Open datasets and code for multi-scale relations on structure, function and neuro-genetics in the human brain.

The human brain is an extremely complex network of structural and functional connections that operate at multiple spatial and temporal scales. Investigating the relationship between these multi-scale connections is critical to advancing our comprehension of brain function and disorders. However, accurately predicting structural connectivity from its functional counterpart remains a challenging pursuit. One of the major impediments is the lack of public repositories that integrate structural and functional networks at diverse resolutions, in conjunction with modular transcriptomic profiles, which are essential for comprehensive biological interpretation. To mitigate this limitation, our contribution encompasses the provision of an open-access dataset consisting of derivative matrices of functional and structural connectivity across multiple scales, accompanied by code that facilitates the investigation of their interrelations. We also provide additional resources focused on neuro-genetic associations of module-level network metrics, which present promising opportunities to further advance research in the field of network neuroscience, particularly concerning brain disorders.

Investigating Dynamic High-Order Interactions in Physiological Networks through Predictive Information Decomposition.

We present an approach to assess redundant and synergistic interactions in network systems via the information-theoretic analysis of multivariate physiological processes. The approach sets up a strategy to decompose the information shared between the present states of a group of random processes and their own past states into unique contributions arising from the past of subgroups of processes and redundant and synergistic contributions arising from the dynamic interaction among the subgroups. The method is illustrated in a theoretical example of linearly interacting Gaussian processes, showing that redundancy and synergy are related mostly to unidirectional coupling and to bidirectional coupling with internal dynamics. It is then applied to the network of short-term heart period, arterial pressure and respiratory variability probed in healthy subjects, showing that redundancy and synergy prevail respectively in cardiorespiratory interactions and in cardiovascular interactions in the resting state, and that postural stress increases the predictive information and the redundancy of physiological interactions.

Prefrontal dysfunction in post-COVID-19 hyposmia: an EEG/fNIRS study.

Introduction: Subtle cognitive dysfunction and mental fatigue are frequent after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, characterizing the so-called long COVID-19 syndrome. This study aimed to correlate cognitive, neurophysiological, and olfactory function in a group of subjects who experienced acute SARS-CoV-2 infection with persistent hyposmia at least 12 weeks before the observation. Methods: For each participant (32 post-COVID-19 patients and 16 controls), electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS) data were acquired using an integrated EEG-fNIRS system during the execution of a P300 odd-ball task and a Stroop test. The Sniffin' Sticks test was conducted to assess subjects' olfactory performance. The Montreal Cognitive Assessment (MoCA) and the Frontal Assessment Battery (FAB) were also administered. Results: The post-COVID-19 group consisted of 32 individuals (20 women and 12 men) with an average education level of 12.9 ± 3.12 years, while the control group consisted of 16 individuals (10 women and 6 men) with an average education level of 14.9 ± 3.2 years. There were no significant differences in gender (X2 = 0, p = 1) or age between the two groups (age 44.81 ± 13.9 vs. 36.62 ± 11.4, p = 0.058). We identified a lower concentration of oxyhemoglobin (p < 0.05) at the prefrontal cortical level in post-COVID-19 subjects during the execution of the Stroop task, as well as a reduction in the amplitude of the P3a response. Moreover, we found that post-COVID-19 subjects performed worst at the MoCA screening test (p = 0.001), Sniffin's Sticks test (p < 0.001), and Stroop task response latency test (p < 0.001). Conclusions: This study showed that post-COVID-19 patients with persistent hyposmia present mild deficits in prefrontal function, even 4 months after the end of the infection. These deficits, although subtle, could have long-term implications for quality of life and cognitive wellbeing. It is essential to continue monitoring and evaluating these patients to better understand the extent and duration of cognitive impairments associated with long COVID-19.

Galcanezumab treatment changes visual related EEG connectivity patterns in migraine patients.

BACKGROUND: Monoclonal antibodies against calcitonin gene-related peptides (CGRP) are innovative therapies for migraine treatment. Although they are clinically effective, how anti-CGRP treatment reduces migraine attacks still remains unclear. OBJECTIVE: In this observational case-control study, we aimed to apply graph theory to EEG data from 20 migraine patients and 10 controls to investigate the effects of 3 months of galcanezumab on brain connectivity. METHODS: We analyzed EEG rhythms during black-white pattern reversal stimulation with 0.5 cycle per degree spatial frequency before (T0) galcanezumab injection, as well as after 3 months (T2). EEG recordings made 1 hour after galcanezumab administration served as the control session (T1). Patients' connectivity patterns obtained at T0, T1 and T2 were compared with normal controls. RESULTS: We found that galcanezumab increased network integration (with a 5% significance level corrected with the false discovery rate), changing the intensity of connections between the occipital through the frontal areas. At 3 months follow up, patients with persistent high headache intensity had a minor effect on the strength of connections (evaluated using Kendall's rank correlation test and p < 0.05). CONCLUSIONS: The potent anti-nociceptive action that galcanezumab exerts at a peripheral level could restore cortical connections and possibly factors predisposing to attack onset.

Gradients of O-information highlight synergy and redundancy in physiological applications.

The study of high order dependencies in complex systems has recently led to the introduction of statistical synergy, a novel quantity corresponding to a form of emergence in which patterns at large scales are not traceable from lower scales. As a consequence, several works in the last years dealt with the synergy and its counterpart, the redundancy. In particular, the O-information is a signed metric that measures the balance between redundant and synergistic statistical dependencies. In spite of its growing use, this metric does not provide insight about the role played by low-order scales in the formation of high order effects. To fill this gap, the framework for the computation of the O-information has been recently expanded introducing the so-called gradients of this metric, which measure the irreducible contribution of a variable (or a group of variables) to the high order informational circuits of a system. Here, we review the theory behind the O-information and its gradients and present the potential of these concepts in the field of network physiology, showing two new applications relevant to brain functional connectivity probed via functional resonance imaging and physiological interactions among the variability of heart rate, arterial pressure, respiration and cerebral blood flow.

Pairwise and high-order dependencies in the cryptocurrency trading network.

In this paper we analyse the effects of information flows in cryptocurrency markets. We first define a cryptocurrency trading network, i.e. the network made using cryptocurrencies as nodes and the Granger causality among their weekly log returns as links, later we analyse its evolution over time. In particular, with reference to years 2020 and 2021, we study the logarithmic US dollar price returns of the cryptocurrency trading network using both pairwise and high-order statistical dependencies, quantified by Granger causality and O-information, respectively. With reference to the former, we find that it shows peaks in correspondence of important events, like e.g., Covid-19 pandemic turbulence or occasional sudden prices rise. The corresponding network structure is rather stable, across weekly time windows in the period considered and the coins are the most influential nodes in the network. In the pairwise description of the network, stable coins seem to play a marginal role whereas, turning high-order dependencies, they appear in the highest number of synergistic information circuits, thus proving that they play a major role for high order effects. With reference to redundancy and synergy with the time evolution of the total transactions in US dollars, we find that their large volume in the first semester of 2021 seems to have triggered a transition in the cryptocurrency network toward a more complex dynamical landscape. Our results show that pairwise and high-order descriptions of complex financial systems provide complementary information for cryptocurrency analysis.

Information Dynamics of Electric Field Intensity before and during the COVID-19 Pandemic.

This work investigates the temporal statistical structure of time series of electric field (EF) intensity recorded with the aim of exploring the dynamical patterns associated with periods with different human activity in urban areas. The analyzed time series were obtained from a sensor of the EMF RATEL monitoring system installed in the campus area of the University of Novi Sad, Serbia. The sensor performs wideband cumulative EF intensity monitoring of all active commercial EF sources, thus including those linked to human utilization of wireless communication systems. Monitoring was performed continuously during the years 2019 and 2020, allowing us to investigate the effects on the patterns of EF intensity of varying conditions of human mobility, including regular teaching and exam activity within the campus, as well as limitations to mobility related to the COVID-19 pandemic. Time series analysis was performed using both simple statistics (mean and variance) and combining the information-theoretic measure of information storage (IS) with the method of surrogate data to quantify the regularity of EF dynamic patterns and detect the presence of nonlinear dynamics. Moreover, to assess the possible coexistence of dynamic behaviors across multiple temporal scales, IS analysis was performed over consecutive observation windows lasting one day, week, month, and year, respectively coarse grained at time scales of 6 min, 30 min, 2 h, and 1 day. Our results document that the EF intensity patterns of variability are modulated by the movement of people at daily, weekly, and monthly scales, and are blunted during periods of restricted mobility related to the COVID-19 pandemic. Mobility restrictions also affected significantly the regularity of the EF intensity time series, resulting in lower values of IS observed simultaneously with a loss of nonlinear dynamics. Thus, our analysis can be useful to investigate changes in the global patterns of human mobility both during pandemics or other types of events, and from this perspective may serve to implement strategies for safety assessment and for optimizing the design of networks of EF sensors.

The structure of anticorrelated networks in the human brain.

During the performance of a specific task--or at rest--, the activity of different brain regions shares statistical dependencies that reflect functional connections. While these relationships have been studied intensely for positively correlated networks, considerably less attention has been paid to negatively correlated networks, a. k.a. anticorrelated networks (ACNs). Although the most celebrated of all ACNs is the default mode network (DMN), and has even been extensively studied in health and disease, for systematically all ACNs other than DMN, there is no comprehensive study yet. Here, we have addressed this issue by making use of three neuroimaging data sets: one of N = 192 healthy young adults to fully describe ACN, another of N = 40 subjects to compare ACN between two groups of young and old participants, and another of N = 1,000 subjects from the Human Connectome Project to evaluate the association between ACN and cognitive scores. We first provide a comprehensive description of the anatomical composition of all ACNs, each of which participated in distinct resting-state networks (RSNs). In terms of participation ranking, from highest to the lowest, the major anticorrelated brain areas are the precuneus, the anterior supramarginal gyrus and the central opercular cortex. Next, by evaluating a more detailed structure of ACN, we show it is possible to find significant differences in ACN between specific conditions, in particular, by comparing groups of young and old participants. Our main finding is that of increased anticorrelation for cerebellar interactions in older subjects. Finally, in the voxel-level association study with cognitive scores, we show that ACN has multiple clusters of significance, clusters that are different from those obtained from positive correlated networks, indicating a functional cognitive meaning of ACN. Overall, our results give special relevance to ACN and suggest their use to disentangle unknown alterations in certain conditions, as could occur in early-onset neurodegenerative diseases or in some psychiatric conditions.

A Controlled Thermoalgesic Stimulation Device for Exploring Novel Pain Perception Biomarkers.

OBJECTIVE: To develop a new device for identifying physiological markers of pain perception by reading the brain's electrical activity and hemodynamic interactions while applying thermoalgesic stimulation. METHODS: We designed a compact prototype that generates well-controlled thermal stimuli using a computer-driven Peltier cell while simultaneously capturing electroencephalography (EEG) and photoplethysmography (PPG) signals. The study was performed on 35 healthy subjects (mean age 30.46 years, SD 4.93 years; 20 males, 15 females). We first determined the heat pain threshold (HPT) for each subject, defined as the maximum temperature that the subject can withstand when the Peltier cell gradually increased the temperature. Next, we defined the painful condition as the one occurring at temperature equal to 90% of the HPT, comparing this to the no-pain state (control) in the absence of thermoalgesic stimulation. RESULTS: Both the one-dimensional and the two-dimensional spectral entropy (SE) obtained from both the EEG and PPG signals differentiated the condition of pain. In particular, the SE for PPG was significantly reduced in association with pain, while the SE for EEG increased slightly. Moreover, significant discrimination occurred within a specific range of frequencies, 26-30 Hz for EEG and about 5-10 Hz for PPG. CONCLUSION: Hemodynamics, brain dynamics and their interactions can discriminate thermal pain perception. SIGNIFICANCE: The possibility of monitoring on-line variations in thermal pain perception using a similar device and algorithms may be of interest to study different pathologies that affect the peripheral nervous system, such as small fiber neuropathies, fibromyalgia or painful diabetic neuropathy.

Local Granger causality.

Granger causality (GC) is a statistical notion of causal influence based on prediction via linear vector autoregression. For Gaussian variables it is equivalent to transfer entropy, an information-theoretic measure of time-directed information transfer between jointly dependent processes. We exploit such equivalence and calculate exactly the local Granger causality, i.e., the profile of the information transferred from the driver to the target process at each discrete time point; in this frame, GC is the average of its local version. We show that the variability of the local GC around its mean relates to the interplay between driver and innovation (autoregressive noise) processes, and it may reveal transient instances of information transfer not detectable from its average values. Our approach offers a robust and computationally fast method to follow the information transfer along the time history of linear stochastic processes, as well as of nonlinear complex systems studied in the Gaussian approximation.

Synergistic Information Transfer in the Global System of Financial Markets.

Uncovering dynamic information flow between stock market indices has been the topic of several studies which exploited the notion of transfer entropy or Granger causality, its linear version. The output of the transfer entropy approach is a directed weighted graph measuring the information about the future state of each target provided by the knowledge of the state of each driving stock market index. In order to go beyond the pairwise description of the information flow, thus looking at higher order informational circuits, here we apply the partial information decomposition to triplets consisting of a pair of driving markets (belonging to America or Europe) and a target market in Asia. Our analysis, on daily data recorded during the years 2000 to 2019, allows the identification of the synergistic information that a pair of drivers carry about the target. By studying the influence of the closing returns of drivers on the subsequent overnight changes of target indexes, we find that (i) Korea, Tokyo, Hong Kong, and Singapore are, in order, the most influenced Asian markets; (ii) US indices SP500 and Russell are the strongest drivers with respect to the bivariate Granger causality; and (iii) concerning higher order effects, pairs of European and American stock market indices play a major role as the most synergetic three-variables circuits. Our results show that the Synergy, a proxy of higher order predictive information flow rooted in information theory, provides details that are complementary to those obtained from bivariate and global Granger causality, and can thus be used to get a better characterization of the global financial system.

Brain connectivity and cognitive functioning in individuals six months after multiorgan failure.

Multiorgan failure (MOF) is a life-threating condition that affects two or more systems of organs not involved in the disorder that motivates admission to an Intensive Care Unit (ICU). Patients who survive MOF frequently present long-term functional, neurological, cognitive, and psychiatric sequelae. However, the changes to the brain that explain such symptoms remain unclear. OBJECTIVE: To determine brain connectivity and cognitive functioning differences between a group of MOF patients six months after ICU discharge and healthy controls (HC). METHODS: 22 MOF patients and 22 HC matched by age, sex, and years of education were recruited. Both groups were administered a 3T magnetic resonance imaging (MRI), including structural T1 and functional BOLD, as well as a comprehensive neuropsychological evaluation that included tests of learning and memory, speed of information processing and attention, executive function, visual constructional abilities, and language. Voxel-based morphometry was used to analyses T1 images. For the functional data at rest, functional connectivity (FC) analyses were performed. RESULTS: There were no significant differences in structural imaging and neuropsychological performance between groups, even though patients with MOF performed worse in all the cognitive tests. Functional neuroimaging in the default mode network (DMN) showed hyper-connectivity towards sensory-motor, cerebellum, and visual networks. DMN connectivity had a significant association with the severity of MOF during ICU stay and with the neuropsychological scores in tests of attention and visual constructional abilities. CONCLUSIONS: In MOF patients without structural brain injury, DMN connectivity six months after ICU discharge is associated with MOF severity and neuropsychological impairment, which supports the use of resting-state functional MRI as a potential tool to predict the onset of long-term cognitive deficits in these patients. Similar to what occurs at the onset of other pathologies, the observed hyper-connectivity might suggest network re-adaptation following MOF.

Quantifying Dynamical High-Order Interdependencies From the O-Information: An Application to Neural Spiking Dynamics.

We address the problem of efficiently and informatively quantifying how multiplets of variables carry information about the future of the dynamical system they belong to. In particular we want to identify groups of variables carrying redundant or synergistic information, and track how the size and the composition of these multiplets changes as the collective behavior of the system evolves. In order to afford a parsimonious expansion of shared information, and at the same time control for lagged interactions and common effect, we develop a dynamical, conditioned version of the O-information, a framework recently proposed to quantify high-order interdependencies via multivariate extension of the mutual information. The dynamic O-information, here introduced, allows to separate multiplets of variables which influence synergistically the future of the system from redundant multiplets. We apply this framework to a dataset of spiking neurons from a monkey performing a perceptual discrimination task. The method identifies synergistic multiplets that include neurons previously categorized as containing little relevant information individually.

Synergistic information in a dynamical model implemented on the human structural connectome reveals spatially distinct associations with age.

We implement the dynamical Ising model on the large-scale architecture of white matter connections of healthy subjects in the age range 4-85 years, and analyze the dynamics in terms of the synergy, a quantity measuring the extent to which the joint state of pairs of variables is projected onto the dynamics of a target one. We find that the amount of synergy in explaining the dynamics of the hubs of the structural connectivity (in terms of degree strength) peaks before the critical temperature, and can thus be considered as a precursor of a critical transition. Conversely, the greatest amount of synergy goes into explaining the dynamics of more central nodes. We also find that the aging of structural connectivity is associated with significant changes in the simulated dynamics: There are brain regions whose synergy decreases with age, in particular the frontal pole, the subcallosal area, and the supplementary motor area; these areas could then be more likely to show a decline in terms of the capability to perform higher order computation (if structural connectivity was the sole variable). On the other hand, several regions in the temporal cortex show a positive correlation with age in the first 30 years of life, that is, during brain maturation.

Clinical correlates of mathematical modeling of cortical spreading depression: Single-cases study.

INTRODUCTION: Considerable connections between migraine with aura and cortical spreading depression (CSD), a depolarization wave originating in the visual cortex and traveling toward the frontal lobe, lead to the hypothesis that CSD is underlying migraine aura. The highly individual and complex characteristics of the brain cortex suggest that the geometry might impact the propagation of cortical spreading depression. METHODS: In a single-case study, we simulated the CSD propagation for five migraine with aura patients, matching their symptoms during a migraine attack to the CSD wavefront propagation. This CSD wavefront was simulated on a patient-specific triangulated cortical mesh obtained from individual MRI imaging and personalized diffusivity tensors derived locally from diffusion tensor imaging data. RESULTS: The CSD wave propagation was simulated on both hemispheres, despite in all but one patient the symptoms were attributable to one hemisphere. The CSD wave diffused with a large wavefront toward somatosensory and prefrontal regions, devoted to pain processing. DISCUSSION: This case-control study suggests that the cortical geometry may contribute to the modality of CSD evolution and partly to clinical expression of aura symptoms. The simulated CSD is a large and diffuse phenomenon, possibly capable to activate trigeminal nociceptors and to involve cortical areas devoted to pain processing.

Connectome sorting by consensus clustering increases separability in group neuroimaging studies.

A fundamental challenge in preprocessing pipelines for neuroimaging datasets is to increase the signal-to-noise ratio for subsequent analyses. In the same line, we suggest here that the application of the consensus clustering approach to brain connectivity matrices can be a valid additional step for connectome processing to find subgroups of subjects with reduced intragroup variability and therefore increasing the separability of the distinct subgroups when connectomes are used as a biomarker. Moreover, by partitioning the data with consensus clustering before any group comparison (for instance, between a healthy population vs. a pathological one), we demonstrate that unique regions within each cluster arise and bring new information that could be relevant from a clinical point of view.

Multiscale Information Decomposition Dissects Control Mechanisms of Heart Rate Variability at Rest and During Physiological Stress.

Heart rate variability (HRV; variability of the RR interval of the electrocardiogram) results from the activity of several coexisting control mechanisms, which involve the influence of respiration (RESP) and systolic blood pressure (SBP) oscillations operating across multiple temporal scales and changing in different physiological states. In this study, multiscale information decomposition is used to dissect the physiological mechanisms related to the genesis of HRV in 78 young volunteers monitored at rest and during postural and mental stress evoked by head-up tilt (HUT) and mental arithmetics (MA). After representing RR, RESP and SBP at different time scales through a recently proposed method based on multivariate state space models, the joint information transfer T RESP , SBP → RR is decomposed into unique, redundant and synergistic components, describing the strength of baroreflex modulation independent of respiration ( U SBP → RR ), nonbaroreflex ( U RESP → RR ) and baroreflex-mediated ( R RESP , SBP → RR ) respiratory influences, and simultaneous presence of baroreflex and nonbaroreflex respiratory influences ( S RESP , SBP → RR ), respectively. We find that fast (short time scale) HRV oscillations-respiratory sinus arrhythmia-originate from the coexistence of baroreflex and nonbaroreflex (central) mechanisms at rest, with a stronger baroreflex involvement during HUT. Focusing on slower HRV oscillations, the baroreflex origin is dominant and MA leads to its higher involvement. Respiration influences independent on baroreflex are present at long time scales, and are enhanced during HUT.

Raman spectroscopy monitoring of MCF10A cells irradiated by protons at clinical doses.

PURPOSE: Proton therapy has been recently proposed as a radiotherapy form for breast cancer treatment in view of its potentially decreased normal-tissue toxicity compared with conventional photon-based radiotherapy. However, the risks for the healthy tissue cannot be completely eliminated. In the present study, the suitability of Raman spectroscopy to monitor the radiosensitivity of normal cells exposed to clinical proton beam was investigated. MATERIALS AND METHODS: MCF10A normal human breast cells were irradiated at two different proton doses: 0.5 Gy and 4 Gy. They were fixed immediately after irradiation and measured by means of Raman spectroscopy technique. The obtained data were analyzed both by evaluating the intensity ratio of specific Raman spectral peaks and through Multivariate Distance Matrix Regression technique. RESULTS: Certain Raman peaks associated with DNA showed a systematic suppression at both dose levels. In particular, the intensity of a Raman peak at 784 cm-1, related to a stretching mode inside the phosphate group of DNA, is very sensitive to the proton beam exposure, even at the lowest investigated dose. Therefore, it could be considered as a spectral marker of cytogenetic damage. CONCLUSIONS: The obtained results are encouraging for the future of Raman spectroscopy in radiobiology research, particularly for improving risk assessment in the field of proton radiotherapy. Specifically, these findings validate Raman spectroscopy to measure biological response in human breast cells exposed to standard proton therapy doses used in clinical setting.

Predicting functional networks from region connectivity profiles in task-based versus resting-state fMRI data.

Intrinsic Connectivity Networks, patterns of correlated activity emerging from "resting-state" BOLD time series, are increasingly being associated with cognitive, clinical, and behavioral aspects, and compared with patterns of activity elicited by specific tasks. We study the reconfiguration of brain networks between task and resting-state conditions by a machine learning approach, to highlight the Intrinsic Connectivity Networks (ICNs) which are more affected by the change of network configurations in task vs. rest. To this end, we use a large cohort of publicly available data in both resting and task-based fMRI paradigms. By applying a battery of different supervised classifiers relying only on task-based measurements, we show that the highest accuracy to predict ICNs is reached with a simple neural network of one hidden layer. In addition, when testing the fitted model on resting state measurements, such architecture yields a performance close to 90% for areas connected to the task performed, which mainly involve the visual and sensorimotor cortex, whilst a relevant decrease of the performance is observed in the other ICNs. On one hand, our results confirm the correspondence of ICNs in both paradigms (task and resting) thus opening a window for future clinical applications to subjects whose participation in a required task cannot be guaranteed. On the other hand it is shown that brain areas not involved in the task display different connectivity patterns in the two paradigms.

Structure-function multi-scale connectomics reveals a major role of the fronto-striato-thalamic circuit in brain aging.

Physiological aging affects brain structure and function impacting morphology, connectivity, and performance. However, whether some brain connectivity metrics might reflect the age of an individual is still unclear. Here, we collected brain images from healthy participants (N = 155) ranging from 10 to 80 years to build functional (resting state) and structural (tractography) connectivity matrices, both data sets combined to obtain different connectivity features. We then calculated the brain connectome age-an age estimator resulting from a multi-scale methodology applied to the structure-function connectome, and compared it to the chronological age (ChA). Our results were twofold. First, we found that aging widely affects the connectivity of multiple structures, such as anterior cingulate and medial prefrontal cortices, basal ganglia, thalamus, insula, cingulum, hippocampus, parahippocampus, occipital cortex, fusiform, precuneus, and temporal pole. Second, we found that the connectivity between basal ganglia and thalamus to frontal areas, also known as the fronto-striato-thalamic (FST) circuit, makes the major contribution to age estimation. In conclusion, our results highlight the key role played by the FST circuit in the process of healthy aging. Notably, the same methodology can be generally applied to identify the structural-functional connectivity patterns correlating to other biomarkers than ChA.