Theodoros P. Zanos

Removal of Spurious Correlations Between Spikes and Local Field Potentials

Single neurons carry out important sensory and motor functions related to the larger networks in which they are embedded. Understanding the relationships between single-neuron spiking and network activity is therefore of great importance and the latter can be readily estimated from low-frequency brain signals known as local field potentials (LFPs). In this work we examine a number of issues related to the estimation of spike and LFP signals. We show that spike trains and individual spikes contain power at the frequencies that are typically thought to be exclusively related to LFPs, such that simple frequency-domain filtering cannot be effectively used to separate the two signals. Ground-truth simulations indicate that the commonly used method of estimating the LFP signal by low-pass filtering the raw voltage signal leads to artifactual correlations between spikes and LFPs and that these correlations exert a powerful influence on popular metrics of spike-LFP synchronization. Similar artifactual results were seen in data obtained from electrophysiological recordings in macaque visual cortex, when low-pass filtering was used to estimate LFP signals. In contrast LFP tuning curves in response to sensory stimuli do not appear to be affected by spike contamination, either in simulations or in real data. To address the issue of spike contamination, we devised a novel Bayesian spike removal algorithm and confirmed its effectiveness in simulations and by applying it to the electrophysiological data. The algorithm, based on a rigorous mathematical framework, outperforms other methods of spike removal on most metrics of spike-LFP correlations. Following application of this spike removal algorithm, many of our electrophysiological recordings continued to exhibit spike-LFP correlations, confirming previous reports that such relationships are a genuine aspect of neuronal activity. Overall, these results show that careful preprocessing is necessary to remove spikes from LFP signals, but that when effective spike removal is used, spike-LFP correlations can potentially yield novel insights about brain function.

Nonlinear Modeling of Causal Interrelationships in Neuronal Ensembles

The increasing availability of multiunit recordings gives new urgency to the need for effective analysis of ldquomultidimensionalrdquo time-series data that are derived from the recorded activity of neuronal ensembles in the form of multiple sequences of action potentials-treated mathematically as point-processes and computationally as spike-trains. Whether in conditions of spontaneous activity or under conditions of external stimulation, the objective is the identification and quantification of possible causal links among the neurons generating the observed binary signals. A multiple-input/multiple-output (MIMO) modeling methodology is presented that can be used to quantify the neuronal dynamics of causal interrelationships in neuronal ensembles using spike-train data recorded from individual neurons. These causal interrelationships are modeled as transformations of spike-trains recorded from a set of neurons designated as the ldquoinputsrdquo into spike-trains recorded from another set of neurons designated as the ldquooutputsrdquo. The MIMO model is composed of a set of multiinput/single-output (MISO) modules, one for each output. Each module is the cascade of a MISO Volterra model and a threshold operator generating the output spikes. The Laguerre expansion approach is used to estimate the Volterra kernels of each MISO module from the respective input-output data using the least-squares method. The predictive performance of the model is evaluated with the use of the receiver operating characteristic (ROC) curve, from which the optimum threshold is also selected. The Mann-Whitney statistic is used to select the significant inputs for each output by examining the statistical significance of improvements in the predictive accuracy of the model when the respective inputs is included. Illustrative examples are presented for a simulated system and for an actual application using multiunit data recordings from the hippocampus of a behaving rat.

A Sensorimotor Role for Traveling Waves in Primate Visual Cortex

Traveling waves of neural activity are frequently observed to occur in concert with the presentation of a sensory stimulus or the execution of a movement. Although such waves have been studied for decades, little is known about their function. Here we show that traveling waves in the primate extrastriate visual cortex provide a means of integrating sensory and motor signals. Specifically, we describe a traveling wave of local field potential (LFP) activity in cortical area V4 of macaque monkeys that is triggered by the execution of saccadic eye movements. These waves sweep across the V4 retinotopic map, following a consistent path from the foveal to the peripheral representations of space; their amplitudes correlate with the direction and size of each saccade. Moreover, these waves are associated with a reorganization of the postsaccadic neuronal firing patterns, which follow a similar retinotopic progression, potentially prioritizing the processing of behaviorally relevant stimuli.

Relationships between spike-free local field potentials and spike timing in human temporal cortex

Intracortical recordings comprise both fast events, action potentials (APs), and slower events, known as local field potentials (LFPs). Although it is believed that LFPs mostly reflect local synaptic activity, it is unclear which of their signal components are most closely related to synaptic potentials and would therefore be causally related to the occurrence of individual APs. This issue is complicated by the significant contribution from AP waveforms, especially at higher LFP frequencies. In recordings of single-cell activity and LFPs from the human temporal cortex, we computed quantitative, nonlinear, causal dynamic models for the prediction of AP timing from LFPs, at millisecond resolution, before and after removing AP contributions to the LFP. In many cases, the timing of a significant number of single APs could be predicted from spike-free LFPs at different frequencies. Not surprisingly, model performance was superior when spikes were not removed. Cells whose activity was predicted by the spike-free LFP models generally fell into one of two groups: in the first group, neuronal spike activity was associated with specific phases of low LFP frequencies, lower spike activity at high LFP frequencies, and a stronger linear component in the spike-LFP model; in the second group, neuronal spike activity was associated with larger amplitude of high LFP frequencies, less frequent phase locking, and a stronger nonlinear model component. Spike timing in the first group was better predicted by the sign and level of the LFP preceding the spike, whereas spike timing in the second group was better predicted by LFP power during a certain time window before the spike.

Local field potentials reflect multiple spatial scales in V4

Local field potentials (LFP) reflect the properties of neuronal circuits or columns recorded in a volume around a microelectrode (Buzsáki et al., 2012). The extent of this integration volume has been a subject of some debate, with estimates ranging from a few hundred microns (Katzner et al., 2009; Xing et al., 2009) to several millimeters (Kreiman et al., 2006). We estimated receptive fields (RFs) of multi-unit activity (MUA) and LFPs at an intermediate level of visual processing, in area V4 of two macaques. The spatial structure of LFP receptive fields varied greatly as a function of time lag following stimulus onset, with the retinotopy of LFPs matching that of MUAs at a restricted set of time lags. A model-based analysis of the LFPs allowed us to recover two distinct stimulus-triggered components: an MUA-like retinotopic component that originated in a small volume around the microelectrodes (~350 μm), and a second component that was shared across the entire V4 region; this second component had tuning properties unrelated to those of the MUAs. Our results suggest that the LFP reflects neural activity across multiple spatial scales, which both complicates its interpretation and offers new opportunities for investigating the large-scale structure of network processing.

Functional connectivity during surround suppression in macaque area V4

Surround suppression is a common feature of sensory neurons. For neurons of the visual cortex, it occurs when a visual stimulus extends beyond a neurons classical receptive field, reducing the neurons firing rate. While several studies have been attributing the suppression effect on horizontal, long-range lateral or feedback connections, the underlying circuitry for surround modulation remain unidentified. Since most of these models have been relying on single neuron recordings, the contribution of lateral connections can only be suggested from the surround field properties. A more straightforward approach would be to detect these connections and their dynamics using simultaneous recordings from multiple neurons in one or more visual areas. We have developed a method for estimating these connections and we analyzed data obtained from 100-electrode Utah arrays chronically implanted into area V4 of the macaque monkey. Using a method based on the nonlinear Volterra modeling approach, we computed estimates of the strength and statistical reliability of connections among neurons, including nonlinear interactions and excitatory and inhibitory connections. Our results thus far reveal a pattern of connectivity within V4 that conforms to the results of previous anatomical work: Excitatory connections are far more common than inhibitory connections (∼65%), stronger connections are found among neurons that are physically near one another, and connections are stronger among neurons with similar receptive field properties. However, this connectivity is capable of reorganizing on short time scales according to the stimulus: Stimuli that evoke strong suppression at the single-unit level introduce stronger inhibition among V4 neurons, identifying recurrent connectivity as the source of the suppression. Overall, these results provide insight into the dynamic nature of neuronal organization within V4 and its contribution to surround suppression.

A multi-input modeling approach to quantify hippocampal nonlinear dynamic transformations

A multi-input modeling approach is introduced to quantify hippocampal neural dynamics. It is based on the Volterra modeling approach extended to multiple inputs. The computed Volterra kernels allow quantitative description of hippocampal transformations and define a predictive model that can produce responses to arbitrary input patterns. Electrophysiological data from several CA3 and CA1 cells in behaving rats were recorded simultaneously using an array of penetrating electrodes. This activity was used to compute kernels up to third order for single and multiple input cases. Representative sets of kernels illustrate the variability of the dynamics of the CA3-CA1 transformations. Our models predictive accuracy was evaluated using ROC curves

Boolean Modeling of Neural Systems with Point-Process Inputs and Outputs. Part I: Theory and Simulations

This paper presents a new modeling approach for neural systems with point-process (spike) inputs and outputs that utilizes Boolean operators (i.e. modulo 2 multiplication and addition that correspond to the logical AND and OR operations respectively, as well as the AND_NOT logical operation representing inhibitory effects). The form of the employed mathematical models is akin to a “Boolean-Volterra” model that contains the product terms of all relevant input lags in a hierarchical order, where terms of order higher than first represent nonlinear interactions among the various lagged values of each input point-process or among lagged values of various inputs (if multiple inputs exist) as they reflect on the output. The coefficients of this Boolean-Volterra model are also binary variables that indicate the presence or absence of the respective term in each specific model/system. Simulations are used to explore the properties of such models and the feasibility of their accurate estimation from short data-records in the presence of noise (i.e. spurious spikes). The results demonstrate the feasibility of obtaining reliable estimates of such models, with excitatory and inhibitory terms, in the presence of considerable noise (spurious spikes) in the outputs and/or the inputs in a computationally efficient manner. A pilot application of this approach to an actual neural system is presented in the companion paper (Part II).

Functional connectivity through nonlinear modeling: An application to the rat hippocampus

Implementation of neuroprosthetic devices requires a reliable and accurate quantitative representation of the input-output transformations performed by the involved neuronal populations. Nonparametric, data driven models with predictive capabilities are excellent candidates for these purposes. When modeling input-output relations in multi-input neuronal systems, it is important to select the subset of inputs that are functionally and causally related to the output. Inputs that do not convey information about the actual transformation not only increase the computational burden but also affect the generalization of the model. Moreover, a reliable functional connectivity measure can provide patterns of information flow that can be linked to physiological and anatomical properties of the system. We propose a method based on the Volterra modeling approach that selects distinct subsets of inputs for each output based on the prediction of the respective models and its statistical evaluation. The algorithm builds successive models with increasing number of inputs and examines whether the inclusion of additional inputs benefits the predictive accuracy of the overall model. It also explores possible second-order (inter-modulatory) interactions among the inputs. The method was applied to multi-unit recordings from the CA3 (input) and CA1 (output) regions of the hippocampus in behaving rats, in order to reveal spatiotemporal connectivity maps of the input-output transformation taking place in the CA3-CA1 synapse.

Identification of cytokine-specific sensory neural signals by decoding murine vagus nerve activity

Significance Evolution conferred animals with molecular sensors that monitor cellular and organ function to detect changes in the environment. These activate sensory neural responses that drive the action of reflexes that maintain cellular and physiological homeostasis. Recent advances reveal that neural reflexes modulate the immune system, but it was previously unknown whether cytokine mediators of immunity mediate specific neural signals. Here we develop methods to isolate and decode specific neural signals recorded from the vagus nerve to discriminate between the cytokines IL-1β and TNF. This methodological waveform successfully detects and discriminates between specific cytokine exposures using neural signals. The nervous system maintains physiological homeostasis through reflex pathways that modulate organ function. This process begins when changes in the internal milieu (e.g., blood pressure, temperature, or pH) activate visceral sensory neurons that transmit action potentials along the vagus nerve to the brainstem. IL-1β and TNF, inflammatory cytokines produced by immune cells during infection and injury, and other inflammatory mediators have been implicated in activating sensory action potentials in the vagus nerve. However, it remains unclear whether neural responses encode cytokine-specific information. Here we develop methods to isolate and decode specific neural signals to discriminate between two different cytokines. Nerve impulses recorded from the vagus nerve of mice exposed to IL-1β and TNF were sorted into groups based on their shape and amplitude, and their respective firing rates were computed. This revealed sensory neural groups responding specifically to TNF and IL-1β in a dose-dependent manner. These cytokine-mediated responses were subsequently decoded using a Naive Bayes algorithm that discriminated between no exposure and exposures to IL-1β and TNF (mean successful identification rate 82.9 ± 17.8%, chance level 33%). Recordings obtained in IL-1 receptor-KO mice were devoid of IL-1β–related signals but retained their responses to TNF. Genetic ablation of TRPV1 neurons attenuated the vagus neural signals mediated by IL-1β, and distal lidocaine nerve block attenuated all vagus neural signals recorded. The results obtained in this study using the methodological framework suggest that cytokine-specific information is present in sensory neural signals within the vagus nerve.