Simulations to benchmark time-varying connectivity methods for fMRI

Published: May 29, 2018There is a current interest in quantifying time-varying connectivity (TVC) based on neuroimaging data such as fMRI. Many methods have been proposed, and are being applied, revealing new insight into the brain’s dynamics. However, given that the ground truth for TVC in the brain is unknown, many concerns remain regarding the accuracy of proposed estimates. Since there exist many TVC methods it is difficult to assess differences in time-varying connectivity between studies. In this paper, we present tvc_benchmarker, which is a Python package containing four simulations to test TVC methods. Here, we evaluate five different methods that together represent a wide spectrum of current approaches to estimating TVC (sliding window, tapered sliding window, multiplication of temporal derivatives, spatial distance and jackknife correlation). These simulations were designed to test each method’s ability to track changes in covariance over time, which is a key property in TVC analysis. We found that all tested methods correlated positively with each other, but there were large differences in the strength of the correlations between methods. To facilitate comparisons with future TVC methods, we propose that the described simulations can act as benchmark tests for evaluation of methods. Using tvc_benchmarker researchers can easily add, compare and submit their own TVC methods to evaluate its performance.WHT acknowledges support from the Knut och Alice Wallenbergs Stiftelse (SE) (grant no. 2016.0473, http://kaw.wallenberg.org). PR acknowledges support from the Swedish Research Council (Vetenskapsrådet) (grants no. 2016-03352 and 773 013-61X-08276-26-4) (http://vr.se) and the Swedish e-Science Research Center (http://e- science.se/). CGR acknowledges financial support from the Spanish Ministry of Economy and Competitiveness, through the ªSevero Ochoaº Programme for Centres/Units of Excellence in R&Dº (SEV-2015-490, http://csic.es/)

The Dynamics of Functional Brain Networks:Integrated Network States during Cognitive Task Performance

Higher brain function relies upon the ability to flexibly integrate information across specialized communities of brain regions, however it is unclear how this mechanism manifests over time. In this study, we use time-resolved network analysis of functional magnetic resonance imaging data to demonstrate that the human brain traverses between two functional states that maximize either segregation into tight-knit communities or integration across otherwise disparate neural regions. The integrated state enables faster and more accurate performance on a cognitive task, and is associated with dilations in pupil diameter, suggesting that ascending neuromodulatory systems may govern the transition between these alternative modes of brain function. Our data confirm a direct link between cognitive performance and the dynamic reorganization of the network structure of the brain.Comment: 38 pages, 4 figure

Improving fMRI Analysis and MR Reconstruction with the Incorporation of MR Relaxivities and Correlation Effect Examination

Functional magnetic resonance imaging (fMRI) and functional connectivity MRI (fcMRI) use the physical principles of nuclear MR to provide high resolution representations of brain activity and connectivity. As the fMRI and fcMRI signals are detected from the excited hydrogen atoms in a magnetic field, the acquired data is determined by the underlying physical processes, such as the MR relaxivities. In fMRI and fcMRI, the Fourier encoded frequency space measurements are reconstructed into brain images, then spatiotemporal processing operations are applied before computing the brain activation and connectivity statistics. This dissertation seeks to utilize the magnetic resonance (MR) relaxivities at different stages of the fMRI pipeline, and aims to observe the statistical implications of the spatiotemporal processing operators on the fMRI and fcMRI data. We first develop a new statistical complex-valued nonlinear fMRI activation model that incorporates the MR relaxivities of gray matter into the brain activation statistics by utilizing the physical MR magnetization equation and the first scans of the fMRI data. We provide both theoretical and experimental comparison between the proposed model with the conventional linear magnitude-only and complex-valued fMRI activation models. Our statistical analysis results show that the new model provides better accuracy in computing brain activation statistics while theoretically eliminating false positives in non-gray matter areas. We then develop a linear Fourier reconstruction operator that incorporates the MR relaxivities into the image reconstruction process to account for their effects. The utilization of a linear system makes it achievable to theoretically compute the statistical implications of the use of the proposed operator. By focusing on longitudinal relaxation time, T1, to include into the image reconstruction, we show that the application of the proposed Fourier reconstruction operator provides better image contrast in the reconstructed images by recovering the information of the tissue characteristics that exist prior to T1 equilibrium. We finally examine the effects of time series preprocessing on computed functional correlations through the use of linear operators and provide ways of accounting for such effects in computing functional activity and connectivity statistics. Using both theoretical and experimentally acquired functional connectivity data, we examine the correlations induced by commonly used spatial and temporal processing operations. Furthermore, we provide the expansion of the statistical fcMRI and fMRI models to incorporate the quantified processing induced correlations in computing brain activity and connectivity statistics

Neural Connectivity with Hidden Gaussian Graphical State-Model

The noninvasive procedures for neural connectivity are under questioning. Theoretical models sustain that the electromagnetic field registered at external sensors is elicited by currents at neural space. Nevertheless, what we observe at the sensor space is a superposition of projected fields, from the whole gray-matter. This is the reason for a major pitfall of noninvasive Electrophysiology methods: distorted reconstruction of neural activity and its connectivity or leakage. It has been proven that current methods produce incorrect connectomes. Somewhat related to the incorrect connectivity modelling, they disregard either Systems Theory and Bayesian Information Theory. We introduce a new formalism that attains for it, Hidden Gaussian Graphical State-Model (HIGGS). A neural Gaussian Graphical Model (GGM) hidden by the observation equation of Magneto-encephalographic (MEEG) signals. HIGGS is equivalent to a frequency domain Linear State Space Model (LSSM) but with sparse connectivity prior. The mathematical contribution here is the theory for high-dimensional and frequency-domain HIGGS solvers. We demonstrate that HIGGS can attenuate the leakage effect in the most critical case: the distortion EEG signal due to head volume conduction heterogeneities. Its application in EEG is illustrated with retrieved connectivity patterns from human Steady State Visual Evoked Potentials (SSVEP). We provide for the first time confirmatory evidence for noninvasive procedures of neural connectivity: concurrent EEG and Electrocorticography (ECoG) recordings on monkey. Open source packages are freely available online, to reproduce the results presented in this paper and to analyze external MEEG databases

Fluctuations between high- and low-modularity topology in time-resolved functional connectivity

Modularity is an important topological attribute for functional brain networks. Recent studies have reported that modularity of functional networks varies not only across individuals being related to demographics and cognitive performance, but also within individuals co-occurring with fluctuations in network properties of functional connectivity, estimated over short time intervals. However, characteristics of these time-resolved functional networks during periods of high and low modularity have remained largely unexplored. In this study we investigate spatiotemporal properties of time-resolved networks in the high and low modularity periods during rest, with a particular focus on their spatial connectivity patterns, temporal homogeneity and test-retest reliability. We show that spatial connectivity patterns of time-resolved networks in the high and low modularity periods are represented by increased and decreased dissociation of the default mode network module from task-positive network modules, respectively. We also find that the instances of time-resolved functional connectivity sampled from within the high (low) modularity period are relatively homogeneous (heterogeneous) over time, indicating that during the low modularity period the default mode network interacts with other networks in a variable manner. We confirmed that the occurrence of the high and low modularity periods varies across individuals with moderate inter-session test-retest reliability and that it is correlated with previously-reported individual differences in the modularity of functional connectivity estimated over longer timescales. Our findings illustrate how time-resolved functional networks are spatiotemporally organized during periods of high and low modularity, allowing one to trace individual differences in long-timescale modularity to the variable occurrence of network configurations at shorter timescales.Comment: Reorganized the paper; to appear in NeuroImage; arXiv abstract shortened to fit within character limit

Integrated metastate functional connectivity networks predict change in symptom severity in clinical high risk for psychosis

The ability to identify biomarkers of psychosis risk is essential in defining effective preventive measures to potentially circumvent the transition to psychosis. Using samples of people at clinical high risk for psychosis (CHR) and Healthy controls (HC) who were administered a task fMRI paradigm, we used a framework for labelling time windows of fMRI scans as ‘integrated’ FC networks to provide a granular representation of functional connectivity (FC). Periods of integration were defined using the ‘cartographic profile’ of time windows and k‐means clustering, and sub‐network discovery was carried out using Network Based Statistics (NBS). There were no network differences between CHR and HC groups. Within the CHR group, using integrated FC networks, we identified a sub‐network negatively associated with longitudinal changes in the severity of psychotic symptoms. This sub‐network comprised brain areas implicated in bottom‐up sensory processing and in integration with motor control, suggesting it may be related to the demands of the fMRI task. These data suggest that extracting integrated FC networks may be useful in the investigation of biomarkers of psychosis risk

Brain network mechanisms in learning behavior

The study of learning has been a central focus of psychology and neuroscience since their inception. Cognitive neuroscience’s traditional approach to understanding learn-ing has been to decompose it into discrete cognitive processes with separable and localized underlying neural systems. While this focus on modular cognitive functions for individual brain areas has led to considerable progress, there is increasing evidence that much of learn-ing behavior relies on overlapping cognitive and neural systems, which may be harder to disentangle than previously envisioned. This is not surprising, as the processes underlying learning must involve widespread integration of information from sensory, affective, and motor sources. The standard tools of cognitive neuroscience limit our ability to describe processes that rely on widespread coordination of brain activity. To understand learning, it will be necessary to characterize dynamic co-activation at the circuit level. In this dissertation, I present three studies that seek to describe the roles of distrib-uted brain networks in learning. I begin by giving an overview of our current understand-ing of multiple forms of learning, describing the neural and computational mechanisms thought to underlie incremental feedback-based learning and flexible episodic memory. I will focus in particular on the difficulties in separating these processes at the cognitive level and in localizing them to individual regions at the neural level. I will then describe recent findings that have begun to characterize the brain’s large-scale network structure, emphasiz-ing the potential roles that distributed networks could play in understanding learning and cognition more generally. I will end the introduction by reviewing current attempts to char-acterize the dynamics of large-scale brain networks, which will be essential for providing a mechanistic link to learning behavior. Chapter 2 is a study demonstrating that intrinsic connectivity between the hippo-campus and the ventromedial prefrontal cortex, as well as between these regions and dis-tributed brain networks, is related to individual differences in the transfer of learning on a sensory preconditioning task. The hippocampus and ventromedial prefrontal cortex have both been shown to be involved in this type of learning, and this study represents an early attempt to link connectivity between individual regions and broader networks to learning processes. Chapter 3 is a study that takes advantage of recent developments in mathematical modeling of temporal networks to demonstrate a relationship between large-scale network dynamics and reinforcement learning within individuals. This study shows that the flexibil-ity of network connectivity in the striatum is related to learning performance over time, as well as to individual differences in parameters estimated from computational models of re-inforcement learning. Notably, connectivity between the striatum and visual as well as or-bitofrontal regions increased over the course of the task, which is consistent with an inte-grative role for the region in learning value-based associations. Network flexibility in a dis-tinct set of regions is associated with episodic memory for object images presented during the learning task. Chapter 4 examines the role of dopamine, a neurotransmitter strongly linked to val-ue updating in reinforcement learning, in the dynamic network changes occurring during learning. Patients with Parkinson’s disease, who experience a loss of dopaminergic neu-rons in the substantia nigra, performed a reversal-learning task while undergoing functional magnetic resonance imaging. Patients were scanned on and off of a dopamine precursor medication (levodopa) in a within-subject design in order to examine the impact of dopa-mine on brain network dynamics during learning. The reversal provided an experimental manipulation of dynamic connectivity, and patients on medication showed greater modula-tion of striatal-cortical connectivity. Similar results were found in a number of regions re-ceiving midbrain projections including the prefrontal cortex and medial temporal lobe. This study indicates that dopamine inputs from the midbrain modulate large-scale network dy-namics during learning, providing a direct link between reinforcement learning theories of value updating and network neuroscience accounts of dynamic connectivity. Together, these results indicate that large-scale networks play a critical role in multi-ple forms of learning behavior. Each highlights the potential importance of understanding dynamic routing and integration of information across large-scale circuits for our concep-tion of learning and other cognitive processes. Understanding the when, where, and how of this information flow in the brain may provide an alternative or compliment to traditional theories of distinct learning systems. These studies also illustrate challenges in integrating this perspective with established theories in cognitive neuroscience. Chapter 5 will situate the studies in a broader discussion of how brain activity relates to cognition in general, while pointing out current roadblocks and potential ways forward for a cognitive network neuroscience of learning