuss the advantages and disadvantages of each. We also provide an example of a roadmap for selecting a method based on the problem’s particular analysis issues and scientific goals.

Neural Network Poisson Models for Behavioural and Neural Spike Train Data

It is now possible to monitor the activity of a large number of neurons across the brain as animals perform behavioural tasks. A primary aim for modeling is to reveal (i) how sensory inputs are represented in neural activities and (ii) how these representations translate into behavioural responses. Predominant methods apply rather disjoint techniques to (i) and (ii); by contrast, we suggest an end-to-end model which jointly fits both behaviour and neural activities and tracks their covariabilities across trials using inferred noise correlations. Our model exploits recent developments of flexible, but tractable, neural network point-process models to characterize dependencies between stimuli, actions and neural data. We apply the framework to a dataset collected using Neuropixel probes in a visual discrimination task and analyse noise correlations to gain novel insights into the relationships between neural activities and behaviour.

Comparison of Different Spike Train Synchrony Measures Regarding Their Robustness to Erroneous Data From Bicuculline-Induced Epileptiform Activity

As synchronized activity is associated with basic brain functions and pathological states, spike train synchrony has become an important measure to analyze experimental neuronal data. Many measures of spike train synchrony have been proposed, but there is no gold standard allowing for comparison of results from different experiments. This work aims to provide guidance on which synchrony measure is best suited to quantify the effect of epileptiform-inducing substances (e.g., bicuculline, BIC) in in vitro neuronal spike train data. Spike train data from recordings are likely to suffer from erroneous spike detection, such as missed spikes (false negative) or noise (false positive). Therefore, different timescale-dependent (cross-correlation, mutual information, spike time tiling coefficient) and timescale-independent (Spike-contrast, phase synchronization (PS), A-SPIKE-synchronization, A-ISI-distance, ARI-SPIKE-distance) synchrony measures were compared in terms of their robustness to erroneous spike trains. For this purpose, erroneous spike trains were generated by randomly adding (false positive) or deleting (false negative) spikes (in silico manipulated data) from experimental data. In addition, experimental data were analyzed using different spike detection threshold factors in order to confirm the robustness of the synchrony measures. All experimental data were recorded from cortical neuronal networks on microelectrode array chips, which show epileptiform activity induced by the substance BIC. As a result of the in silico manipulated data, Spike-contrast was the only measure that was robust to false-negative as well as false-positive spikes. Analyzing the experimental data set revealed that all measures were able to capture the effect of BIC in a statistically significant way, with Spike-contrast showing the highest statistical significance even at low spike detection thresholds. In summary, we suggest using Spike-contrast to complement established synchrony measures because it is timescale independent and robust to erroneous spike trains.

Inferring synaptic inputs from spikes with a conductance-based neural encoding model

Descriptive statistical models of neural responses generally aim to characterize the mapping from stimuli to spike responses while ignoring biophysical details of the encoding process. Here, we introduce an alternative approach, the conductance-based encoding model (CBEM), which describes a mapping from stimuli to excitatory and inhibitory synaptic conductances governing the dynamics of sub-threshold membrane potential. Remarkably, we show that the CBEM can be fit to extracellular spike train data and then used to predict excitatory and inhibitory synaptic currents. We validate these predictions with intracellular recordings from macaque retinal ganglion cells. Moreover, we offer a novel quasi-biophysical interpretation of the Poisson generalized linear model (GLM) as a special case of the CBEM in which excitation and inhibition are perfectly balanced. This work forges a new link between statistical and biophysical models of neural encoding and sheds new light on the biophysical variables that underlie spiking in the early visual pathway.

Analysis of Neural Activity of the Human Basal Ganglia in Dystonia: a Review

Deep brain stimulation of the globus pallidus internus is an efective symptomatic treatment for pharmacoresistant dystonic syndromes, where pathophysiological mechanisms of action are not yet fully understood. The aim of this review article is to provide an overview of the state-of-the-art approaches for processing of microelectrode recordings in dystonia; in order to define biomarkers to identify patients who will benefit from the clinical deep brain stimulation. For this purpose, the essential elements of microelectrode processing are examined. Next, we investigate a real example of spike sorting processing in this field. Herein, we describe baseline elements of microrecordings processing including data collection, preprocessing phase, features computation, spike detection and sorting and finally, advanced spike train data analysis. This study will help readers acquire the necessary information about these elements and their associated techniques. Thus, this study is supposed to assist during identification and proposal of interesting clinical hypotheses in the field of single unit neuronal recordings in dystonia.

Inferring the collective dynamics of neuronal populations from single-trial spike trains using mechanistic models

Multi-neuronal spike-train data recorded in vivo often exhibit rich dynamics as well as considerable variability across cells and repetitions of identical experimental conditions (trials). Efforts to characterize and predict the population dynamics and the contributions of individual neurons require model-based tools. Abstract statistical models allow for principled parameter estimation and model selection, but possess only limited interpretive power because they typically do not incorporate prior biophysical constraints. Here we present a statistically principled approach based on a population of doubly-stochastic integrate-and-fire neurons, taking into account basic biophysics. This model class comprises an idealized description for the dynamics of the neuronal membrane voltage in response to fast independent and slower shared input fluctuations. To efficiently estimate the model parameters and compare different model variants we compute the likelihood of observed single-trail spike trains by leveraging analytical methods for spiking neuron models combined with inference techniques for hidden Markov models. This allows us to reconstruct the shared input variations, classify their dynamics, obtain precise spike rate estimates, and quantify how individual neurons couple to the low-dimensional overall population dynamics, all from a single trial. Extensive evaluations based on simulated data show that our method correctly identifies the dynamics of the shared input process and accurately estimates the model parameters. Validations on ground truth recordings of neurons in vitro demonstrate that our approach successfully reconstructs the dynamics of hidden inputs and yields improved fits compared to a typical phenomenological model. Finally, we apply the method to a neuronal population recorded in vivo, for which we assess the contributions of individual neurons to the overall spiking dynamics. Altogether, our work provides statistical inference tools for a class of reasonably constrained, mechanistic models and demonstrates the benefits of this approach to analyze measured spike train data.