WITHDRAWN: Dynamic functional connectivity: Why the controversy?

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Dissecting unsupervised learning through hidden Markov modeling in electrophysiological data.

Unsupervised, data-driven methods are commonly used in neuroscience to automatically decompose data into interpretable patterns. These patterns differ from one another depending on the assumptions of the models. How these assumptions affect specific data decompositions in practice, however, is often unclear, which hinders model applicability and interpretability. For instance, the hidden Markov model (HMM) automatically detects characteristic, recurring activity patterns (so-called states) from time series data. States are defined by a certain probability distribution, whose state-specific parameters are estimated from the data. But what specific features, from all of those that the data contain, do the states capture? That depends on the choice of probability distribution and on other model hyperparameters. Using both synthetic and real data, we aim to better characterize the behavior of two HMM types that can be applied to electrophysiological data. Specifically, we study which differences in data features (such as frequency, amplitude, or signal-to-noise ratio) are more salient to the models and therefore more likely to drive the state decomposition. Overall, we aim at providing guidance for the appropriate use of this type of analysis on one- or two-channel neural electrophysiological data and an informed interpretation of its results given the characteristics of the data and the purpose of the analysis.NEW & NOTEWORTHY Compared with classical supervised methods, unsupervised methods of analysis have the advantage to be freer of subjective biases. However, it is not always clear what aspects of the data these methods are most sensitive to, which complicates interpretation. Focusing on the hidden Markov model, commonly used to describe electrophysiological data, we explore in detail the nature of its estimates through simulations and real data examples, providing important insights about what to expect from these models.

Balance between competing spectral states in subthalamic nucleus is linked to motor impairment in Parkinson's disease.

Exaggerated local field potential bursts of activity at frequencies in the low beta band are a well-established phenomenon in the subthalamic nucleus of patients with Parkinson's disease. However, such activity is only moderately correlated with motor impairment. Here we test the hypothesis that beta bursts are just one of several dynamic states in the subthalamic nucleus local field potential in Parkinson's disease, and that together these different states predict motor impairment with high fidelity. Local field potentials were recorded in 32 patients (64 hemispheres) undergoing deep brain stimulation surgery targeting the subthalamic nucleus. Recordings were performed following overnight withdrawal of anti-parkinsonian medication, and after administration of levodopa. Local field potentials were analysed using hidden Markov modelling to identify transient spectral states with frequencies under 40 Hz. Findings in the low beta frequency band were similar to those previously reported; levodopa reduced occurrence rate and duration of low beta states, and the greater the reductions, the greater the improvement in motor impairment. However, additional local field potential states were distinguished in the theta, alpha and high beta bands, and these behaved in an opposite manner. They were increased in occurrence rate and duration by levodopa, and the greater the increases, the greater the improvement in motor impairment. In addition, levodopa favoured the transition of low beta states to other spectral states. When all local field potential states and corresponding features were considered in a multivariate model it was possible to predict 50% of the variance in patients' hemibody impairment OFF medication, and in the change in hemibody impairment following levodopa. This only improved slightly if signal amplitude or gamma band features were also included in the multivariate model. In addition, it compares with a prediction of only 16% of the variance when using beta bursts alone. We conclude that multiple spectral states in the subthalamic nucleus local field potential have a bearing on motor impairment, and that levodopa-induced shifts in the balance between these states can predict clinical change with high fidelity. This is important in suggesting that some states might be upregulated to improve parkinsonism and in suggesting how local field potential feedback can be made more informative in closed-loop deep brain stimulation systems.

The relationship between frequency content and representational dynamics in the decoding of neurophysiological data.

Decoding of high temporal resolution, stimulus-evoked neurophysiological data is increasingly used to test theories about how the brain processes information. However, a fundamental relationship between the frequency spectra of the neural signal and the subsequent decoding accuracy timecourse is not widely recognised. We show that, in commonly used instantaneous signal decoding paradigms, each sinusoidal component of the evoked response is translated to double its original frequency in the subsequent decoding accuracy timecourses. We therefore recommend, where researchers use instantaneous signal decoding paradigms, that more aggressive low pass filtering is applied with a cut-off at one quarter of the sampling rate, to eliminate representational alias artefacts. However, this does not negate the accompanying interpretational challenges. We show that these can be resolved by decoding paradigms that utilise both a signal's instantaneous magnitude and its local gradient information as features for decoding. On a publicly available MEG dataset, this results in decoding accuracy metrics that are higher, more stable over time, and free of the technical and interpretational challenges previously characterised. We anticipate that a broader awareness of these fundamental relationships will enable stronger interpretations of decoding results by linking them more clearly to the underlying signal characteristics that drive them.

Spatiotemporally resolved multivariate pattern analysis for M/EEG.

An emerging goal in neuroscience is tracking what information is represented in brain activity over time as a participant completes some task. While electroencephalography (EEG) and magnetoencephalography (MEG) offer millisecond temporal resolution of how activity patterns emerge and evolve, standard decoding methods present significant barriers to interpretability as they obscure the underlying spatial and temporal activity patterns. We instead propose the use of a generative encoding model framework that simultaneously infers the multivariate spatial patterns of activity and the variable timing at which these patterns emerge on individual trials. An encoding model inversion maps from these parameters to the equivalent decoding model, allowing predictions to be made about unseen test data in the same way as in standard decoding methodology. These SpatioTemporally Resolved MVPA (STRM) models can be flexibly applied to a wide variety of experimental paradigms, including classification and regression tasks. We show that these models provide insightful maps of the activity driving predictive accuracy metrics; demonstrate behaviourally meaningful variation in the timing of pattern emergence on individual trials; and achieve predictive accuracies that are either equivalent or surpass those achieved by more widely used methods. This provides a new avenue for investigating the brain's representational dynamics and could ultimately support more flexible experimental designs in the future.

Effective psychological therapy for PTSD changes the dynamics of specific large-scale brain networks.

In posttraumatic stress disorder (PTSD), re-experiencing of the trauma is a hallmark symptom proposed to emerge from a de-contextualised trauma memory. Cognitive therapy for PTSD (CT-PTSD) addresses this de-contextualisation through different strategies. At the brain level, recent research suggests that the dynamics of specific large-scale brain networks play an essential role in both the healthy response to a threatening situation and the development of PTSD. However, very little is known about how these dynamics are altered in the disorder and rebalanced after treatment and successful recovery. Using a data-driven approach and fMRI, we detected recurring large-scale brain functional states with high temporal precision in a population of healthy trauma-exposed and PTSD participants before and after successful CT-PTSD. We estimated the total amount of time that each participant spent on each of the states while being exposed to trauma-related and neutral pictures. We found that PTSD participants spent less time on two default mode subnetworks involved in different forms of self-referential processing in contrast to PTSD participants after CT-PTSD (mtDMN+ and dmDMN+ ) and healthy trauma-exposed controls (only mtDMN+ ). Furthermore, re-experiencing severity was related to decreased time spent on the default mode subnetwork involved in contextualised retrieval of autobiographical memories, and increased time spent on the salience and visual networks. Overall, our results support the hypothesis that PTSD involves an imbalance in the dynamics of specific large-scale brain network states involved in self-referential processes and threat detection, and suggest that successful CT-PTSD might rebalance this dynamic aspect of brain function.

A new model for simultaneous dimensionality reduction and time-varying functional connectivity estimation.

An important question in neuroscience is whether or not we can interpret spontaneous variations in the pattern of correlation between brain areas, which we refer to as functional connectivity or FC, as an index of dynamic neuronal communication in fMRI. That is, can we measure time-varying FC reliably? And, if so, can FC reflect information transfer between brain regions at relatively fast-time scales? Answering these questions in practice requires dealing with the statistical challenge of having high-dimensional data and a comparatively lower number of time points or volumes. A common strategy is to use PCA to reduce the dimensionality of the data, and then apply some model, such as the hidden Markov model (HMM) or a mixture model of Gaussian distributions, to find a set of distinct FC patterns or states. The distinct spatial properties of these FC states together with the time-resolved switching between them offer a flexible description of time-varying FC. In this work, I show that in this context PCA can suffer from systematic biases and loss of sensitivity for the purposes of finding time-varying FC. To get around these issues, I propose a novel variety of the HMM, named HMM-PCA, where the states are themselves PCA decompositions. Since PCA is based on the data covariance, the state-specific PCA decompositions reflect distinct patterns of FC. I show, theoretically and empirically, that fusing dimensionality reduction and time-varying FC estimation in one single step can avoid these problems and outperform alternative approaches, facilitating the quantification of transient communication in the brain.

Dissociable Components of Information Encoding in Human Perception.

Brain decoding can predict visual perception from non-invasive electrophysiological data by combining information across multiple channels. However, decoding methods typically conflate the composite and distributed neural processes underlying perception that are together present in the signal, making it unclear what specific aspects of the neural computations involved in perception are reflected in this type of macroscale data. Using MEG data recorded while participants viewed a large number of naturalistic images, we analytically decomposed the brain signal into its oscillatory and non-oscillatory components, and used this decomposition to show that there are at least three dissociable stimulus-specific aspects to the brain data: a slow, non-oscillatory component, reflecting the temporally stable aspect of the stimulus representation; a global phase shift of the oscillation, reflecting the overall speed of processing of specific stimuli; and differential patterns of phase across channels, likely reflecting stimulus-specific computations. Further, we show that common cognitive interpretations of decoding analysis, in particular about how representations generalize across time, can benefit from acknowledging the multicomponent nature of the signal in the study of perception.

Learning patterns of the ageing brain in MRI using deep convolutional networks.

Both normal ageing and neurodegenerative diseases cause morphological changes to the brain. Age-related brain changes are subtle, nonlinear, and spatially and temporally heterogenous, both within a subject and across a population. Machine learning models are particularly suited to capture these patterns and can produce a model that is sensitive to changes of interest, despite the large variety in healthy brain appearance. In this paper, the power of convolutional neural networks (CNNs) and the rich UK Biobank dataset, the largest database currently available, are harnessed to address the problem of predicting brain age. We developed a 3D CNN architecture to predict chronological age, using a training dataset of 12,802 T1-weighted MRI images and a further 6,885 images for testing. The proposed method shows competitive performance on age prediction, but, most importantly, the CNN prediction errors ΔBrainAge=AgePredicted-AgeTrue correlated significantly with many clinical measurements from the UK Biobank in the female and male groups. In addition, having used images from only one imaging modality in this experiment, we examined the relationship between ΔBrainAge and the image-derived phenotypes (IDPs) from all other imaging modalities in the UK Biobank, showing correlations consistent with known patterns of ageing. Furthermore, we show that the use of nonlinearly registered images to train CNNs can lead to the network being driven by artefacts of the registration process and missing subtle indicators of ageing, limiting the clinical relevance. Due to the longitudinal aspect of the UK Biobank study, in the future it will be possible to explore whether the ΔBrainAge from models such as this network were predictive of any health outcomes.

Transient visual pathway critical for normal development of primate grasping behavior.

An evolutionary hallmark of anthropoid primates, including humans, is the use of vision to guide precise manual movements. These behaviors are reliant on a specialized visual input to the posterior parietal cortex. Here, we show that normal primate reaching-and-grasping behavior depends critically on a visual pathway through the thalamic pulvinar, which is thought to relay information to the middle temporal (MT) area during early life and then swiftly withdraws. Small MRI-guided lesions to a subdivision of the inferior pulvinar subnucleus (PIm) in the infant marmoset monkey led to permanent deficits in reaching-and-grasping behavior in the adult. This functional loss coincided with the abnormal anatomical development of multiple cortical areas responsible for the guidance of actions. Our study reveals that the transient retino-pulvinar-MT pathway underpins the development of visually guided manual behaviors in primates that are crucial for interacting with complex features in the environment.

Optimising network modelling methods for fMRI.

A major goal of neuroimaging studies is to develop predictive models to analyze the relationship between whole brain functional connectivity patterns and behavioural traits. However, there is no single widely-accepted standard pipeline for analyzing functional connectivity. The common procedure for designing functional connectivity based predictive models entails three main steps: parcellating the brain, estimating the interaction between defined parcels, and lastly, using these integrated associations between brain parcels as features fed to a classifier for predicting non-imaging variables e.g., behavioural traits, demographics, emotional measures, etc. There are also additional considerations when using correlation-based measures of functional connectivity, resulting in three supplementary steps: utilising Riemannian geometry tangent space parameterization to preserve the geometry of functional connectivity; penalizing the connectivity estimates with shrinkage approaches to handle challenges related to short time-series (and noisy) data; and removing confounding variables from brain-behaviour data. These six steps are contingent on each-other, and to optimise a general framework one should ideally examine these various methods simultaneously. In this paper, we investigated strengths and short-comings, both independently and jointly, of the following measures: parcellation techniques of four kinds (categorized further depending upon number of parcels), five measures of functional connectivity, the decision of staying in the ambient space of connectivity matrices or in tangent space, the choice of applying shrinkage estimators, six alternative techniques for handling confounds and finally four novel classifiers/predictors. For performance evaluation, we have selected two of the largest datasets, UK Biobank and the Human Connectome Project resting state fMRI data, and have run more than 9000 different pipeline variants on a total of ∼14000 individuals to determine the optimum pipeline. For independent performance validation, we have run some best-performing pipeline variants on ABIDE and ACPI datasets (∼1000 subjects) to evaluate the generalisability of proposed network modelling methods.

Spontaneous network activity <35 ​Hz accounts for variability in stimulus-induced gamma responses.

Gamma activity is thought to serve several cognitive processes, including attention and memory. Even for the simplest stimulus, the occurrence of gamma activity is highly variable, both within and between individuals. The sources of this variability, however, are largely unknown. In this paper, we address one possible cause: the cross-frequency influence of spontaneous, whole-brain network activity on visual stimulus processing. By applying Hidden Markov modelling to MEG data, we reveal that the trial-averaged gamma response to a moving grating depends on the individual network dynamics, inferred from slower brain activity (<35 â€‹Hz) in the absence of stimulation (resting-state and task baseline). In addition, we demonstrate that modulations of network activity in task baseline influence the gamma response on the level of trials. In summary, our results reveal a cross-frequency and cross-session association between gamma responses induced by visual stimulation and spontaneous network activity. These findings underline the dependency of visual stimulus processing on the individual, functional network architecture.

The role of transient spectral 'bursts' in functional connectivity: A magnetoencephalography study.

Neural oscillations dominate electrophysiological measures of macroscopic brain activity and fluctuations in these rhythms offer an insightful window on cortical excitation, inhibition, and connectivity. However, in recent years the 'classical' picture of smoothly varying oscillations has been challenged by the idea that many 'oscillations' may actually be formed from the recurrence of punctate high-amplitude bursts in activity, whose spectral composition intersects the traditionally defined frequency ranges (e.g. alpha/beta band). This finding offers a new interpretation of measurable brain activity, however neither the methodological means to detect bursts, nor their link to other findings (e.g. connectivity) have been settled. Here, we use a new approach to detect bursts in magnetoencephalography (MEG) data. We show that a time-delay embedded Hidden Markov Model (HMM) can be used to delineate single-region bursts which are in agreement with existing techniques. However, unlike existing techniques, the HMM looks for specific spectral patterns in timecourse data. We characterise the distribution of burst duration, frequency of occurrence and amplitude across the cortex in resting state MEG data. During a motor task we show how the movement related beta decrease and post movement beta rebound are driven by changes in burst occurrence. Finally, we show that the beta band functional connectome can be derived using a simple measure of burst overlap, and that coincident bursts in separate regions correspond to a period of heightened coherence. In summary, this paper offers a new methodology for burst identification and connectivity analysis which will be important for future investigations of neural oscillations.

Temporally Unconstrained Decoding Reveals Consistent but Time-Varying Stages of Stimulus Processing.

In this article, we propose a method to track trial-specific neural dynamics of stimulus processing and decision making with high temporal precision. By applying this novel method to a perceptual template-matching task, we tracked representational brain states associated with the cascade of neural processing, from early sensory areas to higher order areas that are involved in integration and decision making. We address a major limitation of the traditional decoding approach: that it relies on consistent timing of these processes over trials. Using a TUDA approach, we found that the timing of the cognitive processes involved in perceptual judgments can vary considerably over trials. This revealed that the sequence of processing states was consistent for all subjects and trials, even when the timing of these states varied. Furthermore, we found that the specific timing of states on each trial was related to the quality of performance over trials. Altogether, this work not only highlights the serious pitfalls and misleading interpretations that result from assuming stimulus processing to be synchronous across trials but can also open important avenues to investigate learning and quantify plasticity.

Brain network dynamics are hierarchically organized in time.

The brain recruits neuronal populations in a temporally coordinated manner in task and at rest. However, the extent to which large-scale networks exhibit their own organized temporal dynamics is unclear. We use an approach designed to find repeating network patterns in whole-brain resting fMRI data, where networks are defined as graphs of interacting brain areas. We find that the transitions between networks are nonrandom, with certain networks more likely to occur after others. Further, this nonrandom sequencing is itself hierarchically organized, revealing two distinct sets of networks, or metastates, that the brain has a tendency to cycle within. One metastate is associated with sensory and motor regions, and the other involves areas related to higher order cognition. Moreover, we find that the proportion of time that a subject spends in each brain network and metastate is a consistent subject-specific measure, is heritable, and shows a significant relationship with cognitive traits.

Estimation of brain age delta from brain imaging.

It is of increasing interest to study "brain age" - the apparent age of a subject, as inferred from brain imaging data. The difference between brain age and actual age (the "delta") is typically computed, reflecting deviation from the population norm. This therefore may reflect accelerated aging (positive delta) or resilience (negative delta) and has been found to be a useful correlate with factors such as disease and cognitive decline. However, although there has been a range of methods proposed for estimating brain age, there has been little study of the optimal ways of computing the delta. In this technical note we describe problems with the most common current approach, and present potential improvements. We evaluate different estimation methods on simulated and real data. We also find the strongest correlations of corrected brain age delta with 5,792 non-imaging variables (non-brain physical measures, life-factor measures, cognitive test scores, etc.), and also with 2,641 multimodal brain imaging-derived phenotypes, with data from 19,000 participants in UK Biobank.

Stable between-subject statistical inference from unstable within-subject functional connectivity estimates.

Spatial or temporal aspects of neural organization are known to be important indices of how cognition is organized. However, measurements and estimations are often noisy and many of the algorithms used are probabilistic, which in combination have been argued to limit studies exploring the neural basis of specific aspects of cognition. Focusing on static and dynamic functional connectivity estimations, we propose to leverage this variability to improve statistical efficiency in relating these estimations to behavior. To achieve this goal, we use a procedure based on permutation testing that provides a way of combining the results from many individual tests that refer to the same hypothesis. This is needed when testing a measure whose value is obtained from a noisy process, which can be repeated multiple times, referred to as replications. Focusing on functional connectivity, this noisy process can be: (a) computational, for example, when using an approximate inference algorithm for which different runs can produce different results or (b) observational, if we have the capacity to acquire data multiple times, and the different acquired data sets can be considered noisy examples of some underlying truth. In both cases, we are not interested in the individual replications but on the unobserved process generating each replication. In this note, we show how results can be combined instead of choosing just one of the estimated models. Using both simulations and real data, we show the benefits of this approach in practice.

Altered transient brain dynamics in multiple sclerosis: Treatment or pathology?

Multiple sclerosis (MS) is a demyelinating, neuroinflammatory, and -degenerative disease that affects the brain's neurophysiological functioning through brain atrophy, a reduced conduction velocity and decreased connectivity. Currently, little is known on how MS affects the fast temporal dynamics of activation and deactivation of the different large-scale, ongoing brain networks. In this study, we investigated whether these temporal dynamics are affected in MS patients and whether these changes are induced by the pathology or by the use of benzodiazepines (BZDs), an important symptomatic treatment that aims at reducing insomnia, spasticity and anxiety and reinforces the inhibitory effect of GABA. To this aim, we employed a novel method capable of detecting these fast dynamics in 90 MS patients and 46 healthy controls. We demonstrated a less dynamic frontal default mode network in male MS patients and a reduced activation of the same network in female MS patients, regardless of BZD usage. Additionally, BZDs strongly altered the brain's dynamics by increasing the time spent in the deactivating sensorimotor network and the activating occipital network. Furthermore, BZDs induced a decreased power in the theta band and an increased power in the beta band. The latter was strongly expressed in those states without activation of the sensorimotor network. In summary, we demonstrate gender-dependent changes to the brain dynamics in the frontal DMN and strong effects from BZDs. This study is the first to characterise the effect of multiple sclerosis and BZDs in vivo in a spatially, temporally and spectrally defined way.

Unpacking Transient Event Dynamics in Electrophysiological Power Spectra.

Electrophysiological recordings of neuronal activity show spontaneous and task-dependent changes in their frequency-domain power spectra. These changes are conventionally interpreted as modulations in the amplitude of underlying oscillations. However, this overlooks the possibility of underlying transient spectral 'bursts' or events whose dynamics can map to changes in trial-average spectral power in numerous ways. Under this emerging perspective, a key challenge is to perform burst detection, i.e. to characterise single-trial transient spectral events, in a principled manner. Here, we describe how transient spectral events can be operationalised and estimated using Hidden Markov Models (HMMs). The HMM overcomes a number of the limitations of the standard amplitude-thresholding approach to burst detection; in that it is able to concurrently detect different types of bursts, each with distinct spectral content, without the need to predefine frequency bands of interest, and does so with less dependence on a priori threshold specification. We describe how the HMM can be used for burst detection and illustrate its benefits on simulated data. Finally, we apply this method to empirical data to detect multiple burst types in a task-MEG dataset, and illustrate how we can compute burst metrics, such as the task-evoked timecourse of burst duration.

Dynamics of large-scale electrophysiological networks: A technical review.

For several years it has been argued that neural synchronisation is crucial for cognition. The idea that synchronised temporal patterns between different neural groups carries information above and beyond the isolated activity of these groups has inspired a shift in focus in the field of functional neuroimaging. Specifically, investigation into the activation elicited within certain regions by some stimulus or task has, in part, given way to analysis of patterns of co-activation or functional connectivity between distal regions. Recently, the functional connectivity community has been looking beyond the assumptions of stationarity that earlier work was based on, and has introduced methods to incorporate temporal dynamics into the analysis of connectivity. In particular, non-invasive electrophysiological data (magnetoencephalography/electroencephalography (MEG/EEG)), which provides direct measurement of whole-brain activity and rich temporal information, offers an exceptional window into such (potentially fast) brain dynamics. In this review, we discuss challenges, solutions, and a collection of analysis tools that have been developed in recent years to facilitate the investigation of dynamic functional connectivity using these imaging modalities. Further, we discuss the applications of these approaches in the study of cognition and neuropsychiatric disorders. Finally, we review some existing developments that, by using realistic computational models, pursue a deeper understanding of the underlying causes of non-stationary connectivity.