State-transition dynamics of resting-state functional magnetic resonance imaging data: model comparison and test-to-retest analysis.

Electroencephalogram (EEG) microstate analysis entails finding dynamics of quasi-stable and generally recurrent discrete states in multichannel EEG time series data and relating properties of the estimated state-transition dynamics to observables such as cognition and behavior. While microstate analysis has been widely employed to analyze EEG data, its use remains less prevalent in functional magnetic resonance imaging (fMRI) data, largely due to the slower timescale of such data. In the present study, we extend various data clustering methods used in EEG microstate analysis to resting-state fMRI data from healthy humans to extract their state-transition dynamics. We show that the quality of clustering is on par with that for various microstate analyses of EEG data. We then develop a method for examining test-retest reliability of the discrete-state transition dynamics between fMRI sessions and show that the within-participant test-retest reliability is higher than between-participant test-retest reliability for different indices of state-transition dynamics, different networks, and different data sets. This result suggests that state-transition dynamics analysis of fMRI data could discriminate between different individuals and is a promising tool for performing fingerprinting analysis of individuals.

Single trial variability in neural activity during a working memory task reveals multiple distinct information processing sequences.

Successful encoding, maintenance, and retrieval of information stored in working memory requires persistent coordination of activity among multiple brain regions. It is generally assumed that the pattern of such coordinated activity remains consistent for a given task. Thus, to separate this task-relevant signal from noise, multiple trials of the same task are completed, and the neural response is averaged across trials to generate an event-related potential (ERP). However, from trial to trial, the neuronal activity recorded with electroencephalogram (EEG) is actually spatially and temporally diverse, conflicting with the assumption of a single pattern of activity for a given task. Here, we show that variability in neuronal activity among single time-locked trials arises from the presence of multiple forms of stimulus dependent synchronized activity (i.e., distinct ERPs). We develop a data-driven classification method based on community detection to identify three discrete spatio-temporal clusters, or subtypes, of trials with different patterns of activation that are further associated with differences in decision-making processes. These results demonstrate that differences in the patterns of neural activity during working memory tasks represent fluctuations in the engagement of distinct brain networks and cognitive processes, suggesting that the brain can choose from multiple mechanisms to perform a given task.

Kainate receptors modulate the microstructure of synchrony during dentate gyrus epileptiform activity.

Temporal Lobe Epilepsy (TLE) is the most common form of epilepsy in adults. In TLE, recurrent mossy fiber (rMF) sprouting from dentate gyrus granule cells (DGCs) forms an aberrant epileptogenic network between dentate granule cells (DGCs) that operates via ectopically expressed kainate receptors (KARs). It was previously shown that KARs expressed at the rMF-DGC synapses play a prominent role in epileptiform network events in TLE. However, it is not well understood how KARs influence neuronal network dynamics and contribute to the generation of epileptiform network activity in the dentate gyrus. To address this question, we monitored the activity of DGCs using single-cell resolution calcium imaging performed in a reliable in vitro model of TLE. Under our experimental conditions, the most prominent DGC activity patterns were interictal-like epileptiform network events, which were correlated with high levels of neuronal synchronization. The pharmacological blockade of KARs reduced the frequency as well as the number of neurons involved in these events, without altering their spatiotemporal dynamics. Analysis of the microstructure of synchrony showed that blockade of KARs diminished the fraction of neurons forming the main functional cluster. Therefore, we propose that KARs act as modulators in the epileptic network by facilitating the recruitment of neurons into coactive cell assemblies, thereby contributing to the occurrence of epileptiform network events.

Interneuron Desynchronization Precedes Seizures in a Mouse Model of Dravet Syndrome.

Recurrent seizures, which define epilepsy, are transient abnormalities in the electrical activity of the brain. The mechanistic basis of seizure initiation, and the contribution of defined neuronal subtypes to seizure pathophysiology, remains poorly understood. We performed in vivo two-photon calcium imaging in neocortex during temperature-induced seizures in male and female Dravet syndrome (Scn1a+/-) mice, a neurodevelopmental disorder with prominent temperature-sensitive epilepsy. Mean activity of both putative principal cells and parvalbumin-positive interneurons (PV-INs) was higher in Scn1a+/- relative to wild-type controls during quiet wakefulness at baseline and at elevated core body temperature. However, wild-type PV-INs showed a progressive synchronization in response to temperature elevation that was absent in PV-INs from Scn1a+/- mice. Hence, PV-IN activity remains intact interictally in Scn1a+/- mice, yet exhibits decreased synchrony immediately before seizure onset. We suggest that impaired PV-IN synchronization may contribute to the transition to the ictal state during temperature-induced seizures in Dravet syndrome.SIGNIFICANCE STATEMENT Epilepsy is a common neurological disorder defined by recurrent, unprovoked seizures. However, basic mechanisms of seizure initiation and propagation remain poorly understood. We performed in vivo two-photon calcium imaging in an experimental model of Dravet syndrome (Scn1a+/- mice)-a severe neurodevelopmental disorder defined by temperature-sensitive, treatment-resistant epilepsy-and record activity of putative excitatory neurons and parvalbumin-positive GABAergic neocortical interneurons (PV-INs) during naturalistic seizures induced by increased core body temperature. PV-IN activity was higher in Scn1a+/- relative to wild-type controls during quiet wakefulness. However, wild-type PV-INs showed progressive synchronization in response to temperature elevation that was absent in PV-INs from Scn1a+/- mice before seizure onset. Hence, impaired PV-IN synchronization may contribute to transition to seizure in Dravet syndrome.

Scale-specific dynamics of high-amplitude bursts in EEG capture behaviorally meaningful variability.

Cascading high-amplitude bursts in neural activity, termed avalanches, are thought to provide insight into the complex spatially distributed interactions in neural systems. In human neuroimaging, for example, avalanches occurring during resting-state show scale-invariant dynamics, supporting the hypothesis that the brain operates near a critical point that enables long range spatial communication. In fact, it has been suggested that such scale-invariant dynamics, characterized by a power-law distribution in these avalanches, are universal in neural systems and emerge through a common mechanism. While the analysis of avalanches and subsequent criticality is increasingly seen as a framework for using complex systems theory to understand brain function, it is unclear how the framework would account for the omnipresent cognitive variability, whether across individuals or tasks. To address this, we analyzed avalanches in the EEG activity of healthy humans during rest as well as two distinct task conditions that varied in cognitive demands and produced behavioral measures unique to each individual. In both rest and task conditions we observed that avalanche dynamics demonstrate scale-invariant characteristics, but differ in their specific features, demonstrating individual variability. Using a new metric we call normalized engagement, which estimates the likelihood for a brain region to produce high-amplitude bursts, we also investigated regional features of avalanche dynamics. Normalized engagement showed not only the expected individual and task dependent variability, but also scale-specificity that correlated with individual behavior. Our results suggest that the study of avalanches in human brain activity provides a tool to assess cognitive variability. Our findings expand our understanding of avalanche features and are supportive of the emerging theoretical idea that the dynamics of an active human brain operate close to a critical-like region and not a singular critical-state.

Structure, function, and control of the human musculoskeletal network.

The human body is a complex organism, the gross mechanical properties of which are enabled by an interconnected musculoskeletal network controlled by the nervous system. The nature of musculoskeletal interconnection facilitates stability, voluntary movement, and robustness to injury. However, a fundamental understanding of this network and its control by neural systems has remained elusive. Here we address this gap in knowledge by utilizing medical databases and mathematical modeling to reveal the organizational structure, predicted function, and neural control of the musculoskeletal system. We constructed a highly simplified whole-body musculoskeletal network in which single muscles connect to multiple bones via both origin and insertion points. We demonstrated that, using this simplified model, a muscle's role in this network could offer a theoretical prediction of the susceptibility of surrounding components to secondary injury. Finally, we illustrated that sets of muscles cluster into network communities that mimic the organization of control modules in primary motor cortex. This novel formalism for describing interactions between the muscular and skeletal systems serves as a foundation to develop and test therapeutic responses to injury, inspiring future advances in clinical treatments.

Data-driven brain network models differentiate variability across language tasks.

The relationship between brain structure and function has been probed using a variety of approaches, but how the underlying structural connectivity of the human brain drives behavior is far from understood. To investigate the effect of anatomical brain organization on human task performance, we use a data-driven computational modeling approach and explore the functional effects of naturally occurring structural differences in brain networks. We construct personalized brain network models by combining anatomical connectivity estimated from diffusion spectrum imaging of individual subjects with a nonlinear model of brain dynamics. By performing computational experiments in which we measure the excitability of the global brain network and spread of synchronization following a targeted computational stimulation, we quantify how individual variation in the underlying connectivity impacts both local and global brain dynamics. We further relate the computational results to individual variability in the subjects' performance of three language-demanding tasks both before and after transcranial magnetic stimulation to the left-inferior frontal gyrus. Our results show that task performance correlates with either local or global measures of functional activity, depending on the complexity of the task. By emphasizing differences in the underlying structural connectivity, our model serves as a powerful tool to assess individual differences in task performances, to dissociate the effect of targeted stimulation in tasks that differ in cognitive demand, and to pave the way for the development of personalized therapeutics.

Applications of community detection techniques to brain graphs: Algorithmic considerations and implications for neural function.

The human brain can be represented as a graph in which neural units such as cells or small volumes of tissue are heterogeneously connected to one another through structural or functional links. Brain graphs are parsimonious representations of neural systems that have begun to offer fundamental insights into healthy human cognition, as well as its alteration in disease. A critical open question in network neuroscience lies in how neural units cluster into densely interconnected groups that can provide the coordinated activity that is characteristic of perception, action, and adaptive behaviors. Tools that have proven particularly useful for addressing this question are community detection approaches, which can identify communities or modules: groups of neural units that are densely interconnected with other units in their own group but sparsely interconnected with units in other groups. In this paper, we describe a common community detection algorithm known as modularity maximization, and we detail its applications to brain graphs constructed from neuroimaging data. We pay particular attention to important algorithmic considerations, especially in recent extensions of these techniques to graphs that evolve in time. After recounting a few fundamental insights that these techniques have provided into brain function, we highlight potential avenues of methodological advancements for future studies seeking to better characterize the patterns of coordinated activity in the brain that accompany human behavior. This tutorial provides a naive reader with an introduction to theoretical considerations pertinent to the generation of brain graphs, an understanding of modularity maximization for community detection, a resource of statistical measures that can be used to characterize community structure, and an appreciation of the usefulness of these approaches in uncovering behaviorally-relevant network dynamics in neuroimaging data.

Within-subject reproducibility varies in multi-modal, longitudinal brain networks.

Network neuroscience provides important insights into brain function by analyzing complex networks constructed from diffusion Magnetic Resonance Imaging (dMRI), functional MRI (fMRI) and Electro/Magnetoencephalography (E/MEG) data. However, in order to ensure that results are reproducible, we need a better understanding of within- and between-subject variability over long periods of time. Here, we analyze a longitudinal, 8 session, multi-modal (dMRI, and simultaneous EEG-fMRI), and multiple task imaging data set. We first confirm that across all modalities, within-subject reproducibility is higher than between-subject reproducibility. We see high variability in the reproducibility of individual connections, but observe that in EEG-derived networks, during both rest and task, alpha-band connectivity is consistently more reproducible than connectivity in other frequency bands. Structural networks show a higher reliability than functional networks across network statistics, but synchronizability and eigenvector centrality are consistently less reliable than other network measures across all modalities. Finally, we find that structural dMRI networks outperform functional networks in their ability to identify individuals using a fingerprinting analysis. Our results highlight that functional networks likely reflect state-dependent variability not present in structural networks, and that the type of analysis should depend on whether or not one wants to take into account state-dependent fluctuations in connectivity.

Differential Patterns of Change in Brain Connectivity Resulting from Severe Traumatic Brain Injury.

Background: Traumatic brain injury (TBI) damages white matter tracts, disrupting brain network structure and communication. There exists a wide heterogeneity in the pattern of structural damage associated with injury, as well as a large heterogeneity in behavioral outcomes. However, little is known about the relationship between changes in network connectivity and clinical outcomes. Materials and Methods: We utilize the rat lateral fluid-percussion injury model of severe TBI to study differences in brain connectivity in 8 animals that received the insult and 11 animals that received only a craniectomy. Diffusion tensor imaging is performed 5 weeks after the injury and network theory is used to investigate changes in white matter connectivity. Results: We find that (1) global network measures are not able to distinguish between healthy and injured animals; (2) injury induced alterations predominantly exist in a subset of connections (subnetworks) distributed throughout the brain; and (3) injured animals can be divided into subgroups based on changes in network motifs-measures of local structural connectivity. In addition, alterations in predicted functional connectivity indicate that the subgroups have different propensities to synchronize brain activity, which could relate to the heterogeneity of clinical outcomes. Discussion: These results suggest that network measures can be used to quantify progressive changes in brain connectivity due to injury and differentiate among subpopulations with similar injuries, but different pathological trajectories.

Data-driven computational modeling predicts "superhubs" play key role in epileptic dynamics.

How individual neurons influence epileptic networks remains an open question. In this issue of Neuron, Hadjiabadi et al. (2021) use data-driven, computational models to predict the presence of "superhubs": highly connected neurons that drive network activity through feedforward motifs.

Quantitative systems pharmacology in neuroscience: Novel methodologies and technologies.

The development and application of quantitative systems pharmacology models in neuroscience have been modest relative to other fields, such as oncology and immunology, which may reflect the complexity of the brain. Technological and methodological advancements have enhanced the quantitative understanding of brain physiology and pathophysiology and the effects of pharmacological interventions. To maximize the knowledge gained from these novel data types, pharmacometrics modelers may need to expand their toolbox to include additional mathematical and statistical frameworks. A session was held at the 10th annual American Conference on Pharmacometrics (ACoP10) to highlight several recent advancements in quantitative and systems neuroscience. In this mini-review, we provide a brief overview of technological and methodological advancements in the neuroscience therapeutic area that were discussed during the session and how these can be leveraged with quantitative systems pharmacology modeling to enhance our understanding of neurological diseases. Microphysiological systems using human induced pluripotent stem cells (IPSCs), digital biomarkers, and large-scale imaging offer more clinically relevant experimental datasets, enhanced granularity, and a plethora of data to potentially improve the preclinical-to-clinical translation of therapeutics. Network neuroscience methodologies combined with quantitative systems models of neurodegenerative disease could help bridge the gap between cellular and molecular alterations and clinical end points through the integration of information on neural connectomics. Additional topics, such as the neuroimmune system, microbiome, single-cell transcriptomic technologies, and digital device biomarkers, are discussed in brief.

Cognitive chimera states in human brain networks.

The human brain is a complex dynamical system, and how cognition emerges from spatiotemporal patterns of regional brain activity remains an open question. As different regions dynamically interact to perform cognitive tasks, variable patterns of partial synchrony can be observed, forming chimera states. We propose that the spatial patterning of these states plays a fundamental role in the cognitive organization of the brain and present a cognitively informed, chimera-based framework to explore how large-scale brain architecture affects brain dynamics and function. Using personalized brain network models, we systematically study how regional brain stimulation produces different patterns of synchronization across predefined cognitive systems. We analyze these emergent patterns within our framework to understand the impact of subject-specific and region-specific structural variability on brain dynamics. Our results suggest a classification of cognitive systems into four groups with differing levels of subject and regional variability that reflect their different functional roles.

Locally stable brain states predict suppression of epileptic activity by enhanced cognitive effort.

Cognitive effort is known to play a role in healthy brain state organization, but little is known about its effects on pathological brain dynamics. When cortical stimulation is used to map functional brain areas prior to surgery, a common unwanted side effect is the appearance of afterdischarges (ADs), epileptiform and potentially epileptogenic discharges that can progress to a clinical seizure. It is therefore desirable to suppress this activity. Here, we analyze electrocorticography recordings from 15 patients with epilepsy. We show that a cognitive intervention in the form of asking an arithmetic question can be effective in suppressing ADs, but that its effectiveness is dependent upon the brain state at the time of intervention. By applying novel techniques from network analysis to quantify brain states, we find that the spatial organization of ADs with respect to coherent brain regions relates to the success of the cognitive intervention: if ADs are mainly localized within a single stable brain region, a cognitive intervention is likely to suppress the ADs. These findings show that cognitive effort is a useful tactic to modify unstable pathological activity associated with epilepsy, and suggest that the success of therapeutic interventions to alter activity may depend on an individual's brain state at the time of intervention.

The Energy Landscape of Neurophysiological Activity Implicit in Brain Network Structure.

A critical mystery in neuroscience lies in determining how anatomical structure impacts the complex functional dynamics of the brain. How does large-scale brain circuitry constrain states of neuronal activity and transitions between those states? We address these questions using a maximum entropy model of brain dynamics informed by white matter tractography. We demonstrate that the most probable brain states - characterized by minimal energy - display common activation profiles across brain areas: local spatially-contiguous sets of brain regions reminiscent of cognitive systems are co-activated frequently. The predicted activation rate of these systems is highly correlated with the observed activation rate measured in a separate resting state fMRI data set, validating the utility of the maximum entropy model in describing neurophysiological dynamics. This approach also offers a formal notion of the energy of activity within a system, and the energy of activity shared between systems. We observe that within- and between-system energies cleanly separate cognitive systems into distinct categories, optimized for differential contributions to integrated versus segregated function. These results support the notion that energetic and structural constraints circumscribe brain dynamics, offering insights into the roles that cognitive systems play in driving whole-brain activation patterns.

The role of inhibition in epileptic networks.

Inhibition plays many roles in cortical circuits, including coordination of network activity in different brain rhythms and neuronal clusters, gating of activity, gain control, and dictating the manner in which activity flows through the network. This latter is particularly relevant to epileptic states, when extreme hypersynchronous discharges can spread across cortical territories. We review these different physiological and pathological roles and discuss how inhibition can be compromised and why this predisposes the network to seizures.