Organization of areal connectivity in the monkey frontoparietal network.

Activity observed in biological neural networks is determined by anatomical connectivity between cortical areas. The monkey frontoparietal network facilitates cognitive functions, but the organization of its connectivity is unknown. Here, a new connectivity matrix is proposed which shows that the network utilizes a small-world architecture and the 3-node M9 motif. Its areas exhibit relatively homogeneous connectivity with no suggestion of the hubs seen in scale-free networks. Crucially, its M9 dynamical relay motif is optimally arranged for near-zero and non-zero phase synchrony to arise in support of cognition, serving as a candidate topological mechanism for previously reported findings. These results can serve as a benchmark to be used in the treatment of neurological disorders where the types of cognition the frontoparietal network supports are impaired.

Measuring directed functional connectivity using non-parametric directionality analysis: Validation and comparison with non-parametric Granger Causality.

BACKGROUND: 'Non-parametric directionality' (NPD) is a novel method for estimation of directed functional connectivity (dFC) in neural data. The method has previously been verified in its ability to recover causal interactions in simulated spiking networks in Halliday et al. (2015). METHODS: This work presents a validation of NPD in continuous neural recordings (e.g. local field potentials). Specifically, we use autoregressive models to simulate time delayed correlations between neural signals. We then test for the accurate recovery of networks in the face of several confounds typically encountered in empirical data. We examine the effects of NPD under varying: a) signal-to-noise ratios, b) asymmetries in signal strength, c) instantaneous mixing, d) common drive, e) data length, and f) parallel/convergent signal routing. We also apply NPD to data from a patient who underwent simultaneous magnetoencephalography and deep brain recording. RESULTS: We demonstrate that NPD can accurately recover directed functional connectivity from simulations with known patterns of connectivity. The performance of the NPD measure is compared with non-parametric estimators of Granger causality (NPG), a well-established methodology for model-free estimation of dFC. A series of simulations investigating synthetically imposed confounds demonstrate that NPD provides estimates of connectivity that are equivalent to NPG, albeit with an increased sensitivity to data length. However, we provide evidence that: i) NPD is less sensitive than NPG to degradation by noise; ii) NPD is more robust to the generation of false positive identification of connectivity resulting from SNR asymmetries; iii) NPD is more robust to corruption via moderate amounts of instantaneous signal mixing. CONCLUSIONS: The results in this paper highlight that to be practically applied to neural data, connectivity metrics should not only be accurate in their recovery of causal networks but also resistant to the confounding effects often encountered in experimental recordings of multimodal data. Taken together, these findings position NPD at the state-of-the-art with respect to the estimation of directed functional connectivity in neuroimaging.

From nodes to networks: How methods for defining nodes influence inferences regarding network interactions.

Functional connectivity (FC) analysis of fMRI data typically rests on prior identification of network nodes from activation profiles. We compared Activation Likelihood Estimate (ALE) and the Experimentally Derived Estimate (EDE) approaches to network node identification and functional inference for both verbal and visual forms of working memory. ALE arrives at canonical activation maxima that are assumed to reliably represent peaks of brain activity underlying a psychological process (e.g., working memory). By comparison, EDEs of activation maxima are typically derived from individual participant data, and are thus sensitive to individual participant activation profiles. Here, nodes were localized by both ALE and EDE methods for each participant, and subsequently extracted time series were compared using connectivity analysis. Two sets of significance tests were performed: (1) correlations computed between nodal time series of each method were compared, and (2) correlations computed between network edges (functional connections) of each network node pair were compared. Large proportions of edge correlations significantly differed between methods. ALE effectively summarizes working memory network node locations across studies and subjects, but the sensitivity to individual functional loci suggest that EDE methods provide individualized estimates of network connectivity. We suggest that a hybrid method incorporating both ALE and EDE is optimal for network inference.

Granger-Geweke causality: Estimation and interpretation.

In a recent PNAS article1, Stokes and Purdon performed numerical simulations to argue that Granger-Geweke causality (GGC) estimation is severely biased, or of high variance, and GGC application to neuroscience is problematic because the GGC measure is independent of 'receiver' dynamics. Here, we use the same simulation examples to show that GGC measures, when properly estimated either via the spectral factorization-enabled nonparametric approach or the VAR-model based parametric approach, do not have the claimed bias and high variance problems. Further, the receiver-independence property of GGC does not present a problem for neuroscience applications. When the nature and context of experimental measurements are taken into consideration, GGC, along with other spectral quantities, yield neurophysiologically interpretable results.

Response Hand and Motor Set Differentially Modulate the Connectivity of Brain Pathways During Simple Uni-manual Motor Behavior.

We investigated the flexible modulation of undirected functional connectivity (uFC) of brain pathways during simple uni-manual responding. Two questions were central to our interests: (1) does response hand (dominant vs. non-dominant) differentially modulate connectivity and (2) are these effects related to responding under varying motor sets. fMRI data were acquired in twenty right-handed volunteers who responded with their right (dominant) or left (non-dominant) hand (blocked across acquisitions). Within acquisitions, the task oscillated between periodic responses (promoting the emergence of motor sets) or randomly induced responses (disrupting the emergence of motor sets). Conjunction analyses revealed eight shared nodes across response hand and condition, time series from which were analyzed. For right hand responses connectivity of the M1 ←→ Thalamus and SMA ←→ Parietal pathways was more significantly modulated during periodic responding. By comparison, for left hand responses, connectivity between five network pairs (including M1 and SMA, insula, basal ganglia, premotor cortex, parietal cortex, thalamus) was more significantly modulated during random responding. uFC analyses were complemented by directed FC based on multivariate autoregressive models of times series from the nodes. These results were complementary and highlighted significant modulation of dFC for SMA → Thalamus, SMA → M1, basal ganglia → Insula and basal ganglia → Thalamus. The results demonstrate complex effects of motor organization and task demand and response hand on different connectivity classes of fMRI data. The brain's sub-networks are flexibly modulated by factors related to motor organization and/or task demand, and our results have implications for assessment of medical conditions associated with motor dysfunction.

A role for versican in the development of leiomyosarcoma.

Leiomyosarcoma (LMS) is a mesenchymal cancer that occurs throughout the body. Although LMS is easily recognized histopathologically, the cause of the disease remains unknown. Versican, an extracellular matrix proteoglycan, increases in LMS. Microarray analyses of 80 LMSs and 24 leiomyomas showed a significant elevated expression of versican in human LMS versus benign leiomyomas. To explore the importance of versican in this smooth muscle cell tumor, we used versican-directed siRNA to knock down versican expression in a LMS human cell line, SK-LMS-1. Decreased versican expression was accompanied by slower rates of LMS cell proliferation and migration, increased adhesion, and decreased accumulation of the extracellular matrix macromolecule hyaluronan. Addition of purified versican to cells expressing versican siRNA restored cell proliferation to the level of LMS controls, increased the pericellular coat and the retention of hyaluronan, and decreased cell adhesion in a dose-dependent manner. The presence of versican was not only synergistic with hyaluronan in increasing cell proliferation, but the depletion of versican decreased hyaluronan synthase expression and decreased the retention of hyaluronan. When LMS cells stably expressing versican siRNA were injected into nude mice, the resulting tumors displayed significantly less versican and hyaluronan staining, had lower volumes, and had reduced levels of mitosis as compared with controls. Collectively, these results suggest a role for using versican as a point of control in the management and treatment of LMS.

Past makes future: role of pFC in prediction.

The pFC enables the essential human capacities for predicting future events and preadapting to them. These capacities rest on both the structure and dynamics of the human pFC. Structurally, pFC, together with posterior association cortex, is at the highest hierarchical level of cortical organization, harboring neural networks that represent complex goal-directed actions. Dynamically, pFC is at the highest level of the perception-action cycle, the circular processing loop through the cortex that interfaces the organism with the environment in the pursuit of goals. In its predictive and preadaptive roles, pFC supports cognitive functions that are critical for the temporal organization of future behavior, including planning, attentional set, working memory, decision-making, and error monitoring. These functions have a common future perspective and are dynamically intertwined in goal-directed action. They all utilize the same neural infrastructure: a vast array of widely distributed, overlapping, and interactive cortical networks of personal memory and semantic knowledge, named cognits, which are formed by synaptic reinforcement in learning and memory acquisition. From this cortex-wide reservoir of memory and knowledge, pFC generates purposeful, goal-directed actions that are preadapted to predicted future events.

A symbolic information approach to determine anticipated and delayed synchronization in neuronal circuit models.

The phenomenon of synchronization between two or more areas of the brain coupled asymmetrically is a relevant issue for understanding mechanisms and functions within the cerebral cortex. Anticipated synchronization (AS) refers to the situation in which the receiver system synchronizes to the future dynamics of the sender system while the intuitively expected delayed synchronization (DS) represents exactly the opposite case. AS and DS are investigated in the context of causal information formalism. More specifically, we use a multi-scale symbolic information-theory approach for discriminating the time delay displayed between two areas of the brain when they exchange information.

Modeling positive Granger causality and negative phase lag between cortical areas.

Different measures of directional influence have been employed to infer effective connectivity in the brain. When the connectivity between two regions is such that one of them (the sender) strongly influences the other (the receiver), a positive phase lag is often expected. The assumption is that the time difference implicit in the relative phase reflects the transmission time of neuronal activity. However, Brovelli et al. (2004) observed that, in monkeys engaged in processing a cognitive task, a dominant directional influence from one area of sensorimotor cortex to another may be accompanied by either a negative or a positive time delay. Here we present a model of two brain regions, coupled with a well-defined directional influence, that displays similar features to those observed in the experimental data. This model is inspired by the theoretical framework of Anticipated Synchronization developed in the field of dynamical systems. Anticipated Synchronization is a form of synchronization that occurs when a unidirectional influence is transmitted from a sender to a receiver, but the receiver leads the sender in time. This counterintuitive synchronization regime can be a stable solution of two dynamical systems coupled in a master-slave (sender-receiver) configuration when the slave receives a negative delayed self-feedback. Despite efforts to understand the dynamics of Anticipated Synchronization, experimental evidence for it in the brain has been lacking. By reproducing experimental delay times and coherence spectra, our results provide a theoretical basis for the underlying mechanisms of the observed dynamics, and suggest that the primate cortex could operate in a regime of Anticipated Synchronization as part of normal neurocognitive function.

Measuring Granger causality between cortical regions from voxelwise fMRI BOLD signals with LASSO.

Functional brain network studies using the Blood Oxygen-Level Dependent (BOLD) signal from functional Magnetic Resonance Imaging (fMRI) are becoming increasingly prevalent in research on the neural basis of human cognition. An important problem in functional brain network analysis is to understand directed functional interactions between brain regions during cognitive performance. This problem has important implications for understanding top-down influences from frontal and parietal control regions to visual occipital cortex in visuospatial attention, the goal motivating the present study. A common approach to measuring directed functional interactions between two brain regions is to first create nodal signals by averaging the BOLD signals of all the voxels in each region, and to then measure directed functional interactions between the nodal signals. Another approach, that avoids averaging, is to measure directed functional interactions between all pairwise combinations of voxels in the two regions. Here we employ an alternative approach that avoids the drawbacks of both averaging and pairwise voxel measures. In this approach, we first use the Least Absolute Shrinkage Selection Operator (LASSO) to pre-select voxels for analysis, then compute a Multivariate Vector AutoRegressive (MVAR) model from the time series of the selected voxels, and finally compute summary Granger Causality (GC) statistics from the model to represent directed interregional interactions. We demonstrate the effectiveness of this approach on both simulated and empirical fMRI data. We also show that averaging regional BOLD activity to create a nodal signal may lead to biased GC estimation of directed interregional interactions. The approach presented here makes it feasible to compute GC between brain regions without the need for averaging. Our results suggest that in the analysis of functional brain networks, careful consideration must be given to the way that network nodes and edges are defined because those definitions may have important implications for the validity of the analysis.

Dynamic activation of frontal, parietal, and sensory regions underlying anticipatory visual spatial attention.

Although it is well established that multiple frontal, parietal, and occipital regions in humans are involved in anticipatory deployment of visual spatial attention, less is known about the electrophysiological signals in each region across multiple subsecond periods of attentional deployment. We used MEG measures of cortical stimulus-locked, signal-averaged (event-related field) activity during a task in which a symbolic cue directed covert attention to the relevant location on each trial. Direction-specific attention effects occurred in different cortical regions for each of multiple time periods during the delay between the cue and imperative stimulus. A sequence of activation from V1/V2 to extrastriate, parietal, and frontal regions occurred within 110 ms after cue, possibly related to extraction of cue meaning. Direction-specific activations ∼300 ms after cue in frontal eye field (FEF), lateral intraparietal area (LIP), and cuneus support early covert targeting of the cued location. This was followed by coactivation of a frontal-parietal system [superior frontal gyrus (SFG), middle frontal gyrus (MFG), LIP, anterior intraparietal sulcus (IPSa)] that may coordinate the transition from targeting the cued location to sustained deployment of attention to both space and feature in the last period. The last period involved direction-specific activity in parietal regions and both dorsal and ventral sensory regions [LIP, IPSa, ventral IPS, lateral occipital region, and fusiform gyrus], which was accompanied by activation that was not direction specific in right hemisphere frontal regions (FEF, SFG, MFG). Behavioral performance corresponded with the magnitude of attention-related activity in different brain regions at each time period during deployment. The results add to the emerging electrophysiological characterization of different cortical networks that operate during anticipatory deployment of visual spatial attention.

Wiener-Granger causality: a well established methodology.

For decades, the main ways to study the effect of one part of the nervous system upon another have been either to stimulate or lesion the first part and investigate the outcome in the second. This article describes a fundamentally different approach to identifying causal connectivity in neuroscience: a focus on the predictability of ongoing activity in one part from that in another. This approach was made possible by a new method that comes from the pioneering work of Wiener (1956) and Granger (1969). The Wiener-Granger method, unlike stimulation and ablation, does not require direct intervention in the nervous system. Rather, it relies on the estimation of causal statistical influences between simultaneously recorded neural time series data, either in the absence of identifiable behavioral events or in the context of task performance. Causality in the Wiener-Granger sense is based on the statistical predictability of one time series that derives from knowledge of one or more others. This article defines Wiener-Granger Causality, discusses its merits and limitations in neuroscience, and outlines recent developments in its implementation.

Brain Synchronization and Multivariate Autoregressive (MVAR) Modeling in Cognitive Neurodynamics.

This paper is a review of cognitive neurodynamics research as it pertains to recent advances in Multivariate Autoregressive (MVAR) modeling. Long-range synchronization between the frontoparietal network (FPN) and forebrain subcortical systems occurs when multiple neuronal actions are coordinated across time (Chafee and Goldman-Rakic, 1998), resulting in large-scale measurable activity in the EEG. This paper reviews the power and advantages of the MVAR method to analyze long-range synchronization between brain regions (Kaminski et al., 2016; Kaminski and Blinowska, 2017). It explores the synchronization expressed in neurocognitive networks that is observable in the local field potential (LFP), an EEG-like signal, and in fMRI time series. In recent years, the surge in MVAR modeling in cognitive neurodynamics experiments has highlighted the effectiveness of the method, particularly in analyzing continuous neural signals such as EEG and fMRI (Pereda et al., 2005). MVAR modeling has been particularly useful in identifying causality, a multichannel time-series measure that can only be consistently computed with multivariate processes. Due to the multivariate nature of neuronal communication, multiple non-linear multivariate-analysis models are successful, presenting results with much greater accuracy and speed than non-linear univariate-analysis methods. Granger's framework provides causal information about neuronal flow using neural time and frequency analysis, comprising the basis of the MVAR model. Recent advancements in MVAR modeling have included Directed Transfer Function (DTF) and Partial Directed Coherence (PDC), multivariate methods based on MVAR modeling that are capable of determining causal influences and directed propagation of EEG activity. The related Granger causality is an increasingly popular tool for measuring directed functional interactions from time series data.

Identifying true cortical interactions in MEG using the nulling beamformer.

Modeling functional brain interaction networks using non-invasive EEG and MEG data is more challenging than using intracranial recording data. This is because most interaction measures are not robust to the cross-talk (interference) between cortical regions, which may arise due to the limited spatial resolution of EEG/MEG inverse procedures. In this article, we describe a modified beamforming approach to accurately measure cortical interactions from EEG/MEG data, designed to suppress cross-talk between cortical regions. We estimate interaction measures from the output of the modified beamformer and test for statistical significance using permutation tests. Since the underlying neuronal sources and their interactions are unknown in real MEG data, we demonstrate the performance of the proposed beamforming method in a novel simulation scheme, where intracranial recordings from a macaque monkey are used as neural sources to simulate realistic MEG signals. The advantage of this approach is that local field potentials are more realistic representations of true neuronal sources than simulation models and therefore are more suitable to indicate the performance of our nulling beamforming method.

ALE meta-analysis, its role in node identification and the effects on estimates of local network organization.

Functional connectivity analyses for task-based fMRI data are generally preceded by methods for identification of network nodes. As there is no general canonical approach to identifying network nodes, different identification techniques may exert different effects on inferences drawn regarding functional network properties. Here, we compared the impact of two different node identification techniques on estimates of local node importance (based on Degree Centrality, DC) in two working memory domains: verbal and visual. The two techniques compared were the commonly used Activation Likelihood Estimate (ALE) technique (with node locations based on data aggregation), against a hybrid technique, Experimentally Derived Estimation (EDE). In the latter, ALE was first used to isolate regions of interest; then participant-specific nodes were identified based on individual-participant local maxima. Time series were extracted at each node for each dataset and subsequently used in functional connectivity analysis to: (1) assess the impact of choice of technique on estimates of DC, and (2) assess the difference between the techniques in the ranking of nodes (based on DC) in the networks they produced. In both domains, we found a significant Technique by Node interaction, signifying that the two techniques yielded networks with different DC estimates. Moreover, for the majority of participants, node rankings were uncorrelated between the two techniques (85% for the verbal working memory task and 92% for the visual working memory task). The latter effect is direct evidence that the identification techniques produced different rankings at the level of individual participants. These results indicate that node choice in task-based fMRI data exerts downstream effects that will impact interpretation and reverse inference regarding brain function.

Top-down control of human visual cortex by frontal and parietal cortex in anticipatory visual spatial attention.

Advance information about an impending stimulus facilitates its subsequent identification and ensuing behavioral responses. This facilitation is thought to be mediated by top-down control signals from frontal and parietal cortex that modulate sensory cortical activity. Here we show, using Granger causality measures on blood oxygen level-dependent time series, that frontal eye field (FEF) and intraparietal sulcus (IPS) activity predicts visual occipital activity before an expected visual stimulus. Top-down levels of Granger causality from FEF and IPS to visual occipital cortex were significantly greater than both bottom-up and mean cortex-wide levels in all individual subjects and the group. In the group and most individual subjects, Granger causality was significantly greater from FEF to IPS than from IPS to FEF, and significantly greater from both FEF and IPS to intermediate-tier than lower-tier ventral visual areas. Moreover, top-down Granger causality from right IPS to intermediate-tier areas was predictive of correct behavioral performance. These results suggest that FEF and IPS modulate visual occipital cortex, and FEF modulates IPS, in relation to visual attention. The current approach may prove advantageous for the investigation of interregional directed influences in other human brain functions.

Differential medial temporal lobe and default-mode network functional connectivity and morphometric changes in Alzheimer's disease.

We report group level differential detection of medial temporal lobe resting-state functional connectivity disruption and morphometric changes in the transition from cognitively normal to early mild cognitive impairment in an age-, education- and gender-matched 105 subjects Alzheimer's Disease Neuroimaging Initiative dataset. In mild Alzheimer's Disease, but not early mild cognitive impairment, characteristic brain atrophy was detected in FreeSurfer estimates of subcortical and hippocampal subfield volumes and cortical thinning. By contrast, functional connectivity analysis detected earlier significant changes. In early mild cognitive impairment these changes involved medial temporal lobe regions of transentorhinal, perirhinal and entorhinal cortices (associated with the earliest stages of neurofibrillary changes in Alzheimer's Disease), hippocampus, parahippocampal gyrus and temporal pole, and cortical regions comprising or co-activated with the default-mode network, including rostral and medial prefrontal cortex, anterior cingulate cortex, precuneus and inferior temporal cortex. Key findings include: a) focal, bilaterally symmetric spatial organization of affected medial temporal lobe regions; b) mutual hyperconnectivity involving ventral medial temporal lobe structures (temporal pole, uncus); c) dorsal medial temporal lobe hypoconnectivity with anterior and posterior midline default-mode network nodes; and d) a complex pattern of transient and persistent changes in hypo- and hyper-connectivity across Alzheimer's Disease stages. These findings position medial temporal lobe resting state functional connectivity as a candidate biomarker of an Alzheimer's Disease pathophysiological cascade, potentially in advance of clinical biomarkers, and coincident with biomarkers of the earliest stages of Alzheimer's neuropathology.

Estimating Mental Health Conditions of Patients with Opioid Use Disorder.

OBJECTIVES: Noninvasive estimation of cortical activity aberrance may be a challenge but gives valuable clues of mental health in patients. The goal of the present study was to characterize specificity of electroencephalogram (EEG) electrodes used to assess spectral powers associated with mental health conditions of patients with opioid use disorder. METHODS: This retrospective study included 16 patients who had been diagnosed with opioid use disorder in comparison with 16 sex- and age-matched healthy controls. EEG electrodes were placed in the frontal (FP1, FP2, F3, F4, F7, F8, and Fz), central (C3, C4, and Cz), temporal (T3, T4, T5, and T6), parietal (P3, P4, and Pz), and occipital scalp (O1 and O2). Spectral powers of δ, θ, α, ß, and γ oscillations were determined, and their distribution was topographically mapped with those electrodes on the scalp. RESULTS: Compared to healthy controls, the spectral powers at low frequencies (<8 Hz; δ and θ) were increased in most electrodes across the scalp, while powers at the high frequencies (>12 Hz; ß and γ) were selectively increased only at electrodes located in the frontal and central scalp. Among 19 electrodes, F3, F4, Fz, and Cz were highly specific in detecting increases in δ, θ, ß, and γ powers of patients with opioid use disorders. CONCLUSION: Results of the present study demonstrate that spectral powers are topographically distributed across the scalp, which can be quantitatively characterized. Electrodes located at F3, F4, Fz, and Cz could be specifically utilized to assess mental health in patients with opioid use disorders. Mechanisms responsible for neuroplasticity involving cortical pyramidal neurons and µ-opioid receptor regulations are discussed within the context of changes in EEG microstates.

BSMART: a Matlab/C toolbox for analysis of multichannel neural time series.

We have developed a Matlab/C toolbox, Brain-SMART (System for Multivariate AutoRegressive Time series, or BSMART), for spectral analysis of continuous neural time series data recorded simultaneously from multiple sensors. Available functions include time series data importing/exporting, preprocessing (normalization and trend removal), AutoRegressive (AR) modeling (multivariate/bivariate model estimation and validation), spectral quantity estimation (auto power, coherence and Granger causality spectra), network analysis (including coherence and causality networks) and visualization (including data, power, coherence and causality views). The tools for investigating causal network structures in respect of frequency bands are unique functions provided by this toolbox. All functionality has been integrated into a simple and user-friendly graphical user interface (GUI) environment designed for easy accessibility. Although we have tested the toolbox only on Windows and Linux operating systems, BSMART itself is system independent. This toolbox is freely available (http://www.brain-smart.org) under the GNU public license for open source development.

Top-down beta oscillatory signaling conveys behavioral context in early visual cortex.

Top-down modulation of sensory processing is a critical neural mechanism subserving numerous important cognitive roles, one of which may be to inform lower-order sensory systems of the current 'task at hand' by conveying behavioral context to these systems. Accumulating evidence indicates that top-down cortical influences are carried by directed interareal synchronization of oscillatory neuronal populations, with recent results pointing to beta-frequency oscillations as particularly important for top-down processing. However, it remains to be determined if top-down beta-frequency oscillations indeed convey behavioral context. We measured spectral Granger Causality (sGC) using local field potentials recorded from microelectrodes chronically implanted in visual areas V1/V2, V4, and TEO of two rhesus macaque monkeys, and applied multivariate pattern analysis to the spatial patterns of top-down sGC. We decoded behavioral context by discriminating patterns of top-down (V4/TEO-to-V1/V2) beta-peak sGC for two different task rules governing correct responses to identical visual stimuli. The results indicate that top-down directed influences are carried to visual cortex by beta oscillations, and differentiate task demands even before visual stimulus processing. They suggest that top-down beta-frequency oscillatory processes coordinate processing of sensory information by conveying global knowledge states to early levels of the sensory cortical hierarchy independently of bottom-up stimulus-driven processing.