Deriving a multi-subject functional-connectivity atlas to inform connectome estimation

MICCAI 2014 preprintInternational audienceThe estimation of functional connectivity structure from functional neuroimaging data is an important step toward understanding the mechanisms of various brain diseases and building relevant biomarkers. Yet, such inferences have to deal with the low signal-to-noise ratio and the paucity of the data. With at our disposal a steadily growing volume of publicly available neuroimaging data, it is however possible to improve the estimation procedures involved in connectome mapping. In this work, we propose a novel learning scheme for functional connectivity based on sparse Gaussian graphical models that aims at minimizing the bias induced by the regularization used in the estimation, by carefully separating the estimation of the model support from the coefficients. Moreover, our strategy makes it possible to include new data with a limited computational cost. We illustrate the physiological relevance of the learned prior, that can be identified as a functional connectivity atlas, based on an experiment on 46 subjects of the Human Connectome Dataset

Dynamic trajectories of connectome state transitions are heritable

The brain's functional connectome is dynamic, constantly reconfiguring in an individual-specific manner. However, which characteristics of such reconfigurations are subject to genetic effects, and to what extent, is largely unknown. Here, we identified heritable dynamic features, quantified their heritability, and determined their association with cognitive phenotypes. In resting-state fMRI, we obtained multivariate features, each describing a temporal or spatial characteristic of connectome dynamics jointly over a set of connectome states. We found strong evidence for heritability of temporal features, particularly, Fractional Occupancy (FO) and Transition Probability (TP), representing the duration spent in each connectivity configuration and the frequency of shifting between configurations, respectively. These effects were robust against methodological choices of number of states and global signal regression. Genetic effects explained a substantial proportion of phenotypic variance of these features (h2=0.39, 95% CI= [.24,.54] for FO; h2=0.43, 95% CI=[.29,.57] for TP). Moreover, these temporal phenotypes were associated with cognitive performance. Contrarily, we found no robust evidence for heritability of spatial features of the dynamic states (i.e., states’ Modularity and connectivity pattern). Genetic effects may therefore primarily contribute to how the connectome transitions across states, rather than the precise spatial instantiation of the states in individuals. In sum, genetic effects impact the dynamic trajectory of state transitions (captured by FO and TP), and such temporal features may act as endophenotypes for cognitive abilities

Spatial parcellations, spectral filtering, and connectivity measures in fMRI: Optimizing for discrimination.

The analysis of Functional Connectivity (FC) is a key technique of fMRI, having been used to distinguish brain states and conditions. While many approaches to calculating FC are available, there have been few assessments of their differences, making it difficult to choose approaches and compare results. Here, we assess the impact of methodological choices on discriminability, using a fully controlled dataset of continuous active states involving basic visual and motor tasks, providing robust localized FC changes. We tested a range of anatomical and functional parcellations, including the AAL atlas, parcellations derived from the Human Connectome Project and Independent Component Analysis (ICA) of many dimensionalities. We measure amplitude, covariance, correlation and regularized partial correlation under different temporal filtering choices. We evaluate features derived from these methods for discriminating states using MVPA. We find that multidimensional parcellations derived from functional data performed similarly, outperforming an anatomical atlas, with correlation and partial correlation (p<0.05, FDR). Partial correlation, with appropriate regularization, outperformed correlation. Amplitude and covariance generally discriminated less well, although gave good results with high-dimensionality ICA. We found that discriminative FC properties are frequency specific; higher frequencies performed surprisingly well under certain configurations of atlas choices and dependency measures, with ICA-based parcellations revealing greater discriminability at high frequencies compared to other parcellations. Methodological choices in FC analyses can have a profound impact on results and can be selected to optimize accuracy, interpretability, and sharing of results. This work contributes to a basis for consistent selection of approaches to estimating and analyzing FC

Whole-brain estimates of directed connectivity for human connectomics

Connectomics is essential for understanding large-scale brain networks but requires that individual connection estimates are neurobiologically interpretable. In particular, a principle of brain organization is that reciprocal connections between cortical areas are functionally asymmetric. This is a challenge for fMRI-based connectomics in humans where only undirected functional connectivity estimates are routinely available. By contrast, whole-brain estimates of effective (directed) connectivity are computationally challenging, and emerging methods require empirical validation. Here, using a motor task at 7T, we demonstrate that a novel generative model can infer known connectivity features in a whole-brain network (>200 regions, >40,000 connections) highly efficiently. Furthermore, graph-theoretical analyses of directed connectivity estimates identify functional roles of motor areas more accurately than undirected functional connectivity estimates. These results, which can be achieved in an entirely unsupervised manner, demonstrate the feasibility of inferring directed connections in whole-brain networks and open new avenues for human connectomics

High activity and high functional connectivity are mutually exclusive in resting state zebrafish and human brains

The structural connectivity of neurons in the brain allows active neurons to impact the physiology of target neuron types with which they are functionally connected. While the structural connectome is at the basis of functional connectome, it is the functional connectivity measured through correlations between time series of individual neurophysiological events that underlies behavioral and mental states. However, in light of the diverse neuronal cell types populating the brain and their unique connectivity properties, both neuronal activity and functional connectivity are heterogeneous across the brain, and the nature of their relationship is not clear. Here, we employ brain-wide calcium imaging at cellular resolution in larval zebrafish to understand the principles of resting state functional connectivity. We recorded the spontaneous activity of >12,000 neurons in the awake resting state forebrain. By classifying their activity (i.e., variances of ΔF/F across time) and functional connectivity into three levels (high, medium, low), we find that highly active neurons have low functional connections and highly connected neurons are of low activity. This finding holds true when neuronal activity and functional connectivity data are classified into five instead of three levels, and in whole brain spontaneous activity datasets. Moreover, such activity-connectivity relationship is not observed in randomly shuffled, noise-added, or simulated datasets, suggesting that it reflects an intrinsic brain network property. Intriguingly, deploying the same analytical tools on functional magnetic resonance imaging (fMRI) data from the resting state human brain, we uncover a similar relationship between activity (signal variance over time) and functional connectivity, that is, regions of high activity are non-overlapping with those of high connectivity. We found a mutually exclusive relationship between high activity (signal variance over time) and high functional connectivity of neurons in zebrafish and human brains. These findings reveal a previously unknown and evolutionarily conserved brain organizational principle, which has implications for understanding disease states and designing artificial neuronal networks

Graph analysis of functional brain networks: practical issues in translational neuroscience

The brain can be regarded as a network: a connected system where nodes, or units, represent different specialized regions and links, or connections, represent communication pathways. From a functional perspective communication is coded by temporal dependence between the activities of different brain areas. In the last decade, the abstract representation of the brain as a graph has allowed to visualize functional brain networks and describe their non-trivial topological properties in a compact and objective way. Nowadays, the use of graph analysis in translational neuroscience has become essential to quantify brain dysfunctions in terms of aberrant reconfiguration of functional brain networks. Despite its evident impact, graph analysis of functional brain networks is not a simple toolbox that can be blindly applied to brain signals. On the one hand, it requires a know-how of all the methodological steps of the processing pipeline that manipulates the input brain signals and extract the functional network properties. On the other hand, a knowledge of the neural phenomenon under study is required to perform physiological-relevant analysis. The aim of this review is to provide practical indications to make sense of brain network analysis and contrast counterproductive attitudes

Connectomic Targets für die Tiefenhirnstimulation

Deep brain stimulation (DBS), a highly effective and well-established treatment option for movement disorders, is now also used to treat psychiatric disorders, such as obsessive-compulsive disorder (OCD) or major depression. A variety of surgical targets for DBS have been proposed not only for different diseases but also for the same disease. However, different targets may potentially lie within the same brain network or even alongside the same fiber bundle which is responsible for clinical improvement. Within the scope of this study, we hence investigated whether different stimulation sites would modulate one common tract target mediating beneficial OCD outcome. Specifically, four cohorts of OCD patients that underwent DBS to either the anterior limb of the internal capsule (ALIC) or the subthalamic nucleus (STN) were analyzed using a connectomic approach. Fiber tracts that were associated with clinical improvement – based on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) – were isolated, assigned with predictive values and visualized. The same fronto-subcortical fiber tract that was positively discriminative of good clinical outcome emerged for both target-specific cohorts. Moreover, the tract derived from data of the ALIC-cohort was predictive of clinical improvement in the STN-cohort and vice versa. The results suggest that modulating a specific fronto-subthalamic fiber bundle may represent an important unifying substrate for improving global obsessive-compulsive behavior in OCD across different stimulation sites. In synergy, the study advances the concept of connectomic deep brain stimulation above and beyond OCD, showing for the first time that a connectivity-derived model could potentially facilitate defining the connectomic target for DBS.Die Tiefe Hirnstimulation (DBS), eine hochwirksame und etablierte Behandlungsoption bei Bewegungsstörungen, wird mittlerweile auch bei psychiatrischen Erkrankungen wie Zwangsstörungen (OCD) oder schweren Depressionen eingesetzt. Mehrere chirurgische Ziele für die DBS existieren nicht nur für verschiedene Krankheiten, sondern teilweise auch für dieselbe Krankheit. Möglicherweise liegen jedoch unterschiedliche Ziele innerhalb eines selben Gehirnnetzwerks oder sogar innerhalb desselben Faserbündels, welches für die klinische Verbesserung verantwortlich ist. Im Rahmen dieser Studie untersuchten wir daher, ob verschiedene Stimulationsorte einen gemeinsamen Trakt modulieren, welcher ein vorteilhaftes klinisches OCD-Ergebnis vermittelt. Konkret wurden vier Kohorten von Patienten mit einer Zwangsstörung, bei welchen die Implantation einer DBS entweder an dem vorderen Teil der Capsula interna (ALIC) oder am Nucleus subthalamicus (STN) durchgeführt wurde, unter Benutzung eines strukturellen Konnektoms analysiert. Fasertrakte, die mit einer klinischen Verbesserung assoziiert waren – basierend auf der Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) – wurden isoliert, mit prädiktiven Werten belegt und visualisiert. Für beide zielspezifische Kohorten trat der gleiche fronto-subkortikale Fasertrakt auf, der mit einem guten klinischen Ergebnis assoziiert war. Darüber hinaus war der aus den Daten der ALIC-Kohorte abgeleitete Trakt prädiktiv für eine klinische Verbesserung in der STN-Kohorte und umgekehrt. Die Ergebnisse legen nahe, dass die Modulation eines spezifischen fronto-subthalamischen Faserbündels ein wichtiges verbindendes Substrat zur Verbesserung des Zwangsverhaltens bei Zwangsstörungen über verschiedene Stimulationsorte hinweg darstellen kann. In Synergie entwickelt diese Studie das Konzept der konnektomischen Tiefenhirnstimulation über die Zwangsstörung hinaus und zeigt erstmalig, dass ein von der Konnektivität abgeleitetes Modell möglicherweise die Definition eines konnektomischen Ziels für die DBS erleichtern könnte

Searching for Imaging Biomarkers of Psychotic Dysconnectivity

Background: Progress in precision psychiatry is predicated on identifying reliable individual-level diagnostic biomarkers. For psychosis, measures of structural and functional connectivity could be promising biomarkers given consistent reports of dysconnectivity across psychotic disorders using magnetic resonance imaging. Methods: We leveraged data from four independent cohorts of patients with psychosis and control subjects with observations from approximately 800 individuals. We used group-level analyses and two supervised machine learning algorithms (support vector machines and ridge regression) to test within-, between-, and across-sample classification performance of white matter and resting-state connectivity metrics. Results: Although we replicated group-level differences in brain connectivity, individual-level classification was suboptimal. Classification performance within samples was variable across folds (highest area under the curve [AUC] range = 0.30) and across datasets (average support vector machine AUC range = 0.50; average ridge regression AUC range = 0.18). Classification performance between samples was similarly variable or resulted in AUC values of approximately 0.65, indicating a lack of model generalizability. Furthermore, collapsing across samples (resting-state functional magnetic resonance imaging, N = 888; diffusion tensor imaging, N = 860) did not improve model performance (maximal AUC = 0.67). Ridge regression models generally outperformed support vector machine models, although classification performance was still suboptimal in terms of clinical relevance. Adjusting for demographic covariates did not greatly affect results. Conclusions: Connectivity measures were not suitable as diagnostic biomarkers for psychosis as assessed in this study. Our results do not negate that other approaches may be more successful, although it is clear that a systematic approach to individual-level classification with large independent validation samples is necessary to properly vet neuroimaging features as diagnostic biomarkers

Impact of Machine Learning Pipeline Choices in Autism Prediction from Functional Connectivity Data

Autism Spectrum Disorder (ASD) is a largely prevalent neurodevelopmental condition with a big social and economical impact affecting the entire life of families. There is an intense search for biomarkers that can be assessed as early as possible in order to initiate treatment and preparation of the family to deal with the challenges imposed by the condition. Brain imaging biomarkers have special interest. Specifically, functional connectivity data extracted from resting state functional magnetic resonance imaging (rs-fMRI) should allow to detect brain connectivity alterations. Machine learning pipelines encompass the estimation of the functional connectivity matrix from brain parcellations, feature extraction, and building classification models for ASD prediction. The works reported in the literature are very heterogeneous from the computational and methodological point of view. In this paper, we carry out a comprehensive computational exploration of the impact of the choices involved while building these machine learning pipelines. Specifically, we consider six brain parcellation definitions, five methods for functional connectivity matrix construction, six feature extraction/selection approaches, and nine classifier building algorithms. We report the prediction performance sensitivity to each of these choices, as well as the best results that are comparable with the state of the art.This work has been partially supported by theFEDER funds through MINECO project TIN2017-85827-P. This project has received funding from theEuropean Union’s Horizon 2020 research and inno-vation program under the Marie Sklodowska-Curiegrant agreement No 77772