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The basics of magnetoencephalography (MEG), i.e. the measurement and the analysis of the tiny magnetic fields generated outside the scalp by the working human brain, are reviewed. Three main topics are discussed: (1) the relationship between the magnetic field and its generators, including on one hand the neurophysiological basis and the physical theory of magnetic field generation, and on the other hand the techniques for the estimation of the sources from the magnetic field measurements; (2) the instrumental techniques and the laboratory practice of neuromagnetic field measurement and (3) the main applications of MEG in basic neurophysiology as well as in clinical neurology.

A method for the modeling of human movement‐related cortical activity from combined electroencephalography (EEG) and magnetoencephalography (MEG) data is proposed. This method includes a subject's multi‐compartment head model (scalp, skull, dura mater, cortex) constructed from magnetic resonance images, multi‐dipole source model, and a regularized linear inverse source estimate based on boundary element mathematics. Linear inverse source estimates of cortical activity were regularized by taking into account the covariance of background EG and MEG sensor noise. EEG (121 sensors) and MEG (43 sensors) data were recorded in separate sessions whereas normal subjects executed voluntary right one‐digit movements. Linear inverse source solution of EEG, MEG, and EEG‐MEG data were quantitatively evaluated by using three performance indexes. The first two indexes (Dipole Localization Error [DLE] and Spatial Dispersion [SDis]) were used to compute the localization power for the source solutions obtained. Such indexes were based on the information provided by the column of the resolution matrix (i.e., impulse response). Ideal DLE values tend to zero (the source current was correctly retrieved by the procedure). In contrast, high DLE values suggest severe mislocalization in the source reconstruction. A high value of SDis at a source space point mean that such a source will be retrieved by a large area with the linear inverse source estimation. The remaining performance index assessed the quality of the source solution based on the information provided by the rows of the resolution matrix R, i.e., resolution kernels. The i‐th resolution kernels of the matrix R describe how the estimation of the i‐th source is distorted by the concomitant activity of all other sources. A statistically significant lower dipole localization error was observed and lower spatial dispersion in source solutions produced by combined EEG‐MEG data than from EEG and MEG data considered separately (P < 0.05). These effects were not due to an increased number of sensors in the combined EEG‐MEG solutions. They result from the independence of source information conveyed by the multimodal measurements. From a physiological point of view, the linear inverse source solution of EEG‐MEG data suggested a contralaterally preponderant bilateral activation of primary sensorimotor cortex from the preparation to the execution of the movement. This activation was associated with that of the supplementary motor area. The activation of bilateral primary sensorimotor cortical areas was greater during the processing of afferent information related to the ongoing movement than in the preparation for the motor act. In conclusion, the linear inverse source estimate of combined MEG and EEG data improves the estimate of movement‐related cortical activity. Hum. Brain Mapping 14:197–209, 2001. © 2001 Wiley‐Liss, Inc.

This study was triggered by the experimental evidence that subjects required to tap in synchrony with a heard rhythm spontaneously time their tapping to variations in rhythm frequency even when these variations are so small that they are not consciously detectable. We performed a series of magnetoencephalographic (MEG) measurements, aimed at investigating whether the response of the auditory cortex discriminates randomly administered series of brief tones differing from each other only by their interstimulus intervals (ISI). Moreover, by combining psychophysical measurements, conscious and preconscious adjustments of tapping to rhythm variations were compared with brain cortical responses. The ISIs were varied by 2% or 20% from a "central" value of 500 ms. Subjects always consciously detected the 20% ISI changes and easily adjusted their tapping accordingly, whereas they never consciously detected the 2% ISI changes, even though they always correctly adjusted their tapping to them. Analysis of the auditory evoked fields (AEFs) showed that the intensity of the M100 component decreased with decreasing ISI both for 20% and 2% variations in a statistically significant manner, despite the fact that the 2% variation was not consciously perceived. The M100 behavior indicated that connections between auditory and motor cortexes may exist that are able to use the information on rhythm variations in the stimuli even when these are not consciously identified by the subject. The ability of the auditory cortex to discriminate different time characteristics of the incoming rhythmic stimuli is discussed in this paper in relation to the theories regarding the physiology of time perception and discrimination.

The morphology of somatosensory evoked fields (SEF) following electrical separate stimulation of left and right median nerve in 22 healthy volunteers was explored. The analysis of morphological properties of individual SEFs has been performed, in order to quantify an inter-hemispheric correlation coefficient. Despite a high inter-subject variability of the SEF morphologies, a high intra-subject inter-hemispheric shape correlation occurs in the post-stimulus epoch of 100 ms from the stimulus onset. Accordingly, a normative value for the parameter describing the SEF inter-hemispheric correlation coefficient has been calculated. The present work establishes quantitative and normative descriptions of the shape similarity of SEFs from the two hands in the left and right hemispheres. This provides a database for a new parameter, which might be useful in detecting alterations in the primary sensory cortical activation due to possible unilateral alterations of sensory inflow because of either peripheral or central deficits. The described procedure has been successfully applied to a small number of patients affected by unilateral cerebrovascular lesion.

Recently we developed a new procedure to personalize the electrode to selectively stimulate specific cortical regions by transcranial electric stimulations (tES) [Tecchio et al.,2013] and we showed that tES via this innovative personalized electrode shaped on individual brain MRI can relieve multiple sclerosis fatigue [Tecchio et al., 2014]. This study aims to assess by computational approach the distriution of the intra-cerebral electric field induced by tES through the personalized in comparison with a non-personalized electrode in two realistic human models.

Excitability and conductivity of corticospinal tracts of 10 volunteers were investigated by motor-evoked potentials (MEPs) to transcranial magnetic brain stimulation, before and after anesthetic block of right median (sensory + motor) and radial (sensory) nervous fibers at the wrist. MEPs were simultaneously recorded from two ulnar-supplied muscles during full relaxation and voluntary contraction. These muscles maintained an intact strength following anesthesia, but they were in a remarkably different condition with respect to the surrounding skin: the first dorsal interosseous muscle (FDI) was totally “enveloped” within the anesthetized area but was still dispatching a normal proprioceptive feedback; the abductor digiti minimi (ADM) was preserving both cutaneous and proprioceptive information. Spinal and peripheral nerve excitability were monitored as well. The sensory deprivation induced short-term changes which selectively took place within the hemisphere connected to the anesthetized hand. The physiological latency “anticipation” of MEPs recorded during active contraction versus relaxation was reduced (P< 0.001) in the FDI, but not in the ADM, when values during anesthesia were compared with preanesthesia values. The FDI cortical representation—as analyzed by a mapping procedure of the motor cortex via focal stimuli of several scalp positions—was significantly (P< 0.002) reduced, while the ADM representation remained either unchanged or enlarged. MEP and F-wave variability significantly decreased in the FDI but not in the ADM. F-waves were also affected due to changes in the motoneuronal excitability at spinal level. Peripheral nerve and root stimulation showed no modifications. Results are discussed in view of the short-term modifications of the corticospinal pathway somatotopy produced by the selective reduction of the sensory flow. Implications of the sensory feedback in motor control are also discussed.

Somatotopy of human hand primary sensory cortex has been studied neuromagnetically [C. Baumgartner, A. Doppelbauer, L. Deecke, D.S. Barth, J. Zeitlhofer, G. Lindinger, W.W. Sutherling, Neuromagnetic investigation of somatotopy of human hand somatosensory cortex, Exp. Brain Res. 87 (1991) 641–648.] [1] . Investigation of sensory cortex devoted to the hand will be of major importance in relation to clinical recovery after sensorimotor deficits as well as an index of plasticity phenomena following alterations of peripheral nerves inputs. Here a normative data set has been constructed, on the basis of the neuromagnetic investigation of the primary sensory hand cortical representation in the two hemispheres of 20 healthy volunteers. This can be used to evaluate interhemispheric differences of the `sensory' hand areas during experimental paradigms in the healthy as well as following patients with monohemispheric lesions. The localizations in each hemisphere of the cortical Equivalent Current Dipoles (ECDs) activated with the shortest latencies (N20m and P30m components) by separate stimulation of left and right median nerve, thumb and little finger were analysed. By considering the ECDs to thumb and little finger stimulation the boundaries of the hand cortical representation in primary sensory cortex, the `hand extension' was measured as the distance between the two. For all the considered parameters (related to N20m and P30m ECDs: latency, strength, spatial position in the individual head, `hand extension', interhemispheric differences) the appropriate variable distribution was considered and by including the 98% of the healthy population normative limits were calculated. Themes : Sensory systems Topics : Somatosensory cortex and thalamocortical relationships

Multiple sclerosis (MS) affects myelin sheaths within the central nervous system, concurring to cause brain atrophy and neurodegeneration as well as gradual functional disconnections. To explore early signs of altered connectivity in MS from a structural and functional perspective, the morphology of corpus callosum (CC) was correlated with a dynamic inter-hemispheric connectivity index.Twenty mildly disabled patients affected by a relapsing-remitting (RR) form of MS (EDSS.

Neuroimaging, investigating how specific brain sources play a particular role in a definite cognitive or sensorimotor process, can be achieved from non-invasive electrophysiological (EEG, EMG, MEG) and multimodal (concurrent EEG-fMRI) recordings. However, especially for the non-invasive electrophysiological techniques, the signals measured at the scalp are a mixture of the contributions from multiple generators or sources added to background activity and system noise, meaning that it is often difficult to identify the dynamic activity of generators of interest starting from the electrode/sensor recordings. Although the most common method of overcoming this limitation is time-domain averaging with or without source localization, blind source separation (BSS) algorithms are becoming increasingly widely accepted as a way of extracting the different neuronal sources that contribute to the measured scalp signals without trial exclusion. The advantage of BSS or semi-blind source separation (semi-BSS) techniques compared to methods such as time-domain averaging lies in their ability to extract sources exploring the whole time evolving data. Taking into account the whole signal without averaging, it also provides a means suitable to investigate non-phase locked oscillatory processes and single-trial behaviour. This characteristic becomes a crucial issue when investigating combined EEG-fMRI data, particularly when the focus is on neurovascular coupling definitely dependent on single trial variability of the two datasets. In this context, this chapter describes a semi-BSS technique, Functional Source Separation (FSS), which is a tool to identify cerebral sources by exploiting a priori knowledge, such as spectral or evoked activity, which cannot be expressed by sources other than the one to be identified (functional fingerprint). In other words, FSS allows the identification of specific neuronal pools on the bases of their functional roles, independent of their spatial position.

Multiple sclerosis-related fatigue is highly common and often refractory to medical therapy. Ten fatigued multiple sclerosis patients received two blocks of 5-day anodal bilateral primary somatosensory areas transcranial direct current stimulation in a randomized, doubleblind sham-controlled, cross-over study. The real neuromodulation by a personalized electrode, shaped on the MRderived primary somatosensory cortical strip, reduced fatigue in all patients, by 26% in average ( p = 0.002), which did not change after sham ( p = 0.901). Anodal tDCS over bilateral somatosensory areas was able to relief fatigue in mildly disabled MS patients, when the fatigue related symptoms severely hamper their quality of life. These small-scale study results support the concept that interventions modifying the sensorimotor network activity balances could be a suitable non-pharmacological treatment for multiple sclerosis fatigue.

We performed a neuromagnetic investigation of the sensory hand cortical representation in the two hemispheres of 20 healthy volunteers. The localizations within the brain hemispheres of the cortical Equivalent Current Dipoles (ECDs) activated with the shortest latencies (N20 m and P30 m components) by separate stimulation of contralateral median nerve, thumb and little finger were analysed. The ECD spatial coordinates were in agreement with the known somatotopy of the sensory homunculus: little finger more medial and posterior, thumb more lateral and anterior, median nerve in-between. By considering the ECDs to thumb and little finger stimulation the boundaries of the hand cortical representation in primary sensory cortex, the `hand extension' was evaluated as the distance between the two. This parameter was similar on the two hemispheres, the `hand extension' being 17 mm and 12 mm for N20 m and P30 m components, respectively, with a standard deviation of 5 mm. We provide for the first time the ECDs localization of left and right median nerve, thumb and little finger, as well as the `hand extension' values, and their interhemispheric differences as a normative data set describing the organization of primary sensory cortical areas reserved to the hand in the healthy population. This approach permits objective measurements of absolute values, as well as of interhemispheric differences, of the sensory hand area following a monohemispheric lesion as well as to non-invasively follow-up its reorganization during clinical recovery.

Gait impairment is an important consequence of neurological disease. Passive mobilization of the affected lower limbs is often prescribed in order to safeguard tissue properties and prevent circulatory sequelae during paresis. However, passive movement could play a role also in stimulating cortical areas of the brain devoted to the control of the lower limb, so that deafferentation and learned non-use can be contrasted. The purpose of the present work is to investigate cortical involvement during active and passive movements of the ankle joint, in an attempt to gain deeper insight in the similarities between these two conditions. A wearable device to mobilize the ankle joint was implemented utilizing rotary shape memory alloy actuators. The technical characteristics of this actuator make it very compatible with the tight limitations on electromagnetic noise imposed by diagnostic instrumentation. Eleven healthy volunteers took part in the pre-clinical phase of the study. According to the protocol, brain activity was recorded by 165-channel magnetoencephalography (MEG) under three different conditions: rest, active dorsiflexion of the ankle and passive mobilization of the same joint. The acquired data were processed to obtain cortical ERD/ERS (Event Related Desynchronization/ Synchronization) maps, which were then compared. The results of this analysis show that there are similar patterns of activity between active and passive movement, particularly in β band, in the contralateral primary sensorimotor, dorsal premotor and supplementary motor areas. This result, albeit obtained from healthy subjects, might suggest that passive motion provides somatosensory afferences that, to some extent, are processed in a similar manner as for voluntary control. Should this evidence be confirmed by further experiments on neurological patients, it could support the prescription of passive exercise as a surrogate of active workout, at least, so long as patients are paretic.

Scalp somatosensory evoked potentials (SEPs) were recorded in 10 volunteers after median nerve stimulation, in four experimental conditions of hand movements performance/ideation, and compared with the baseline condition of full relaxation. The experimental conditions were (a) self-improvised hand-finger sequential movements; (b) the same movements according to a read sequence of numbers; (c) mental ideation of finger movements; and (d) passive displacement of fingers in complete relaxation. Latencies and amplitudes of the parietal (N20, P25, N33, and P45) and frontal peaks (P20-22, N30, and P40) were analyzed. Latencies did not vary in any of the paradigms. Among the parietal complexes, only the P25-N33 amplitude was significantly reduced in (a), (b), (c), and (d) and the N20-P25 was reduced in (a) and (d); among frontal waves, N30 and P40 were significantly reduced (20-75%) in (a) and (b). Coronal electrodes showed amplitude decrements maximal at the frontal-rolandic positions contralateral to the stimulated side.

Objective: To investigate the dynamics of communication within the primary somatosensory neuronal network. Methods: Multichannel EEG responses evoked by median nerve stimulation were recorded from six healthy participants. We investigated the directional connectivity of the evoked responses by assessing the Partial Directed Coherence (PDC) among five neuronal nodes (brainstem, thalamus and three in the primary sensorimotor cortex), which had been identified by using the Functional Source Separation (FSS) algorithm. We analyzed directional connectivity separately in the low (1-200. Hz, LF) and high (450-750. Hz, HF) frequency ranges. Results: LF forward connectivity showed peaks at 16, 20, 30 and 50. ms post-stimulus. An estimate of the strength of connectivity was modulated by feedback involving cortical and subcortical nodes. In HF, forward connectivity showed peaks at 20, 30 and 50. ms, with no apparent feedback-related strength changes. Conclusions: In this first non-invasive study in humans, we documented directional connectivity across subcortical and cortical somatosensory pathway, discriminating transmission properties within LF and HF ranges. Significance: The combined use of FSS and PDC in a simple protocol such as median nerve stimulation sheds light on how high and low frequency components of the somatosensory evoked response are functionally interrelated in sustaining somatosensory perception in healthy individuals. Thus, these components may potentially be explored as biomarkers of pathological conditions. © 2012 International Federation of Clinical Neurophysiology.

Objective. To verify whether systemic biometals dysfunctions affect neurotransmission in living Alzheimer’s disease (AD) patients.Methods. We performed a case-control study using magnetoencephalography to detect sensorimotor fields of AD patients, at rest and during median nerve stimulation. We analyzed position and amount of neurons synchronously activated by the stimulation in both hemispheres to investigate the capability of the primary somatosensory cortex to reorganize its circuitry disrupted by the disease. We also assessed systemic levels of copper, ceruloplasmin, non-Cp copper (i.e., copper not bound to ceruloplasmin), peroxides, transferrin, and total antioxidant capacity.Results. Patients’ sensorimotor generators appeared spatially shifted, despite no change of latency and strength, while spontaneous activity sources appeared unchanged. Neuronal reorganization was greater in moderately ill patients, while delta activity increased in severe patients. Non-Cp copper was the only biological variable appearing to be associated with patient sensorimotor transmission.Conclusions. Our data strengthen the notion that non-Cp copper, not copper in general, affects neuronal activity in AD.Significance. High plasticity in the disease early stages in regions controlling more commonly used body parts strengthens the notion that physical and cognitive activities are protective factors against progression of dementia.

To hone knowledge of sensorimotor cerebral organization changes with physiological aging, we focused on the primary somatosensory cortical area (S1). S1 neuronal pools (FS-S1) were identified by the functional source separation (FSS) algorithm applied to magnetoencephalographic recordings during median nerve stimulation. Age-dependence of FS-S1 was then studied at rest separately in the left and right hemispheres of 26 healthy, right-handed subjects between the ages of 24 and 95 years. The resting state FS-S1 spectral features changed with increasing age: (1) alpha activity slowed down; (2) total power increased only in the right hemisphere; (3) right>left interhemispheric asymmetry increased in the whole spectrum; (4) spectral entropy increased with age selectively in the left hemisphere. The present FSS-enriched electrophysiological procedure provided measures of resting state hand representation area sensitive to changes with age. Alterations were stronger in the right hemisphere. Relationships between resting state S1 activity and its responsiveness to external stimuli, revealed that the interhemispheric unbalances which emerged with age were conceivably due to an increased excitability within the right thalamocortical circuit impacting left versus right unbalances of spontaneous firing rates and of local inhibitory-excitatory networks. © 2012 Springer Science+Business Media, LLC.

Rationale: Personalizing transcranial stimulations promises to enhance beneficial effects for individual patients. Objective: To stimulate specific cortical regions by developing a procedure to bend and position custom shaped electrodes; to probe the effects on cortical excitability produced when the properly customized electrode is targeting different cortical areas. Method: An ad hoc neuronavigation procedure was developed to accurately shape and place the personalized electrodes on the basis of individual brain magnetic resonance images (MRI) on bilateral primary motor (M1) and somatosensory (S1) cortices. The transcranial alternating current stimulation (tACS) protocol published by Feurra et al. (2011b) was used to test the effects on cortical excitability of the personalized electrode when targeting S1 or M1. Results: Neuronal excitability as evaluated by tACS was different when targeting M1 or S1, with the General Estimating Equation model indicating a clear tCS Effect (p

The large majority (80%) of people with multiple sclerosis (MS) complain of fatigue, which is the most disabling symptom in half of them. While the few drugs used to treat MS fatigue are limitedly useful, it was recently observed the efficacy of a personalized neuromodulation treatment, supporting the concept that interventions modifying the sensorimotor network activity balances could be suitable non-pharmacological treatments for MS fatigue. Aim of the present study is to strengthen knowledge of the brain unbalances, which proper neuromodulations should target to compensate. We collected electroencephalographic (EEG) data in 18 people with mild MS, while they were in resting state with open eyes. To ensure a wide range of fatigue, we enrolled patients to have Higher- or Lower-Fatigue based on scores of the modified Fatigue Impact Scale (mFIS). We selected the graph theory small-world index, calculated on networks of cortical nodes estimated by eLORETA, to evaluate the characteristics of left and right frontal (Motor) and parieto-occipital-temporal (Sensory) brain networks separately. Fatigue symptoms increased together with the small-world index in the Sensory network of the left dominant hemisphere. This finding hones understanding of the targets of neuromodulation interventions, indicating the sensory network of the dominant left hemisphere as a specific target.

Recent morpho-functional evidences pointed out that abnormalities in the thalamus could play a major role in the expression of migraine neurophysiological and clinical correlates. To this aim, we used Functional Source Separation algorithm to extract, from EEG signals, the activity of different neuronal pools recruited at different latencies along the somatosensory pathway in interictal migraine without aura (MO) patients. Twenty MO patients and twenty healthy volunteers (HV) underwent EEG recording. Four functional sources, two sub-cortical (FS14 at brainstem and FS16 at thalamic level) and two cortical (FS20 radial and FS22 tangential parietal), were extracted along the somatosensory pathway in response to the median nerve stimulation. High-frequency oscillatory (HFO) was extracted using band-pass digital filter (450–750 Hz) from the broadband EEG signal. Significant HFO reduction in the sub-cortical FS14 and FS16 were observed for the MO patients compared to the HV. No significant differences were reached, instead, for the cortical ones. Reduced sub-cortical brainstem and thalamic HFO activations play an important role in MO patients. Present results are the first neurophysiological evidence supporting the hypothesis that a functional disconnection of the thalamus from the subcortical monoaminergic system may underline the interictal cortical abnormal information processing in migraine.

Background Electroencephalographic recording during transcranial magnetic stimulation (EEG/TMS) is used to investigate the state of cortical activity and connectivity (EEG) relative to the non-invasive stimulation of the cortex (TMS). Two technologies have been used so far to acquire the EEG signal during TMS stimulation: the sample-and-hold amplifiers and DC amplifiers with high dynamics. The first bypasses the artefact generated by the pulse itself disabling the acquisition during a short window around the pulse, but with loss of information in that interval. The second records the whole dynamic of the pulse, but there are no solutions yet to deal with a so impacting and unwanted signal. Here we present the procedure that overcomes this limitation: ‘the independent component analysis – decomposition (ICA-D)’. Methods ICA was applied at two levels, on the original data and on the epochs, with identification and automatic reduction of the pulse artefacts from EEG registrations in single subject datasets. Results This pre-processing procedure returns datasets that are approachable as those obtained from sample-and-hold amplifiers but without the intrinsic disadvantages of that technology. Significance ICA-D is an automatic, data-driven and operator independent procedure. In future it could give new possibilities to unveil cortical responses covered by TMS-related artefacts.

Objective To test the need for the electrode personalization to induce neuromodulation effects on the bilateral primary motor cortex (M1) devoted to upper and lower limb representation. Methods We shaped the personalized electrode and positioned it matching the projection on the scalp of the individual central sulcus by a 2 cm strip. The non personalized electrode,equal for all subjects, was a 2 cm wide strip size-matched with the personalized electrode but shaped on a standard model fitting the curve passing through C3-CZ-C4 sites.To test neuromodulation electrode-dependent efficacy, we induced a 20 Hz sinusoidal modulated current (transcranial Alternating Current Stimulation, tACS) because it produces online effects.We simultaneously collected left and right hand and leg motor potentials (MEP) that were evoked by a rounded transcranial magneticstimulation (TMS) coil. Through each electrode we delivered both real and sham stimulations. Results While cortical excitability during tACS increased during both the non-personalized and the personalized electrodes for the leg, the hand representation excitability enhancement was induced selectively when using the personalized electrode. The results were consistent bilaterally. Conclusions Personalized electrode can induce the neuromodulation of a predetermined extended cortical target, which is impossible with a non-personalized electrode. Our findings can help in building neuromodulations that compensate for alterations across specific brain networks.

The brain is a connected network, requiring complex-system measures to describe its organization principles. Here, we aim at testing whether the normalized compression distance (NCD) is a suitable quantifier of the functional connectivity between cortical regions, studied non-invasively by magnetoencephalography (MEG) in healthy people. We used the Functional Source Separation (FSS) algorithm to identify functionally homologous areas in the two hemispheres devoted to the somatosensory hand representation (FS_S1). We calculated NCD between the left and right FS_S1s at rest. NCD between the left and right FS_S1 of the same person was smaller than across different subjects ( p −7 consistently). NCD was smaller within the left dominant hemisphere than within the nondominant right one ( p = 3·10 −7 ) and it became more variable in older than younger people ( p = .01). NCD measures the similarity of neuronal source activities via the signal compression length. NCD has properties expected for brain functional connectivity: within- is higher than between-subjects, in the dominant area is higher than in the non-dominant one, and it depends on age. NCD seems a good candidate for future studies on functional brain connectivity, able to overcome the limitations intrinsic to the classical Fourier or autoregressive estimates in assessing dynamics’ properties of the neuronal activity.

Background and purpose Despite similar clinical onset, recovery from stroke can be largely variable. We searched for electrophysiological prognostic indices, believing that they can guide future neuromodulation treatments boosting clinical recovery. Methods 19-channels resting electroencephalogram (EEG) was collected in 42 patients after 4-10 days (t0) from a unilateral ischemic stroke in the middle cerebral artery (MCA) territory and 20 controls. National Health Institute Stroke Scale (NIHSS) was collected at t0 and 6 months later (t1). Standard spectral band powers and interhemispheric coherences between homologous MCA regions were calculated in both hemispheres. Results Total spectral, delta and theta band powers were higher bilaterally in patients than in controls and directly correlated with NIHSSt0 in both hemispheres. A linear regression model including each EEG patient's variable differing from those of controls and correlating with effective recovery [ER = (NIHSSt0-NIHSSt1)/(NIHSSt0-NIHSS in healthy conditions)] showed contralesional delta power as the only valid predictor of ER. A further regression model including also NIHSSt0 confirmed that contralesional delta power can add prognostic information to acute clinical impairment. Contralesional delta activity increase was best explained, in addition to the increasing ipsilesional delta activity, by a reduction of interhemispheric functional coupling--which did not explain a significantly portion of effective recovery variability by itself. Conclusions Contralesional EEG delta activity retains relevant negative prognostic information in acute stroke patients. Present results point to the interhemispheric interplay as a decisive target in setting up enriched rehabilitations.

Purpose: This work investigates how a direct bidirectional connection between brain and hand prosthesis modifies the bi-hemispheric sensorimotor system devoted to the movement control of the lost limb. Hand prostheses are often unable to satisfy users' expectations, mostly due to the poor performance of their interfacing system. Neural Interfaces implanted inside nerves of the stump offer the advantage of using the bidirectional neural pathways 'naturally' dispatching signals to control proper hand actions and feed-back sensations. Learning to control a neurally-interfaced hand prosthesis and decode sensory information was previously observed to reduce the inter-hemispheric asymmetry of cortical motor maps and the clinical symptoms of phantom limb syndrome. Methods: Electroencephalographic (EEG) data was analysed using Functional Source Separation (FSS), a semi-blind method that incorporates prior knowledge about the signal of interest into data decomposition to give access to cortical patch activities. Results: Bi-hemispheric cortices showed normalization of their activity (topographical and spectral patterns) and of functional connectivity between homologous hand controlling areas, during the delivery of the motor command to the cybernetic prosthesis. Conclusions: The re-establishment of central-peripheral communication with the lost limb induced by a neurally-interfaced hand prosthesis produces beneficial plastic reorganization, not only restructuring contralateral directly-connected control areas, but also their functional balance within the bi-hemispheric system necessary for motor control.

Background: Highly common in multiple sclerosis (MS), fatigue severely impacts patients’ daily lives. Previous findings of altered connectivity patterns led to the hypothesis that the distortion of functional connections within the brain-muscle circuit plays a crucial pathogenic role. Objective: The objective of this paper is to identify markers sensitive to fatigue in multiple sclerosis. Methods: Structural (magnetic resonance imaging with assessment of thalamic volume and cortical thickness of the primary sensorimotor areas) and functional (cortico-muscular coherence (CMC) from simultaneous electroencephalo- and surface electromyographic recordings during a weak handgrip task) measures were used on 20 mildly disabled MS patients (relapsing–remitting course, Expanded Disability Status Scale score ≤ 2) who were recruited in two fatigue-dependent groups according to the Modified Fatigue Index Scale (MFIS) score. Results: The two groups were similar in terms of demographic, clinical and imaging features, as well as task execution accuracy and weariness. In the absence of any fatigue-dependent brain and muscular oscillatory activity alterations, CMC worked at higher frequencies as fatigue increased, explaining 67% of MFIS variance ( p=.002). Conclusion: Brain-muscle functional connectivity emerged as a sensitive marker of phenomena related to the origin of MS fatigue, impacting central-peripheral communication well before the appearance of any impairment in the communicating nodes.

Transient rearrangements of finger representation in primary somatosensory cortex induced by an anesthetic block of the sensory information from adjacent fingers have been shown invasively in animals. Such a phenomenon has been now replicated in seven healthy human volunteers. Somatosensory Evoked Fields (SEFs) have been recorded during separate electrical stimulation of the 1st, 3rd, or 5th finger. Recordings were obtained in control conditions (stage A), following complete ischemic anesthesia of the 4 non-stimulated fingers (stage B), and after regaining sensation (stage C). SEFs were recorded using a 28-channel DC-SQUID magnetometer; a single position of the sensor was enough to identify the source of N20m, P30m and following components using the Equivalent Current Dipole (ECD) model. The amount of afferent input during stages A through C was monitored with surface electrodes placed on the nerve at wrist and elbow. No variation of the nerve compound potential was observed during stages A through C. In stage A, the localizing algorithm was able to discriminate the individual finger representation in accordance with the somatotopic organisation of the sensory homunculus. It was observed that the ECDs responsible for the cortical responses from the unanesthetized finger were significantly changing following a relatively brief period of sensory deprivation from the adjacent fingers. Such changes of the ECDs with respect to the control conditions were characterized by an increase in strength and deepening for the middle finger, and by a shift on the coronal plane for the thumb and the little finger (medial for the former, lateral for the latter). Such changes became progressively evident in stage B, but were persisting in stage C.

Objective. To verify whether markers of metal homeostasis are related to a magnetoencephalographic index representative of glutamate-mediated excitability of the primary somatosensory cortex. The index is identified as the source strength of the earliest component (M20) of the somatosensory magnetic fields (SEFs) evoked by right median nerve stimulation at wrist.Method. Thirty healthy right-handed subjects (51±22years) were enrolled in the study. A source reconstruction algorithm was applied to assess the amount of synchronously activated neurons subtending the M20 and the following SEF component (M30), which is generated by two independent contributions of gabaergic and glutamatergic transmission. Serum copper, ceruloplasmin, iron, transferrin, transferrin saturation, and zinc levels were measured.Results. Total copper and ceruloplasmin negatively correlated with the M20 source strength.Conclusion. This pilot study suggests that higher level of body copper reserve, as marked by ceruloplasmin variations, parallels lower cortical glutamatergic responsiveness.

IntroductionSeveral neuropsychiatric pathologies have been recently linked to oxidative stress.ObjectivesIn this study, we investigated the relationship between depression, markers of oxidative stress and neurotransmission, as expressed by sensory cortex excitability.MethodsSerum levels of oxidative stress markers and somatosensory magnetic fields, evokedby external galvanic stimulation, were measured in 13 depressed patients and 13 controls.ResultsDepressives had higher levels of total and free copper than controls and lower levels oftransferrin. They also showed lower sensory cortex excitability, which correlated with copperlevels in controls, but not in patients. Transferrin correlated with sensory cortex excitability inboth patients and controls, although in opposite ways. Copper level results associated with thepatients’ clinical status.ConclusionsPro-oxidant agents appear to affect neuronal excitability and clinical state ofdepressed patients, as free copper excess alters their cortical glutamatergic neurotransmission.

Background and Purpose— Cerebral vasomotor reactivity (VMR) is a capability of cerebral vessels to dilate in response to hypercapnia. Transcranial direct current stimulation (tDCS) effects on cerebral hemodynamics have been poorly studied. Methods and Results— Ten healthy subjects underwent anodal/cathodal tDCS on the left motor cortex. Before and after tDCS, VMR assessment by transcranial Doppler and an electrocardiogram were performed. Normalized low-frequency band power of heart rate variability and its reactivity from basal to VMR condition (LFN react ) were estimated as relative markers of sympathetic activation. tDCS exerted a polarity-specific effect on both VMR ( P =0.0001) and LFN react ( P =0.001). Anodal tDCS decreased VMR by 3.4%/mm Hg CO 2 bilaterally and increased LFN react , whereas cathodal tDCS increased VMR by 0.8%/mm Hg CO 2 bilaterally and reduced LFN react . Conclusions— Cerebral VMR is modified by tDCS. Based on the consensual changes with heart rate variability, we can hypothesize that the sympathetic nervous system could modulate the bihemispheric modification of VMR. Further studies are needed to confirm this hypothesis.

Demyelination and axonal damage are pathologic hallmarks of multiple sclerosis (MS), leading to loss of neuronal synchronization, functional disconnection amongst brain relays, and clinical sequelae. To investigate these properties, the primary component of the sensorimotor network was analyzed in mildly disabled Relapsing-Remitting MS patients without sensory symptoms at the time of the investigation. By magnetoencephalography (MEG), the recruitment pattern within the primary sensory (S1) and motor (M1) areas was estimated through the morphology of the early components of somatosensory evoked magnetic fields (SEFs), after evaluating the S1 responsiveness to sensory inputs from the contralateral arm. In each hemisphere, network recruitment properties were correlated with ispilateral thalamus volume, estimated by morphometric techniques upon high-resolution 3D structural magnetic resonance images (MRI). S1 activation was preserved, whereas SEF morphology was strikingly distorted in MS patients, marking a disruption of primary somatosensory network patterning. An unbalance of S1–M1 dynamic recruitment was documented and correlated with the thalamic volume reduction in the left hemisphere. These findings support the model of MS as a disconnection syndrome, with major susceptibility to damage experienced by nodes belonging to more frequently recruited and highly specialized networks. Hum Brain Mapp, 2010. © 2010 Wiley-Liss, Inc.

A wide range of essential reasoning tasks rely on contradiction identification, a cornerstone of human rationality, communication and debate founded on the inversion of the logical operators “Every” and “Some.” A high‐density electroencephalographic (EEG) study was performed in 11 normal young adults. The cerebral network involved in the identification of contradiction included the orbito‐frontal and anterior‐cingulate cortices and the temporo‐polar cortices. The event‐related dynamic of this network showed an early negative deflection lasting 500 ms after sentence presentation. This was followed by a positive deflection lasting 1.5 s, which was different for the two logical operators. A lesser degree of network activation (either in neuron number or their level of phase locking or both) occurred while processing statements with “Some,” suggesting that this was a relatively simpler scenario with one example to be figured out, instead of the many examples or the absence of a counterexample searched for while processing statements with “Every.” A self‐generated reward system seemed to resonate the recruited circuitry when the contradictory task is successfully completed. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.

Passive mobilization of the paretic limbs is commonly part of standard care in the first stages after stroke, but at this moment it is not clear whether this can positively impact brain reorganization and functional recovery. Applying passive mobilization during MEG measurements poses the question of finding a way to provide repeatable cycles of movement without interfering too much with the biosignal acquisition. This paper presents SHADE, an active orthosis that promotes ankle dorsiflexion and fulfils these requirements by using shape memory alloy wire actuators. These alloys are very deformable at room temperature but can recover large deformations and generate considerable forces when heated above a characteristic temperature. Heating is provided by Joule’s effect, cooling by natural convection. Since current is provided by a dc-generator, only limited and easily removable magnetic noise is produced. SHADE was tested in a MEG shielded room to evaluate both orthosis performance and sensorimotor cortical involvement during passive mobilization induced in 7 healthy subjects (30.3±6.9y/o). The measurements could be cleaned from any noise produced by SHADE and suitably analyzed to describe the activation patterns of primary sensorimotor areas devoted to the ankle control. The cerebral involvement in these regions during the use of SHADE was significantly different from rest. This suggests that passive stimulation with SHADE could have clinical implications and possibly a role in the recovery of active functionality in stroke patients.

Acute post-stroke rehabilitation protocols include passive mobilisation as a means to prevent contractures, but this technique could also help preserve neuromuscular activation patterns through proprioceptive information. This paper presents SHADE, an active orthosis that provides repetitive passive motion to a flaccid ankle by using shape memory alloy wire actuators. SHADE was studied to assess the promoted passive range of motion (PROM), acceptability and cortical effects. PROM and tolerability was assessed on 3 acute post-stroke patients (58±5y/o) by means of optoelectronic cinematic analysis. EEG/MEG instrumentation was utilised to evaluate sensorimotor cortical involvement during passive mobilization induced by SHADE in 7 healthy subjects (30.3±6.9y/o). These data were compared with voluntary movement (VM). SHADE produced good mobilisation across the available PROM (typically, from 5° plantarflexion to 15° dosiflexion). Acceptability in patients was also good. Suitable functional sources were identified for the primary sensorimotor areas. Cortico-muscular coherence was high not only in primary motor but also in primary somatosensory cortex. The cerebral involvement in these regions during the use of SHADE was similar to VM and significantly different from rest. This suggests that passive stimulation with SHADE could have clinical implications in supporting recovery of active functionality in stroke patients.

Neuroscience studies on the social sharing of observed or imagined pain focused on whether empathic pain resonance is linked to affective or sensory nodes of the pain matrix. However, empathy, like other complex cognitive processes, is inherently linked to the activation of functional networks rather than of separate brain areas. Here, we used magnetoencephalography (MEG) to explore the relationship between empathy and functional coupling of neuronal activity in primary somatosensory (SI) and motor (MI) cortices. MEG recording was performed while healthy participants observed movie-clips depicting the static hand of a stranger model, the same hand deeply penetrated by a needle, or gently touched by a Q-tip. Subjects were asked to rate the movie-derived sensations attributed to self or to the model. For each type of clip observation, we analyzed spectral power and coherence values in α, β, and γ frequency bands. While spectral power indexes separate neural activity in SI and MI, coherence values index functional cross-talk between these two areas. No power changes of SI or MI sources were induced by observation conditions in any of the frequency bands. Crucially, γ-band coherence values were significantly higher during needle-in-hand than touch and static hand observation and correlated with self-and other-referred pain ratings derived from needle-in-hand movies observation. Thus, observation of others' pain increases neuronal synchronization and cross-talk between the onlookers' sensory and motor cortices, indicating that empathic resonance relies upon the activity of functional networks more than of single areas.

Objective: A realistic simulation exploiting real cortical sources identified from non-invasive extra-cranial recordings in healthy subjects has been considered in order to select the most robust procedure for choosing the correct order of multivariate autoregressive (MVAR) models. Different signal-to-noise ratios filter settings and sampling rates were also tested on the estimate of functional connectivity among the network nodes, in simulated and real cases. Methods: Starting from magnetoencephalographic recordings, cortical sources in primary sensorimotor areas of the hand were obtained by functional source separation (FSS). Different criteria for the choice of the model order were compared in the simulated network constructed through one of the FSS-extracted sources and its noise-added delayed copies. In two real cases, a validation of the model order (not known a priori) choice was obtained by comparing the time-frequency properties as depicted by classical non-parametric and MVAR methods at rest, during isometric contraction (stationary states) and while dynamically responding to a sensory stimulation (transient state). For completeness, the whole set of MVAR functional connectivity measures was taken into account, to assess the most suitable for our network description. Results: That the use of an incorrect model order distorts network functional connectivity estimate was documented both in the realistic simulation and in the two real cases. The Minimal Description Length and Schwartz Bayesian Criterion were selected as the most robust for MVAR model order choice. Partial directed coherence (PDC) was the most suitable method for time-frequency connectivity estimate in the simulated as well as in the real cases, both in stationary and transient states. Moreover, the results of MVAR-based connectivity estimate depend on filter setting in the real case. Conclusions: The most robust procedure for choosing the correct MVAR model order was provided. The adjunctive comparison of MVAR to classical methods is recommended to validate the choice in the real case. Significance: Correct MVAR model order choice and band filtering play an important role for the correct network connectivity estimate. © 2008 International Federation of Clinical Neurophysiology.

The dream of controlling and guiding computer-based systems using human brain signals has slowly but steadily become a reality. The available technology allows real-time implementation of systems that measure neuronal activity, convert their signals, and translate their output for the purpose of controlling mechanical and electronic systems. This paper describes the state of the art of non-invasive Brain-Machine Interfaces (BMIs) and critically investigates both the current technological limits and the future potential that BMIs have for space applications. We present an assessment of the advantages that BMIs can provide and justify the preferred candidate concepts for space applications together with a vision of future directions for their implementation.

We propose a novel electroencephalographic application of a recently developed cerebral source extraction method (Functional Source Separation, FSS), which starts from extracranial signals and adds a functional constraint to the cost function of a basic independent component analysis model without requiring solutions to be independent. Five ad‐hoc functional constraints were used to extract the activity reflecting the temporal sequence of sensory information processing along the somatosensory pathway in response to the separate left and right median nerve galvanic stimulation. Constraints required only the maximization of the responsiveness at specific latencies following sensory stimulation, without taking into account that any frequency or spatial information. After source extraction, the reliability of identified FS was assessed based on the position of single dipoles fitted on its retroprojected signals and on a discrepancy measure. The FS positions were consistent with previously reported data (two early subcortical sources localized in the brain stem and thalamus, the three later sources in cortical areas), leaving negligible residual activity at the corresponding latencies. The high‐frequency component of the oscillatory activity (HFO) of the extracted component was analyzed. The integrity of the low amplitude HFOs was preserved for each FS. On the basis of our data, we suggest that FSS can be an effective tool to investigate the HFO behavior of the different neuronal pools, recruited at successive times after median nerve galvanic stimulation. As FSs are reconstructed along the entire experimental session, directional and dynamic HFO synchronization phenomena can be studied. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.

The functional source separation procedure (FSS) was applied to identify the activities of the primary sensorimotor areas (SM1) devoted to hand control. FSS adds a functional constraint to the cost function of the basic independent component analysis, and obtains source activity all along different processing states. Magnetoencephalographic signals from the left SM1 were recorded in 14 healthy subjects during a simple sensorimotor paradigm—galvanic right median nerve stimuli intermingled with submaximal isometric thumb opposition. Two functional sources related to the sensory flow in the primary cortex were extracted requiring maximal responsiveness to the nerve stimulation at around 20 and 30 ms (S1a, S1b). Maximal cortico‐muscular coherence was required for the extraction of the motor source (M1). Sources were multiplied by the Euclidean norm of their corresponding weight vectors, allowing amplitude comparisons among sources in a fixed position. In all subjects, S1a, S1b, M1 were successfully obtained, positioned consistently with the SM1 organization, and behaved as physiologically expected during the movement and processing of the sensory stimuli. The M1 source reacted to the nerve stimulation with higher intensity at latencies around 30 ms than around 20 ms. The FSS method was demonstrated to be able to obtain the dynamics of different primary cortical network activities, two devoted mainly to sensory inflow, and the other to the motor control of the contralateral hand. It was possible to observe each source both during pure sensory processing and during motor tasks. In all conditions, a direct comparison of source intensities can be achieved. Hum Brain Mapp, 2008. © 2007 Wiley‐Liss, Inc.

Growing evidence emphasizes a positive role of brain ipsilesional (IL) reorganization in stroke patients with partial recovery. Ten patients affected by a monohemispheric stroke in the middle cerebral artery territory underwent functional magnetic resonance (fMRI) and magnetoencephalography (MEG) evaluation of the primary sensory (S1) activation via the same paradigm (median nerve galvanic stimulation). Four patients did not present S1 fMRI activation [Rossini, P.M., Altamura, C., Ferretti, A., Vernieri, F., Zappasodi, F., Caulo, M., Pizzella, V., Del Gratta, C., Romani, G.L., Tecchio, F., 2004. Does cerebrovascular disease affect the coupling between neuronal activity and local haemodynamics? Brain 127, 99-110], although inclusion criteria required bilateral identifiable MEG responses. Mean Euclidean distance between fMRI and MEG S1 activation Talairach coordinates was 10.1+/-2.9 mm, with a 3D intra-class correlation (ICC) coefficient of 0.986. Interhemispheric asymmetries, evaluated by an MEG procedure independent of Talairach transformation, were outside or at the boundaries of reference ranges in 6 patients. In 3 of them, the IL activation presented medial or lateral shift with respect to the omega-shaped post-rolandic area while in the other 3, IL areas were outside the peri-rolandic region. In conclusion, despite dissociated intensity, the MEG and fMRI activations displayed good spatial consistency in stroke patients, thus confirming excessive interhemispheric asymmetries as a suitable indicator of unusual recruitments in the ipsilesional hemisphere, within or outside the peri-rolandic region.

In patients affected by monohemispheric stroke in the middle cerebral artery territory, who do not regain a normal neurological function, a positive contribution to the clinical recovery seems to be made by the involvement of primary hand representation areas in the affected hemisphere (AH), excessively asymmetric to its homologous in the unaffected hemisphere (UH). We investigated primary sensory hand areas in 41 chronic patients who had improved their clinical status without reaching complete recovery. The location and strength of the first cerebral sources activated by a contralateral galvanic median nerve stimulation (M20 and M30) were evaluated in both hemispheres, together with their interhemispheric differences. The source displacement in the AH with respect to the UH was positively correlated with clinical recovery (Spearman’s ρ = 0.584, p = 0.003). The excessive interhemispheric asymmetry – as defined on the basis of reference ranges in the healthy population – could be interpreted as the involvement of neuronal pools in the AH outside the hand ‘omega zone’ of the Rolandic sulcus, revealing the presence of plasticity phenomena. The present data provide support to a positive role of cerebral plasticity phenomena, partially contributing to post-stroke recovery in patients unable to achieve normal neurological function.

To investigate neural coding characteristics in the human primary somatosensory cortex, two fingers with different levels of functional skill were studied. Their dexterity was scored by the Fingertip writing test. Each finger was separately provided by a passive simple sensory stimulation and the responsiveness of each finger cortical representation was studied by a novel source extraction method applied to magnetoencephalographic signals recorded in a 14 healthy right handed subject cohort. In the two hemispheres, neural oscillatory activity synchronization was analysed in the three characteristic alpha, beta and gamma frequency bands by two dynamic measures, one isolating the phase locking between neural network components, the other reflecting the total number of synchronous recruited neurons. In the dominant hemisphere, the gamma band phase locking was higher for the thumb than for the little finger and it correlated with the contra-lateral finger dexterity. Neither in the dominant nor in the non-dominant hemisphere, any effect was observed in the alpha and beta bands. In the gamma band, the amplitude showed similar tendency to the phase locking, without reaching statistical significance. These findings suggest the dynamic gamma band phase locking as a code for finger dexterity, in addition to the magnification of somatotopic central maps.

Prolonged environmental noise exposure can induce pathogenic effects on various physical and psychosocial responses. The first aim of this study was to investigate whether long-term occupational noise exposure could affect neurophysiological, neuropsychological and emotional statuses, with particular respect to attention and working memory. The second aim was to evaluate the effects on the tactile P300 of a specific stressor (background traffic noise) vs a non-specific stress inductor (Stroop test). The comparison between a group of noise-exposed workers (traffic police officers), and a control group (office employees) did not show marked differences in cognitive and emotional profiles. The amplitude of the baseline cognitive potential (P300), recorded during a tactile (electric) discrimination task, resulted higher in noise-exposed workers than in controls, and this enhancement was associated with a lower level of trait anxiety and better mood profiles. Moreover, we found a wider P300 amplitude reduction in traffic police officers than in controls, under noisy conditions due to traffic. The effect of the Stroop test as a stress inductor was negligible and similar in the two groups. The wider amplitude of the non-auditory P300 in traffic police officers in the baseline condition could be a sign of cross-modal cerebral plasticity enhancing attentive processes in the 'stress-free' sensory channel. In addition, noise-exposed workers presented a higher cerebral sensitivity to stress selectively when they were exposed to the habitual environmental stressor.