Temporal modes of hub synchronization at rest.

The brain is a dynamic system that generates a broad repertoire of perceptual, motor, and cognitive states by the integration and segregation of different functional domains represented in large-scale brain networks. However, the fundamental mechanisms underlying brain network integration remain elusive. Here, for the first time to our knowledge, we found that in the resting state the brain visits few synchronization modes defined as clusters of temporally aligned functional hubs. These modes alternate over time and their probability of switching leads to specific temporal loops among them. Notably, although each mode involves a small set of nodes, the brain integration seems highly vulnerable to a simulated attack on this temporal synchronization mechanism. In line with the hypothesis that the resting state represents a prior sculpted by the task activity, the observed synchronization modes might be interpreted as a temporal brain template needed to respond to task/environmental demands .

Cortical cores in network dynamics.

Spontaneous brain activity at rest is spatially and temporally organized in networks of cortical and subcortical regions specialized for different functional domains. Even though brain networks were first studied individually through functional Magnetic Resonance Imaging, more recent studies focused on their dynamic 'integration'. Integration depends on two fundamental properties: the structural topology of brain networks and the dynamics of functional connectivity. In this scenario, cortical hub regions, that are central regions highly connected with other areas of the brain, play a fundamental role in serving as way stations for network traffic. In this review, we focus on the functional organization of a set of hub areas that we define as the 'dynamic core'. In the resting state, these regions dynamically interact with other regions of the brain linking multiple networks. First, we introduce and compare the statistical measures used for detecting hubs. Second, we discuss their identification based on different methods (functional Magnetic Resonance Imaging, Diffusion Weighted Imaging, Electro/Magneto Encephalography). Third, we show that the degree of interaction between these core regions and the rest of the brain varies over time, indicating that their centrality is not stationary. Moreover, alternating periods of strong and weak centrality of the core relate to periods of strong and weak global efficiency in the brain. These results indicate that information processing in the brain is not stable, but fluctuates and its temporal and spectral properties are discussed. In particular, the hypothesis of 'pulsed' information processing, discovered in the slow temporal scale, is explored for signals at higher temporal resolution.

A Dynamic Core Network and Global Efficiency in the Resting Human Brain.

Spontaneous brain activity is spatially and temporally organized in the absence of any stimulation or task in networks of cortical and subcortical regions that appear largely segregated when imaged at slow temporal resolution with functional magnetic resonance imaging (fMRI). When imaged at high temporal resolution with magneto-encephalography (MEG), these resting-state networks (RSNs) show correlated fluctuations of band-limited power in the beta frequency band (14-25 Hz) that alternate between epochs of strong and weak internal coupling. This study presents 2 novel findings on the fundamental issue of how different brain regions or networks interact in the resting state. First, we demonstrate the existence of multiple dynamic hubs that allow for across-network coupling. Second, dynamic network coupling and related variations in hub centrality correspond to increased global efficiency. These findings suggest that the dynamic organization of across-network interactions represents a property of the brain aimed at optimizing the efficiency of communication between distinct functional domains (memory, sensory-attention, motor). They also support the hypothesis of a dynamic core network model in which a set of network hubs alternating over time ensure efficient global communication in the whole brain.

Frequency specific interactions of MEG resting state activity within and across brain networks as revealed by the multivariate interaction measure.

Resting state networks (RSNs) are sets of brain regions exhibiting temporally coherent activity fluctuations in the absence of imposed task structure. RSNs have been extensively studied with fMRI in the infra-slow frequency range (nominally <10(-1)Hz). The topography of fMRI RSNs reflects stationary temporal correlation over minutes. However, neuronal communication occurs on a much faster time scale, at frequencies nominally in the range of 10(0)-10(2)Hz. We examined phase-shifted interactions in the delta (2-3.5 Hz), theta (4-7 Hz), alpha (8-12 Hz) and beta (13-30 Hz) frequency bands of resting-state source space MEG signals. These analyses were conducted between nodes of the dorsal attention network (DAN), one of the most robust RSNs, and between the DAN and other networks. Phase shifted interactions were mapped by the multivariate interaction measure (MIM), a measure of true interaction constructed from the maximization of imaginary coherency in the virtual channels comprised of voxel signals in source space. Non-zero-phase interactions occurred between homologous left and right hemisphere regions of the DAN in the delta and alpha frequency bands. Even stronger non-zero-phase interactions were detected between networks. Visual regions bilaterally showed phase-shifted interactions in the alpha band with regions of the DAN. Bilateral somatomotor regions interacted with DAN nodes in the beta band. These results demonstrate the existence of consistent, frequency specific phase-shifted interactions on a millisecond time scale between cortical regions within RSN as well as across RSNs.

Adding dynamics to the Human Connectome Project with MEG.

The Human Connectome Project (HCP) seeks to map the structural and functional connections between network elements in the human brain. Magnetoencephalography (MEG) provides a temporally rich source of information on brain network dynamics and represents one source of functional connectivity data to be provided by the HCP. High quality MEG data will be collected from 50 twin pairs both in the resting state and during performance of motor, working memory and language tasks. These data will be available to the general community. Additionally, using the cortical parcellation scheme common to all imaging modalities, the HCP will provide processing pipelines for calculating connection matrices as a function of time and frequency. Together with structural and functional data generated using magnetic resonance imaging methods, these data represent a unique opportunity to investigate brain network connectivity in a large cohort of normal adult human subjects. The analysis pipeline software and the dynamic connectivity matrices that it generates will all be made freely available to the research community.

The Human Connectome Project: a data acquisition perspective.

The Human Connectome Project (HCP) is an ambitious 5-year effort to characterize brain connectivity and function and their variability in healthy adults. This review summarizes the data acquisition plans being implemented by a consortium of HCP investigators who will study a population of 1200 subjects (twins and their non-twin siblings) using multiple imaging modalities along with extensive behavioral and genetic data. The imaging modalities will include diffusion imaging (dMRI), resting-state fMRI (R-fMRI), task-evoked fMRI (T-fMRI), T1- and T2-weighted MRI for structural and myelin mapping, plus combined magnetoencephalography and electroencephalography (MEG/EEG). Given the importance of obtaining the best possible data quality, we discuss the efforts underway during the first two years of the grant (Phase I) to refine and optimize many aspects of HCP data acquisition, including a new 7T scanner, a customized 3T scanner, and improved MR pulse sequences.

A frontoparietal network for spatial attention reorienting in the auditory domain: a human fMRI/MEG study of functional and temporal dynamics.

Several studies have identified a supramodal network critical to the reorienting of attention toward stimuli at novel locations and which involves the right temporoparietal junction and the inferior frontal areas. The present functional magnetic resonance imaging (fMRI)\magnetoencephalography (MEG) study investigates: 1) the cerebral circuit underlying attentional reorienting to spatially varying sound locations; 2) the circuit related to the regular change of sound location in the same hemifield, the change of sound location across hemifields, or sounds presented randomly at different locations on the azimuth plane; 3) functional temporal dynamics of the observed cortical areas exploiting the complementary characteristics of the fMRI and MEG paradigms. fMRI results suggest 3 distinct roles: the supratemporal plane appears modulated by variations of sound location; the inferior parietal lobule is modulated by the cross-meridian effect; and the inferior frontal cortex is engaged by the inhibition of a motor response. MEG data help to elucidate the temporal dynamics of this network by providing high-resolution time series with which to measure latency of neural activation manipulated by the reorienting of attention.

Multimodal-3D imaging based on µMRI and µCT techniques bridges the gap with histology in visualization of the bone regeneration process.

Bone repair/regeneration is usually investigated through X-ray computed microtomography (µCT) supported by histology of extracted samples, to analyse biomaterial structure and new bone formation processes. Magnetic resonance imaging (µMRI) shows a richer tissue contrast than µCT, despite at lower resolution, and could be combined with µCT in the perspective of conducting non-destructive 3D investigations of bone. A pipeline designed to combine µMRI and µCT images of bone samples is here described and applied on samples of extracted human jawbone core following bone graft. We optimized the coregistration procedure between µCT and µMRI images to avoid bias due to the different resolutions and contrasts. Furthermore, we used an Adaptive Multivariate Clustering, grouping homologous voxels in the coregistered images, to visualize different tissue types within a fused 3D metastructure. The tissue grouping matched the 2D histology applied only on 1 slice, thus extending the histology labelling in 3D. Specifically, in all samples, we could separate and map 2 types of regenerated bone, calcified tissue, soft tissues, and/or fat and marrow space. Remarkably, µMRI and µCT alone were not able to separate the 2 types of regenerated bone. Finally, we computed volumes of each tissue in the 3D metastructures, which might be exploited by quantitative simulation. The 3D metastructure obtained through our pipeline represents a first step to bridge the gap between the quality of information obtained from 2D optical microscopy and the 3D mapping of the bone tissue heterogeneity and could allow researchers and clinicians to non-destructively characterize and follow-up bone regeneration.

Role of angiotensin II and oxidative stress in renal inflammation by hypernatremia: benefits of atrial natriuretic peptide, losartan, and tempol.

The body regulates plasma sodium levels within a small physiologic range, despite large variations in daily sodium and water intake. It is known that sodium transport in the kidneys plays an important role in hypoxia, being the major determinant of renal oxygen consumption. Tubular epithelial cell hypoxia is an important contributor to the development of renal inflammation, and the damage may progress to structural injury, ending in acute renal failure. In this review, we will summarize the renal inflammatory effects of high acute plasma sodium (acute hypernatremia), and the molecular mechanisms involved. We will also discuss recent findings related to the role of oxidative stress and angiotensin II (Ang II) in the pathogenesis of renal injury. We will comment on the effects of agents used to prevent or attenuate the inflammatory response, such as the atrial natriuretic peptide, the superoxide dismutase mimetic - tempol, and losartan.

Topographic organization of the human primary and secondary somatosensory areas: an fMRI study.

The topographical organization of SI and SII somatosensory areas was investigated using fMRI at 1.5 T and electrical sensory stimulation. Electrical stimuli were delivered unilaterally to the median nerve at the wrist and to the tibial nerve at the medial malleolus, during a block paradigm study. In all subjects, activation was observed, contralaterally to the stimulated side, in the post-central gyrus, in the posterior parietal cortex, in the mesial pre-frontal region and, bilaterally, in the supratemporal region at the level of the Sylvian fissure. The latter region, corresponding presumably to SII, showed a rough but clearcut topographical organization, with the median nerve areas located more posteriorly. In addition, weaker activations were observed in some subjects in the ipsilateral mesial prefrontal region and in the ipsilateral posterior parietal cortex. Information contained in the present study represent an interesting database for future investigations on the effects of sensorimotor learning in normal individuals on plastic reorganization following a lesion of the primary sensorimotor centers, i.e. in stroke patients, on the topography and balance between upper and lower limb representations in primary and secondary somatosensory cortices.

A SQUID based AC susceptometer for the investigation of large samples.

We developed a SQUID based susceptometer with a large available magnetized volume for the investigation of large objects. The magnetizing field is generated by a pair of Helmoltz coils. To achieve a high signal-to-noise ratio, the susceptometer is operated in a lock-in mode with an AC magnetizing field. A negative feedback control allows the rejection of the applied field with a relative residual of 1 x 10(-7). The apparatus was tested with substances of known magnetic susceptibility. The overall sensitivity, stated in terms of the magnetic moment, is better than 7 x 10(-11) A m2 for small samples.

The use of an inhomogeneous applied field improves the spatial sensitivity profile of an in vivo SQUID susceptometer.

We present a SQUID susceptometer with a non-homogeneous magnetizing field which is null at the sensing coil and increases towards the patient position with a constant gradient plus a cubic term at large distances. Compared with the magnetizing fields of similar instruments described in the literature, our gradient field enhances the signal due to internal organs with respect to the signal due to superficial tissue. Preliminary measurements have been performed on phantoms of known magnetic susceptibility. The advantage of using a non-homogeneous field compared with a uniform field has been investigated in the case of a double-layer phantom.

Detection and counting of specific cell populations by means of magnetic markers linked to monoclonal antibodies.

We report on experiments aimed at the assessment of a new method for cell marking. This method combines superparamagnetic particles, commonly used for cell separation, linked to monoclonal antibodies, and biomagnetic instrumentation featuring an extremely high magnetic field sensitivity. The final goal of the method is to locate and estimate specific cell populations in the human body. In this experiment, quantitative features of the method are evaluated in vitro with lymphocytes and carcinoma cells. Comparison between estimation and direct counting of cells is quite satisfactory and motivates further development of the technique.

The study of steady magnetic fields associated with primary and secondary ST shift in ischaemic rabbit hearts.

The study of injury potentials associated with DC currents that generate the primary or secondary ST shifts during cardiac ischaemia is possible only through the invasive technique of the DC electrogram. Clinical surface ECG recordings are AC coupled and cannot be used. This paper reports the use of non-invasive and unshielded magnetocardiographic measurements to evaluate the DC injury currents associated with ST shifts during coronary artery occlusions in the isolated rabbit heart. The effect on the magnetic ST shift is studied under different ischaemic conditions including regional ischaemia, global ischaemia, global ischaemia following long periods of regional ischaemia, regional ischaemia after repeated episodes of reversible global ischaemia, and bilateral regional ischaemia. Recording of DC magnetic fields allows the characterization of primary and secondary ST displacement for each induced ischaemic condition. Our measurements show that the ST shift starts earlier when inducing ischaemia in hearts previously subjected to ischaemic episodes than in hearts where the ischaemia was produced for the first time.

Signaling pathways involved in renal oxidative injury: role of the vasoactive peptides and the renal dopaminergic system.

The physiological hydroelectrolytic balance and the redox steady state in the kidney are accomplished by an intricate interaction between signals from extrarenal and intrarenal sources and between antinatriuretic and natriuretic factors. Angiotensin II, atrial natriuretic peptide and intrarenal dopamine play a pivotal role in this interactive network. The balance between endogenous antioxidant agents like the renal dopaminergic system and atrial natriuretic peptide, by one side, and the prooxidant effect of the renin angiotensin system, by the other side, contributes to ensuring the normal function of the kidney. Different pathological scenarios, as nephrotic syndrome and hypertension, where renal sodium excretion is altered, are associated with an impaired interaction between two natriuretic systems as the renal dopaminergic system and atrial natriuretic peptide that may be involved in the pathogenesis of renal diseases. The aim of this review is to update and comment the most recent evidences about the intracellular pathways involved in the relationship between endogenous antioxidant agents like the renal dopaminergic system and atrial natriuretic peptide and the prooxidant effect of the renin angiotensin system in the pathogenesis of renal inflammation.

Calibration of a multichannel MEG system based on the signal space separation method.

For an efficient use of multichannel MEG systems, an accurate sensor calibration is extremely important. This includes the knowledge of both channel sensitivities and channel arrangement, which can deviate from original system plans, e.g., because of thermal stresses. In this paper, we propose a new solution to the calibration of a multichannel MEG sensor array based on the signal space separation (SSS) method. It has been shown that an inaccurate knowledge of sensor calibration limits the performances of the SSS method, resulting in a mismatch between the measured neuromagnetic field and its SSS reconstruction. Given a set of known magnetic sources, we show that an objective function, which strongly depends on sensor geometry, can be derived from the principal angle between the measured vector signal and the SSS basis. Hence, the MEG sensor array calibration is carried out by minimizing the objective function through a standard large-scale optimization technique. Details on the magnetic sources and calibration process are presented here. Finally, an application to the calibration of the 153-channel whole-head MEG system installed at the University of Chieti is discussed.

Neuromagnetic responses reveal the cortical timing of audiovisual synchrony.

Multisensory processing involving visual and auditory inputs is modulated by their relative temporal offsets. In order to assess whether multisensory integration alters the activation timing of primary visual and auditory cortices as a function of the temporal offsets between auditory and visual stimuli, a task was designed in which subjects had to judge the perceptual simultaneity of the onset of visual stimuli and brief acoustic tones. These were presented repeatedly with three different inter-stimulus intervals that were chosen to meet three perceptual conditions: (1) physical synchrony perceived as synchrony by subjects (SYNC); (2) physical asynchrony perceived as asynchrony (ASYNC); (3) physical asynchrony perceived ambiguously (AMB, i.e. 50% perceived as synchrony, 50% as asynchrony). Magnetoencephalographic activity was recorded during crossmodal sessions and unimodal control sessions. The activation of primary visual and auditory cortices peaked at a longer latency for the crossmodal conditions as compared to the unimodal conditions. Moreover, the latency in the auditory cortex was longer in the SYNC than in the ASYNC condition, whereas in the visual cortex the latency in the AMB condition was longer than in the ASYNC condition. These findings suggest that multisensory processing affects temporal dynamics already in primary cortices, that such activity can differ regionally and can be sensitive to the temporal offsets of multisensory inputs. In addition, in the AMB condition the conscious awareness of asynchrony might be associated to a later activation of the primary auditory cortex.

Low- and high-frequency evoked responses following pattern reversal stimuli: a MEG study supported by fMRI constraint.

We investigated the neural generators of N1 and P1 components of visual magnetic responses through the concomitant study of low (1-15 Hz)- and high (15-30 Hz)-frequency brain activities phase-locked to stimulus and elicited by pattern reversal visual stimuli. Whole helmet magnetic recordings and dipole modeling technique with support of functional magnetic resonance imaging (fMRI) were used to characterize locations and orientations of N1 and P1 sources as a function of four stimulated visual field quadrants. A comparison between low- and high-frequency activities revealed fundamental differences among orientations of the quadrants dipoles thus suggesting partly distinct neural populations underlying low- and high-frequency responses to transient contrast visual stimuli. Moreover, for both low- and high-frequency bands the specific study of locations and orientations of N1 and P1 sources indicated V1/V2 cortex as the neural substrate generating the two components. In summary, we provided strong support for a cortical genesis of human oscillatory mass activity following transient contrast stimuli with specific neural districts active in the low- and high-frequency bands. The converging results obtained from the concomitant investigation of probably different brain activities provided new evidences for a striate genesis of N1 and P1 components of the broadband visual-evoked responses following pattern reversal.

Conditioning transcutaneous electrical nerve stimulation induces delayed gating effects on cortical response: a magnetoencephalographic study.

The present study was undertaken to investigate after-effects of 7 Hz non-painful prolonged stimulation of the median nerve on somatosensory-evoked fields (SEFs). The working hypothesis that conditioning peripheral stimulations might produce delayed interfering ("gating") effects on the response of somatosensory cortex to test stimuli was evaluated. In the control condition, electrical thumb stimulation induced SEFs in ten subjects. In the experimental protocol, a conditioning median nerve stimulation at wrist preceded 6 electrical thumb stimulations. Equivalent current dipoles fitting SEFs modeled responses of contralateral primary area (SI) and bilateral secondary somatosensory areas (SII) following control and experimental conditions. Compared to the control condition, conditioning stimulation induced no amplitude modulation of SI response at the initial stimulus-related peak (20 ms). In contrast, later response from SI (35 ms) and response from SII were significantly weakened in amplitude. Gradual but fast recovery towards control amplitude levels was observed for the response from SI-P35, while a slightly slower cycle was featured from SII. These findings point to a delayed "gating" effect on the synchronization of somatosensory cortex after peripheral conditioning stimulations. This effect was found to be more lasting in SII area, as a possible reflection of its integrative role in sensory processing.

A cartesian time--frequency approach to reveal brain interaction dynamics.

The study of large-scale interactions from magnetoencephalographic data based on the magnitude of the complex coherence computed at channel level is a widely used method to track the coupling between neural signals. Traditionally, a measure based on the magnitude of the complex coherence estimated by Fourier analysis, has been used under the assumption that the neural signals are stationary. Here, we split the complex coherence in its real and imaginary parts and focus on the latter with the advantage that the imaginary part is insensitive to spurious connectivity resulting from volume conducted "self interaction". Furthermore, interacting sources alone contribute to a non-vanishing imaginary part of the complex coherence whereas the contribute of non-interacting sources is also mapped from the magnitude of the complex coherence. Since it has been extensively shown that non-stationary stochastic processes contribute to the generation of neural signals, it is fundamental to be able to define interaction measures that are able to follow the temporal variations in the coupling between neural signals. To this purpose time-frequency domain techniques to estimate the magnitude of the complex coherence have been developed in the past decades. Similarly, we extend the analysis of the imaginary part of complex coherence to the time-frequency domain, by using the short-time Fourier transform to analyze the complex coherence as a function of time. In this way, it is possible to get an indication about the dynamic of the underlying source interaction pattern by looking at channel level interactions without the bias introduced by artifactual self-interaction by volume conduction or by the contribute of non-interacting sources. Furthermore, the corresponding imaginary part of the cross-spectrogram can be used to estimate interactions on a source level by localizing pools of sources interacting at a given frequency and by characterizing their dynamics. The method has been applied to magnetoencephalographic data from a cross-modal visual auditory stimulation and provided evidence for the involvement of temporal and occipital areas in the integrated information processing for simultaneous audio-visual stimulation. Furthermore, the source interaction pattern shows a variation in time that reflects a dynamical synchronization of the involved brain sources in the frequency bands of interest.