Contribution of LFP dynamics to single-neuron spiking variability in motor cortex during movement execution

Understanding the sources of variability in single-neuron spiking responses is an important open problem for the theory of neural coding. This variability is thought to result primarily from spontaneous collective dynamics in neuronal networks. Here, we investigate how well collective dynamics reflected in motor cortex local field potentials (LFPs) can account for spiking variability during motor behavior. Neural activity was recorded via microelectrode arrays implanted in ventral and dorsal premotor and primary motor cortices of non-human primates performing naturalistic 3-D reaching and grasping actions. Point process models were used to quantify how well LFP features accounted for spiking variability not explained by the measured 3-D reach and grasp kinematics. LFP features included the instantaneous magnitude, phase and analytic-signal components of narrow band-pass filtered (δ, θ, α, β) LFPs, and analytic signal and amplitude envelope features in higher-frequency bands. Multiband LFP features predicted single-neuron spiking (1ms resolution) with substantial accuracy as assessed via ROC analysis. Notably, however, models including both LFP and kinematics features displayed marginal improvement over kinematics-only models. Furthermore, the small predictive information added by LFP features to kinematic models was redundant to information available in fast-timescale (<100ms) spiking history. Overall, information in multiband LFP features, although predictive of single-neuron spiking during movement execution, was redundant to information available in movement parameters and spiking history. Our findings suggest that, during movement execution, collective dynamics reflected in motor cortex LFPs primarily relate to sensorimotor processes directly controlling movement output, adding little explanatory power to variability not accounted by movement parameters

Revealing the distribution of transmembrane currents along the dendritic tree of a neuron from extracellular recordings.

Revealing the current source distribution along the neuronal membrane is a key step on the way to understanding neural computations, however, the experimental and theoretical tools to achieve sufficient spatiotemporal resolution for the estimation remain to be established. Here we address this problem using extracellularly recorded potentials with arbitrarily distributed electrodes for a neuron of known morphology. We use simulations of models with varying complexity to validate the proposed method and to give recommendations for experimental applications. The method is applied to in vitro data from rat hippocampus

Electrocorticography is superior to subthalamic local field potentials for movement decoding in Parkinson’s disease

Brain signal decoding promises significant advances in the development of clinical brain computer interfaces (BCI). In Parkinson's disease (PD), first bidirectional BCI implants for adaptive deep brain stimulation (DBS) are now available. Brain signal decoding can extend the clinical utility of adaptive DBS but the impact of neural source, computational methods and PD pathophysiology on decoding performance are unknown. This represents an unmet need for the development of future neurotechnology. To address this, we developed an invasive brain-signal decoding approach based on intraoperative sensorimotor electrocorticography (ECoG) and subthalamic LFP to predict grip-force, a representative movement decoding application, in 11 PD patients undergoing DBS. We demonstrate that ECoG is superior to subthalamic LFP for accurate grip-force decoding. Gradient boosted decision trees (XGBOOST) outperformed other model architectures. ECoG based decoding performance negatively correlated with motor impairment, which could be attributed to subthalamic beta bursts in the motor preparation and movement period. This highlights the impact of PD pathophysiology on the neural capacity to encode movement vigor. Finally, we developed a connectomic analysis that could predict grip-force decoding performance of individual ECoG channels across patients by using their connectomic fingerprints. Our study provides a neurophysiological and computational framework for invasive brain signal decoding to aid the development of an individualized precision-medicine approach to intelligent adaptive DBS

Predictive Modeling of Adolescent Cannabis Use From Multimodal Data

Predicting teenage drug use is key to understanding the etiology of substance abuse. However, classic predictive modeling procedures are prone to overfitting and fail to generalize to independent observations. To mitigate these concerns, cross-validated logistic regression with elastic-net regularization was used to predict cannabis use by age 16 from a large sample of fourteen year olds (N=1,319). High-dimensional data (p = 2,413) including parent and child psychometric data, child structural and functional MRI data, and genetic data (candidate single-nucleotide polymorphisms, SNPs ) collected at age 14 were used to predict the initiation of cannabis use (minimum six occasions) by age 16. Analyses were conducted separately for males and females to uncover sex-specific predictive profiles. The performance of the predictive models were assessed using the area under the receiver-operating characteristic curve ( ROC AUC ). Final models returned high predictive performance (generalization mean ROC AUCmales=.71, mean ROC AUCfemales=.81) and contained psychometric features common to both sexes. These common psychometric predictors included greater stressful life events, novelty-seeking personality traits of both the parent and child, and parental cannabis use. In contrast, males exhibited distinct functional neurobiological predictors related to a response- inhibition fMRI task, whereas females exhibited distinct neurobiological predictors related to a social processing fMRI task. Furthermore, the brain predictors exhibited sex- specific effects as the brain predictors of cannabis use for one sex failed to predict cannabis use for the opposite sex. These sex-specific brain predictors also exhibited drug- specific effects as they failed to predict binge-drinking by age 16 in an independent sample of youths. When collapsed across sex, a gene-specific analysis suggested that opioid receptor genetic variation also predicted cannabis use by age 16. Two SNPs on the gene coding for the primary mu-opioid receptor exhibited genetic risk effects, while one SNP on the gene coding for the primary delta-opioid receptor exhibited genetic protective effects. Taken together, these results demonstrate that adolescent cannabis use is reliably predicted in males and females from shared and unique biobehavioral features. These analyses also underscore the need for refined predictive modeling procedures as well as sex-specific inquiries into the etiology of substance abuse. The sex-specific risk-profiles uncovered from these analyses might inform potential etiological mechanisms contributing to substance abuse in adolescence as all predictors were measured prior to the onset of cannabis use

Point process modeling as a framework to dissociate intrinsic and extrinsic components in neural systems

Understanding the factors shaping neuronal spiking is a central problem in neuroscience. Neurons may have complicated sensitivity and, often, are embedded in dynamic networks whose ongoing activity may influence their likelihood of spiking. One approach to characterizing neuronal spiking is the point process generalized linear model (GLM), which decomposes spike probability into explicit factors. This model represents a higher level of abstraction than biophysical models, such as Hodgkin-Huxley, but benefits from principled approaches for estimation and validation. Here we address how to infer factors affecting neuronal spiking in different types of neural systems. We first extend the point process GLM, most commonly used to analyze single neurons, to model population-level voltage discharges recorded during human seizures. Both GLMs and descriptive measures reveal rhythmic bursting and directional wave propagation. However, we show that GLM estimates account for covariance between these features in a way that pairwise measures do not. Failure to account for this covariance leads to confounded results. We interpret the GLM results to speculate the mechanisms of seizure and suggest new therapies. The second chapter highlights flexibility of the GLM. We use this single framework to analyze enhancement, a statistical phenomenon, in three distinct systems. Here we define the enhancement score, a simple measure of shared information between spike factors in a GLM. We demonstrate how to estimate the score, including confidence intervals, using simulated data. In real data, we find that enhancement occurs prominently during human seizure, while redundancy tends to occur in mouse auditory networks. We discuss implications for physiology, particularly during seizure. In the third part of this thesis, we apply point process modeling to spike trains recorded from single units in vitro under external stimulation. We re-parameterize models in a low-dimensional and physically interpretable way; namely, we represent their effects in principal component space. We show that this approach successfully separates the neurons observed in vitro into different classes consistent with their gene expression profiles. Taken together, this work contributes a statistical framework for analyzing neuronal spike trains and demonstrates how it can be applied to create new insights into clinical and experimental data sets

Reconstruction de l'activité corticale à partir de données MEG à l'aide de réseaux cérébraux et de délais de transmission estimés à partir d'IRMd

White matter fibers transfer information between brain regions with delays that are observable with magnetoencephalography and electroencephalography (M/EEG) due to their millisecond temporal resolution. We can represent the brain as a graph where nodes are the cortical sources or areas and edges are the physical connections between them: either local (between adjacent vertices on the cortical mesh) or non-local (long-range white matter fibers). Long-range anatomical connections can be obtained with diffusion MRI (dMRI) tractography which yields a set of streamlines representing white matter fiber bundles. Given the streamlines’ lengths and the information conduction speed, transmission delays can be estimated for each connection. dMRI can thus give an insight into interaction delays of the macroscopicbrain network.Localizing and recovering electrical activity of the brain from M/EEG measurements is known as the M/EEG inverse problem. Generally, there are more unknowns (brain sources) than the number of sensors, so the solution is non-unique and the problem ill-posed. To obtain a unique solution, prior constraints on the characteristics of source distributions are needed. Traditional linear inverse methods deploy different constraints which can favour solutions with minimum norm, impose smoothness constraints in space and/or time along the cortical surface, etc. Yet, structural connectivity is rarely considered and transmission delays almost always neglected.The first contribution of this thesis consists of a multimodal preprocessing pipeline used to integrate structural MRI, dMRI and MEG data into a same framework, and of a simulation procedure of source-level brain activity that was used as a synthetic dataset to validate the proposed reconstruction approaches.In the second contribution, we proposed a new framework to solve the M/EEG inverse problem called Connectivity-Informed M/EEG Inverse Problem (CIMIP), where prior transmission delays supported by dMRI were included to enforce temporal smoothness between time courses of connected sources. This was done by incorporating a Laplacian operator into the regularization, that operates on a time-dependent connectivity graph. Nonetheless, some limitations of the CIMIP approach arised, mainly due to the nature of the Laplacian, which acts on the whole graph, favours smooth solutions across all connections, for all delays, and it is agnostic to directionality.In this thesis, we aimed to investigate patterns of brain activity during visuomotor tasks, during which only a few regions typically get significantly activated, as shown by previous studies. This led us to our third contribution, an extension of the CIMIP approach that addresses the aforementioned limitations, named CIMIP_OML (“Optimal Masked Laplacian”). We restricted the full source space network (the whole cortical mesh) to a network of regions of interest and tried to find how the information is transferred between its nodes. To describe the interactions between nodes in a directed graph, we used the concept of network motifs. We proposed an algorithm that (1) searches for an optimal network motif – an optimal pattern of interaction between different regions and (2) reconstructs source activity given the found motif. Promising results are shown for both simulated and real MEG data for a visuomotor task and compared with 3 different state-of-the-art reconstruction methods.To conclude, we tackled a difficult problem of exploiting delays supported by dMRI for the reconstruction of brain activity, while also considering the directionality in the information transfer, and provided new insights into the complex patterns of brain activity.Les fibres de la matière blanche permettent le transfert d’information dans le cerveau avec des délais observables en Magnétoencéphalographie et Électroencéphalographie (M/EEG) grâce à leur haute résolution temporelle. Le cerveau peut être représenté comme un graphe où les nœuds sont les régions corticales et les liens sont les connexions physiques entre celles-ci: soit locales (entre sommets adjacents sur le maillage cortical), soit non locales (fibres de la matière blanche). Les connexions non-locales peuvent être reconstruites avec la tractographie de l’IRM de diffusion (IRMd) qui génère un ensemble de courbes («streamlines») représentant des fibres de la matière blanche. Sachant les longueurs des fibres et la vitesse de conduction de l’information, les délais de transmission peuvent être estimés. L’IRMd peut donc donner un aperçu des délais d’interaction du réseau cérébral macroscopique.La localisation et la reconstruction de l’activité électrique cérébrale à partir des mesures M/EEG est un problème inverse. En général, il y a plus d’inconnues (sources cérébrales) que de capteurs. La solution n’est donc pas unique et le problème est dit mal posé. Pour obtenir une solution unique, des hypothèses sur les caractéristiques des distributions de sources sont requises. Les méthodes inverses linéaires traditionnelles utilisent différentes hypothèses qui peuvent favoriser des solutions de norme minimale, imposer des contraintes de lissage dans l’espace et/ou dans le temps, etc. Pourtant, la connectivité structurelle est rarement prise en compte et les délais de transmission sont presque toujours négligés.La première contribution de cette thèse est un pipeline de prétraitement multimodal utilisé pour l’intégration des données d’IRM, IRMd et MEG dans un même cadre, et d’une méthode de simulation de l’activité corticale qui a été utilisée comme jeu de données synthétiques pour valider les approches de reconstruction proposées. Nous proposons également une nouvelle approche pour résoudre le problème inverse M/EEG appelée «Problème Inverse M/EEG Informé par la Connectivité» (CIMIP pour Connectivity-Informed M/EEG Inverse Problem), où des délais de transmission provenant de l’IRMd sont inclus pour renforcer le lissage temporel entre les décours des sources connectées. Pour cela, un opérateur Laplacien, basé sur un graphe de connectivité en fonction du temps, a été intégré dans la régularisation. Cependant, certaines limites de l’approche CIMIP sont apparues en raison de la nature du Laplacien qui agit sur le graphe entier et favorise les solutions lisses sur toutes les connexions, pour tous les délais, et indépendamment de la directionnalité.Lors de tâches visuo-motrices, seules quelques régions sont généralement activées significativement. Notre troisième contribution est une extension de CIMIP pour ce type de tâches qui répond aux limitations susmentionnées, nommée CIMIP_OML («Optimal Masked Laplacian») ou Laplacien Masqué Optimal. Nous essayons de trouver comment l’information est transférée entre les nœuds d’un sous-réseau de régions d’intérêt du réseau complet de l’espace des sources. Pour décrire les interactions entre nœuds dans un graphe orienté, nous utilisons le concept de motifs de réseau. Nous proposons un algorithme qui 1) cherche un motif de réseau optimal- un modèle optimal d’interaction entre régions et 2) reconstruit l’activité corticale avec le motif trouvé. Des résultats prometteurs sont présentés pour des données MEG simulées et réelles (tâche visuo-motrice) et comparés avec 3 méthodes de l’état de l’art. Pour conclure, nous avons abordé un problème difficile d’exploitation des délais de l’IRMd lors l’estimation de l’activité corticale en tenant compte de la directionalité du transfert d’information, fournissant ainsi de nouvelles perspectives sur les patterns complexes de l’activité cérébrale