Music in the brain.

Music is ubiquitous across human cultures - as a source of affective and pleasurable experience, moving us both physically and emotionally - and learning to play music shapes both brain structure and brain function. Music processing in the brain - namely, the perception of melody, harmony and rhythm - has traditionally been studied as an auditory phenomenon using passive listening paradigms. However, when listening to music, we actively generate predictions about what is likely to happen next. This enactive aspect has led to a more comprehensive understanding of music processing involving brain structures implicated in action, emotion and learning. Here we review the cognitive neuroscience literature of music perception. We show that music perception, action, emotion and learning all rest on the human brain's fundamental capacity for prediction - as formulated by the predictive coding of music model. This Review elucidates how this formulation of music perception and expertise in individuals can be extended to account for the dynamics and underlying brain mechanisms of collective music making. This in turn has important implications for human creativity as evinced by music improvisation. These recent advances shed new light on what makes music meaningful from a neuroscientific perspective.

Re-awakening the brain: Forcing transitions in disorders of consciousness by external in silico perturbation.

A fundamental challenge in neuroscience is accurately defining brain states and predicting how and where to perturb the brain to force a transition. Here, we investigated resting-state fMRI data of patients suffering from disorders of consciousness (DoC) after coma (minimally conscious and unresponsive wakefulness states) and healthy controls. We applied model-free and model-based approaches to help elucidate the underlying brain mechanisms of patients with DoC. The model-free approach allowed us to characterize brain states in DoC and healthy controls as a probabilistic metastable substate (PMS) space. The PMS of each group was defined by a repertoire of unique patterns (i.e., metastable substates) with different probabilities of occurrence. In the model-based approach, we adjusted the PMS of each DoC group to a causal whole-brain model. This allowed us to explore optimal strategies for promoting transitions by applying off-line in silico probing. Furthermore, this approach enabled us to evaluate the impact of local perturbations in terms of their global effects and sensitivity to stimulation, which is a model-based biomarker providing a deeper understanding of the mechanisms underlying DoC. Our results show that transitions were obtained in a synchronous protocol, in which the somatomotor network, thalamus, precuneus and insula were the most sensitive areas to perturbation. This motivates further work to continue understanding brain function and treatments of disorders of consciousness.

Temporal Irreversibility of Large-Scale Brain Dynamics in Alzheimer's Disease.

Healthy brain dynamics can be understood as the emergence of a complex system far from thermodynamic equilibrium. Brain dynamics are temporally irreversible and thus establish a preferred direction in time (i.e., arrow of time). However, little is known about how the time-reversal symmetry of spontaneous brain activity is affected by Alzheimer's disease (AD). We hypothesized that the level of irreversibility would be compromised in AD, signaling a fundamental shift in the collective properties of brain activity toward equilibrium dynamics. We investigated the irreversibility from resting-state fMRI and EEG data in male and female human patients with AD and elderly healthy control subjects (HCs). We quantified the level of irreversibility and, thus, proximity to nonequilibrium dynamics by comparing forward and backward time series through time-shifted correlations. AD was associated with a breakdown of temporal irreversibility at the global, local, and network levels, and at multiple oscillatory frequency bands. At the local level, temporoparietal and frontal regions were affected by AD. The limbic, frontoparietal, default mode, and salience networks were the most compromised at the network level. The temporal reversibility was associated with cognitive decline in AD and gray matter volume in HCs. The irreversibility of brain dynamics provided higher accuracy and more distinctive information than classical neurocognitive measures when differentiating AD from control subjects. Findings were validated using an out-of-sample cohort. Present results offer new evidence regarding pathophysiological links between the entropy generation rate of brain dynamics and the clinical presentation of AD, opening new avenues for dementia characterization at different levels.SIGNIFICANCE STATEMENT By assessing the irreversibility of large-scale dynamics across multiple brain signals, we provide a precise signature capable of distinguishing Alzheimer's disease (AD) at the global, local, and network levels and different oscillatory regimes. Irreversibility of limbic, frontoparietal, default-mode, and salience networks was the most compromised by AD compared with more sensory-motor networks. Moreover, the time-irreversibility properties associated with cognitive decline and atrophy outperformed and complemented classical neurocognitive markers of AD in predictive classification performance. Findings were generalized and replicated with an out-of-sample validation procedure. We provide novel multilevel evidence of reduced irreversibility in AD brain dynamics that has the potential to open new avenues for understating neurodegeneration in terms of the temporal asymmetry of brain dynamics.

Maternal prenatal distress exposure negatively associates with the stability of neonatal frontoparietal network.

Maternal prenatal distress (PD), frequently defined as in utero prenatal stress exposure (PSE) to the developing fetus, influences the developing brain and numerous associations between PSE and brain structure have been described both in neonates and in older children. Previous studies addressing PSE-linked alterations in neonates' brain activity have focused on connectivity analyses from predefined seed regions, but the effects of PSE at the level of distributed functional networks remains unclear. In this study, we investigated the impact of prenatal distress on the spatial and temporal properties of functional networks detected in functional MRI data from 20 naturally sleeping, term-born (age 25.85 ± 7.72 days, 11 males), healthy neonates. First, we performed group level independent component analysis (GICA) to evaluate an association between PD and the identified functional networks. Second, we searched for an association with PD at the level of the stability of functional networks over time using leading eigenvector dynamics analysis (LEiDA). No statistically significant associations were detected at the spatial level for the GICA-derived networks. However, at the dynamic level, LEiDA revealed that maternal PD negatively associated with the stability of a frontoparietal network. These results imply that maternal PD may influence the stability of frontoparietal connections in neonatal brain network dynamics and adds to the cumulating evidence that frontal areas are especially sensitive to PSE. We advocate for early preventive intervention strategies regarding pregnant mothers. Nevertheless, future research venues are required to assess optimal intervention timing and methods for maximum benefit.

Complex spatiotemporal oscillations emerge from transverse instabilities in large-scale brain networks.

Spatiotemporal oscillations underlie all cognitive brain functions. Large-scale brain models, constrained by neuroimaging data, aim to trace the principles underlying such macroscopic neural activity from the intricate and multi-scale structure of the brain. Despite substantial progress in the field, many aspects about the mechanisms behind the onset of spatiotemporal neural dynamics are still unknown. In this work we establish a simple framework for the emergence of complex brain dynamics, including high-dimensional chaos and travelling waves. The model consists of a complex network of 90 brain regions, whose structural connectivity is obtained from tractography data. The activity of each brain area is governed by a Jansen neural mass model and we normalize the total input received by each node so it amounts the same across all brain areas. This assumption allows for the existence of an homogeneous invariant manifold, i.e., a set of different stationary and oscillatory states in which all nodes behave identically. Stability analysis of these homogeneous solutions unveils a transverse instability of the synchronized state, which gives rise to different types of spatiotemporal dynamics, such as chaotic alpha activity. Additionally, we illustrate the ubiquity of this route towards complex spatiotemporal activity in a network of next generation neural mass models. Altogehter, our results unveil the bifurcation landscape that underlies the emergence of function from structure in the brain.

LSD-induced increase of Ising temperature and algorithmic complexity of brain dynamics.

A topic of growing interest in computational neuroscience is the discovery of fundamental principles underlying global dynamics and the self-organization of the brain. In particular, the notion that the brain operates near criticality has gained considerable support, and recent work has shown that the dynamics of different brain states may be modeled by pairwise maximum entropy Ising models at various distances from a phase transition, i.e., from criticality. Here we aim to characterize two brain states (psychedelics-induced and placebo) as captured by functional magnetic resonance imaging (fMRI), with features derived from the Ising spin model formalism (system temperature, critical point, susceptibility) and from algorithmic complexity. We hypothesized, along the lines of the entropic brain hypothesis, that psychedelics drive brain dynamics into a more disordered state at a higher Ising temperature and increased complexity. We analyze resting state blood-oxygen-level-dependent (BOLD) fMRI data collected in an earlier study from fifteen subjects in a control condition (placebo) and during ingestion of lysergic acid diethylamide (LSD). Working with the automated anatomical labeling (AAL) brain parcellation, we first create "archetype" Ising models representative of the entire dataset (global) and of the data in each condition. Remarkably, we find that such archetypes exhibit a strong correlation with an average structural connectome template obtained from dMRI (r = 0.6). We compare the archetypes from the two conditions and find that the Ising connectivity in the LSD condition is lower than in the placebo one, especially in homotopic links (interhemispheric connectivity), reflecting a significant decrease of homotopic functional connectivity in the LSD condition. The global archetype is then personalized for each individual and condition by adjusting the system temperature. The resulting temperatures are all near but above the critical point of the model in the paramagnetic (disordered) phase. The individualized Ising temperatures are higher in the LSD condition than in the placebo condition (p = 9 × 10-5). Next, we estimate the Lempel-Ziv-Welch (LZW) complexity of the binarized BOLD data and the synthetic data generated with the individualized model using the Metropolis algorithm for each participant and condition. The LZW complexity computed from experimental data reveals a weak statistical relationship with condition (p = 0.04 one-tailed Wilcoxon test) and none with Ising temperature (r(13) = 0.13, p = 0.65), presumably because of the limited length of the BOLD time series. Similarly, we explore complexity using the block decomposition method (BDM), a more advanced method for estimating algorithmic complexity. The BDM complexity of the experimental data displays a significant correlation with Ising temperature (r(13) = 0.56, p = 0.03) and a weak but significant correlation with condition (p = 0.04, one-tailed Wilcoxon test). This study suggests that the effects of LSD increase the complexity of brain dynamics by loosening interhemispheric connectivity-especially homotopic links. In agreement with earlier work using the Ising formalism with BOLD data, we find the brain state in the placebo condition is already above the critical point, with LSD resulting in a shift further away from criticality into a more disordered state.

Using in silico perturbational approach to identify critical areas in schizophrenia.

Schizophrenia is a debilitating neuropsychiatric disorder whose underlying correlates remain unclear despite decades of neuroimaging investigation. One contentious topic concerns the role of global signal (GS) fluctuations and how they affect more focal functional changes. Moreover, it has been difficult to pinpoint causal mechanisms of circuit disruption. Here, we analyzed resting-state fMRI data from 47 schizophrenia patients and 118 age-matched healthy controls and used dynamical analyses to investigate how global fluctuations and other functional metastable states are affected by this disorder. We found that brain dynamics in the schizophrenia group were characterized by an increased probability of globally coherent states and reduced recurrence of a substate dominated by coupled activity in the default mode and limbic networks. We then used the in silico perturbation of a whole-brain model to identify critical areas involved in the disease. Perturbing a set of temporo-parietal sensory and associative areas in a model of the healthy brain reproduced global pathological dynamics. Healthy brain dynamics were instead restored by perturbing a set of medial fronto-temporal and cingulate regions in the model of pathology. These results highlight the relevance of GS alterations in schizophrenia and identify a set of vulnerable areas involved in determining a shift in brain state.

Disrupted resting-sate brain network dynamics in children born extremely preterm.

The developing brain has to adapt to environmental and intrinsic insults after extremely preterm (EPT) birth. Ongoing maturational processes maximize their fit to the environment and this can provide a substrate for neurodevelopmental failures. Resting-state functional magnetic resonance imaging was used to scan 33 children born EPT, at < 27 weeks of gestational age, and 26 full-term controls at 10 years of age. We studied the capability of a brain area to propagate neural information (intrinsic ignition) and its variability across time (node-metastability). This framework was computed for the dorsal attention network (DAN), frontoparietal, default-mode network (DMN), and the salience, limbic, visual, and somatosensory networks. The EPT group showed reduced intrinsic ignition in the DMN and DAN, compared with the controls, and reduced node-metastability in the DMN, DAN, and salience networks. Intrinsic ignition and node-metastability values correlated with cognitive performance at 12 years of age in both groups, but only survived in the term group after adjustment. Preterm birth disturbed the signatures of functional brain organization at rest in 3 core high-order networks: DMN, salience, and DAN. Identifying vulnerable resting-state networks after EPT birth may lead to interventions that aim to rebalance brain function.

Temporal irreversibility of neural dynamics as a signature of consciousness.

Dissipative systems evolve in the preferred temporal direction indicated by the thermodynamic arrow of time. The fundamental nature of this temporal asymmetry led us to hypothesize its presence in the neural activity evoked by conscious perception of the physical world, and thus its covariance with the level of conscious awareness. We implemented a data-driven deep learning framework to decode the temporal inversion of electrocorticography signals acquired from non-human primates. Brain activity time series recorded during conscious wakefulness could be distinguished from their inverted counterparts with high accuracy, both using frequency and phase information. However, classification accuracy was reduced for data acquired during deep sleep and under ketamine-induced anesthesia; moreover, the predictions obtained from multiple independent neural networks were less consistent for sleep and anesthesia than for conscious wakefulness. Finally, the analysis of feature importance scores highlighted transitions between slow ($\approx$20 Hz) and fast frequencies (>40 Hz) as the main contributors to the temporal asymmetry observed during conscious wakefulness. Our results show that a preferred temporal direction is manifest in the neural activity evoked by conscious mentation and in the phenomenology of the passage of time, establishing common ground to tackle the relationship between brain and subjective experience.

Non-reversibility outperforms functional connectivity in characterisation of brain states in MEG data.

Characterising brain states during tasks is common practice for many neuroscientific experiments using electrophysiological modalities such as electroencephalography (EEG) and magnetoencephalography (MEG). Brain states are often described in terms of oscillatory power and correlated brain activity, i.e. functional connectivity. It is, however, not unusual to observe weak task induced functional connectivity alterations in the presence of strong task induced power modulations using classical time-frequency representation of the data. Here, we propose that non-reversibility, or the temporal asymmetry in functional interactions, may be more sensitive to characterise task induced brain states than functional connectivity. As a second step, we explore causal mechanisms of non-reversibility in MEG data using whole brain computational models. We include working memory, motor, language tasks and resting-state data from participants of the Human Connectome Project (HCP). Non-reversibility is derived from the lagged amplitude envelope correlation (LAEC), and is based on asymmetry of the forward and reversed cross-correlations of the amplitude envelopes. Using random forests, we find that non-reversibility outperforms functional connectivity in the identification of task induced brain states. Non-reversibility shows especially better sensitivity to capture bottom-up gamma induced brain states across all tasks, but also alpha band associated brain states. Using whole brain computational models we find that asymmetry in the effective connectivity and axonal conduction delays play a major role in shaping non-reversibility across the brain. Our work paves the way for better sensitivity in characterising brain states during both bottom-up as well as top-down modulation in future neuroscientific experiments.

Computational modelling in disorders of consciousness: Closing the gap towards personalised models for restoring consciousness.

Disorders of consciousness are complex conditions characterised by persistent loss of responsiveness due to brain injury. They present diagnostic challenges and limited options for treatment, and highlight the urgent need for a more thorough understanding of how human consciousness arises from coordinated neural activity. The increasing availability of multimodal neuroimaging data has given rise to a wide range of clinically- and scientifically-motivated modelling efforts, seeking to improve data-driven stratification of patients, to identify causal mechanisms for patient pathophysiology and loss of consciousness more broadly, and to develop simulations as a means of testing in silico potential treatment avenues to restore consciousness. As a dedicated Working Group of clinicians and neuroscientists of the international Curing Coma Campaign, here we provide our framework and vision to understand the diverse statistical and generative computational modelling approaches that are being employed in this fast-growing field. We identify the gaps that exist between the current state-of-the-art in statistical and biophysical computational modelling in human neuroscience, and the aspirational goal of a mature field of modelling disorders of consciousness; which might drive improved treatments and outcomes in the clinic. Finally, we make several recommendations for how the field as a whole can work together to address these challenges.

Integration and segregation manifolds in the brain ensure cognitive flexibility during tasks and rest.

Adapting to a constantly changing environment requires the human brain to flexibly switch among many demanding cognitive tasks, processing both specialized and integrated information associated with the activity in functional networks over time. In this study, we investigated the nature of the temporal alternation between segregated and integrated states in the brain during rest and six cognitive tasks using functional MRI. We employed a deep autoencoder to explore the 2D latent space associated with the segregated and integrated states. Our results show that the integrated state occupies less space in the latent space manifold compared to the segregated states. Moreover, the integrated state is characterized by lower entropy of occupancy than the segregated state, suggesting that integration plays a consolidating role, while segregation may serve as cognitive expertness. Comparing rest and the tasks, we found that rest exhibits higher entropy of occupancy, indicating a more random wandering of the mind compared to the expected focus during task performance. Our study demonstrates that both transient, short-lived integrated and segregated states are present during rest and task performance, flexibly switching between them, with integration serving as information compression and segregation related to information specialization.

The early adolescent brain on music: Analysis of functional dynamics reveals engagement of orbitofrontal cortex reward system.

Music listening plays a pivotal role for children and adolescents, yet it remains unclear how music modulates brain activity at the level of functional networks in this young population. Analysing the dynamics of brain networks occurring and dissolving over time in response to music can provide a better understanding of the neural underpinning of music listening. We collected functional magnetic resonance imaging (fMRI) data from 17 preadolescents aged 10-11 years while listening to two similar music pieces separated by periods without music. We subsequently tracked the occurrence of functional brain networks over the recording time using a recent method that detects recurrent patterns of phase-locking in the fMRI signals: the leading eigenvector dynamics analysis (LEiDA). The probabilities of occurrence and switching profiles of different functional networks were compared between periods of music and no music. Our results showed significantly increased occurrence of a specific functional network during the two music pieces compared to no music, involving the medial orbitofrontal and ventromedial prefrontal cortices-a brain subsystem associated to reward processing. Moreover, the higher the musical reward sensitivity of the preadolescents, the more this network was preceded by a pattern involving the insula. Our findings highlight the involvement of a brain subsystem associated with hedonic and emotional processing during music listening in the early adolescent brain. These results offer novel insight into the neural underpinnings of musical reward in early adolescence, improving our understanding of the important role and the potential benefits of music at this delicate age.

Depression recurrence is accompanied by longer periods in default mode and more frequent attentional and reward processing dynamic brain-states during resting-state activity.

Recurrence in major depressive disorder (MDD) is common, but neurobiological models capturing vulnerability for recurrences are scarce. Disturbances in multiple resting-state networks have been linked to MDD, but most approaches focus on stable (vs. dynamic) network characteristics. We investigated how the brain's dynamical repertoire changes after patients transition from remission to recurrence of a new depressive episode. Sixty two drug-free, MDD-patients with ≥2 episodes underwent a baseline resting-state fMRI scan when in remission. Over 30-months follow-up, 11 patients with a recurrence and 17 matched-remitted MDD-patients without a recurrence underwent a second fMRI scan. Recurrent patterns of functional connectivity were characterized by applying Leading Eigenvector Dynamics Analysis (LEiDA). Differences between baseline and follow-up were identified for the 11 non-remitted patients, while data from the 17 matched-remitted patients was used as a validation dataset. After the transition into a depressive state, basal ganglia-anterior cingulate cortex (ACC) and visuo-attentional networks were detected significantly more often, whereas default mode network activity was found to have a longer duration. Additionally, the fMRI signal in the basal ganglia-ACC areas underlying the reward network, were significantly less synchronized with the rest of the brain after recurrence (compared to a state of remission). No significant changes were observed in the matched-remitted patients who were scanned twice while in remission. These findings characterize changes that may be associated with the transition from remission to recurrence and provide initial evidence of altered dynamical exploration of the brain's repertoire of functional networks when a recurrent depressive episode occurs.

Correction: Graph neural fields: A framework for spatiotemporal dynamical models on the human connectome.

[This corrects the article DOI: 10.1371/journal.pcbi.1008310.].

Strength-dependent perturbation of whole-brain model working in different regimes reveals the role of fluctuations in brain dynamics.

Despite decades of research, there is still a lack of understanding of the role and generating mechanisms of the ubiquitous fluctuations and oscillations found in recordings of brain dynamics. Here, we used whole-brain computational models capable of presenting different dynamical regimes to reproduce empirical data's turbulence level. We showed that the model's fluctuations regime fitted to turbulence more faithfully reproduces the empirical functional connectivity compared to oscillatory and noise regimes. By applying global and local strength-dependent perturbations and subsequently measuring the responsiveness of the model, we revealed each regime's computational capacity demonstrating that brain dynamics is shifted towards fluctuations to provide much-needed flexibility. Importantly, fluctuation regime stimulation in a brain region within a given resting state network modulates that network, aligned with previous empirical and computational studies. Furthermore, this framework generates specific, testable empirical predictions for human stimulation studies using strength-dependent rather than constant perturbation. Overall, the whole-brain models fitted to the level of empirical turbulence together with functional connectivity unveil that the fluctuation regime best captures empirical data, and the strength-dependent perturbative framework demonstrates how this regime provides maximal flexibility to the human brain.

What lies underneath: Precise classification of brain states using time-dependent topological structure of dynamics.

The self-organising global dynamics underlying brain states emerge from complex recursive nonlinear interactions between interconnected brain regions. Until now, most efforts of capturing the causal mechanistic generating principles have supposed underlying stationarity, being unable to describe the non-stationarity of brain dynamics, i.e. time-dependent changes. Here, we present a novel framework able to characterise brain states with high specificity, precisely by modelling the time-dependent dynamics. Through describing a topological structure associated to the brain state at each moment in time (its attractor or 'information structure'), we are able to classify different brain states by using the statistics across time of these structures hitherto hidden in the neuroimaging dynamics. Proving the strong potential of this framework, we were able to classify resting-state BOLD fMRI signals from two classes of post-comatose patients (minimally conscious state and unresponsive wakefulness syndrome) compared with healthy controls with very high precision.

Macroscopic Quantities of Collective Brain Activity during Wakefulness and Anesthesia.

The study of states of arousal is key to understand the principles of consciousness. Yet, how different brain states emerge from the collective activity of brain regions remains unknown. Here, we studied the fMRI brain activity of monkeys during wakefulness and anesthesia-induced loss of consciousness. We showed that the coupling between each brain region and the rest of the cortex provides an efficient statistic to classify the two brain states. Based on this and other statistics, we estimated maximum entropy models to derive collective, macroscopic properties that quantify the system's capabilities to produce work, to contain information, and to transmit it, which were all maximized in the awake state. The differences in these properties were consistent with a phase transition from critical dynamics in the awake state to supercritical dynamics in the anesthetized state. Moreover, information-theoretic measures identified those parameters that impacted the most the network dynamics. We found that changes in the state of consciousness primarily depended on changes in network couplings of insular, cingulate, and parietal cortices. Our findings suggest that the brain state transition underlying the loss of consciousness is predominantly driven by the uncoupling of specific brain regions from the rest of the network.

The effect of external stimulation on functional networks in the aging healthy human brain.

Understanding the brain changes occurring during aging can provide new insights for developing treatments that alleviate or reverse cognitive decline. Neurostimulation techniques have emerged as potential treatments for brain disorders and to improve cognitive functions. Nevertheless, given the ethical restrictions of neurostimulation approaches, in silico perturbation protocols based on causal whole-brain models are fundamental to gaining a mechanistic understanding of brain dynamics. Furthermore, this strategy could serve to identify neurophysiological biomarkers differentiating between age groups through an exhaustive exploration of the global effect of all possible local perturbations. Here, we used a resting-state fMRI dataset divided into middle-aged (N =310, <65 years) and older adults (N =310, $\geq $65) to characterize brain states in each group as a probabilistic metastable substate (PMS) space. We showed that the older group exhibited a reduced capability to access a metastable substate that overlaps with the rich club. Then, we fitted the PMS to a whole-brain model and applied in silico stimulations in each node to force transitions from the brain states of the older- to the middle-aged group. We found that the precuneus was the best stimulation target. Overall, these findings could have important implications for designing neurostimulation interventions for reversing the effects of aging on whole-brain dynamics.

Sleep-deprived new mothers gave their infants a higher priority than themselves.

AIM: To understand why some parents are less sensitive to infant cues than others, we need to understand how healthy parents respond, and how this is influenced by factors such as sleep deprivation. Here, we examined whether sleep deprivation alters the self-infant-prioritisation effect in a population of first-time mothers within their first year of motherhood. METHODS: The study took place at Aarhus University Hospital in Denmark from August 2018 until February 2020. First-time mothers were recruited through Midwife clinics, national and social media. All women completed a perceptual matching task including an infant category. The mothers were divided into two groups depending on their sleep status: below or above 7 h of average night-time sleep, measured with actigraphy. RESULTS: Forty-eight first-time mothers at the age of 29.13 ± 3.87 years were included. In the sleep-deprived group, the infant category was statistically significantly higher in accuracy (p = 0.005) and faster in reaction time (p < 0.001) than all other categories. In contrast, in the non-sleep-deprived group, there was no statistically significant difference between self and infant, neither in accuracy, nor reaction time. CONCLUSION: Sleep-deprived new mothers strongly prioritised infants over self, while non-sleep-deprived new mothers showed no prioritisation of the self over the infant.