Publications by authors named "Carlo Miniussi"

144 Publications

Asymmetric transcallosal conduction delay leads to finer bimanual coordination.

Brain Stimul 2021 Feb 10;14(2):379-388. Epub 2021 Feb 10.

Department of Experimental Medicine, Section of Human Physiology, University of Genoa, Genoa, Italy; Ospedale Policlinico San Martino-IRCCS, Genoa, Italy. Electronic address:

It has been theorized that hemispheric dominance and more segregated information processing have evolved to overcome long conduction delays through the corpus callosum (transcallosal conduction delay - TCD) but that this may still impact behavioral performance, mostly in tasks requiring high timing accuracy. Nevertheless, a thorough understanding of the temporal features of interhemispheric communication is lacking. Here, we aimed to assess the relationship between TCD and behavioral performance with a noninvasive directional cortical measure of TCD obtained from transcranial magnetic stimulation (TMS)-evoked potentials (TEPs) in the motor system. Twenty-one healthy right-handed subjects were tested. TEPs were recorded during an ipsilateral silent period (iSP) paradigm and integrated with diffusion tensor imaging (DTI) and an in-phase bimanual thumb-opposition task. Linear mixed models were applied to test relationships between measures. We found TEP indexes of transcallosal communication at ∼15 ms both after primary motor cortex stimulation (M1-P15) and after dorsal premotor cortex stimulation (dPMC-P15). Both M1-and dPMC-P15 were predicted by mean diffusivity in the callosal body. Moreover, M1-P15 was positively related to iSP. Importantly, M1-P15 latency was linked to bimanual coordination with direction-dependent effects, so that asymmetric TCD was the best predictor of bimanual coordination. Our findings support the idea that transcallosal timing in signal transmission is essential for interhemispheric communication and can impact the final behavioral outcome. However, they challenge the view that a short conduction delay is always beneficial. Rather, they suggest that the effect of the conduction delay may depend on the direction of information flow.
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http://dx.doi.org/10.1016/j.brs.2021.02.002DOI Listing
February 2021

tDCS over posterior parietal cortex increases cortical excitability but decreases learning: An ERPs and TMS-EEG study.

Brain Res 2021 Feb 30;1753:147227. Epub 2020 Dec 30.

Center for Mind/Brain Sciences - CIMeC, University of Trento, Rovereto, TN, Italy. Electronic address:

The application of anodal transcranial direct current stimulation (AtDCS) is generally associated with increased neuronal excitability and enhanced cognitive functioning. Nevertheless, previous work showed that applying this straight reasoning does not always lead to the desired results at behavioural level. Here, we investigated electrophysiological markers of AtDCS-mediated effects on visuo-spatial contextual learning (VSCL). In order to assess cortical excitability changes after 3 mA AtDCS applied over posterior parietal cortex, event-related potentials (ERPs) were collected during task performance. Additionally, AtDCS-induced effects on cortical excitability were explored by measuring TMS-evoked potentials (TEPs) collected before AtDCS, after AtDCS and after AtDCS and VSCL interaction. Behavioural results revealed that the application of AtDCS induced a reduction of VSCL. At the electrophysiological level, ERPs showed enhanced cortical response (P2 component) in the group receiving Real-AtDCS as compared to Sham-AtDCS. Cortical responsiveness at rest as measured by TEP, did not indicate any significant difference between Real- and Sham-tDCS groups, albeit a trend was present. Overall, our results suggest that AtDCS increases cortical response to incoming visuo-spatial stimuli, but with no concurrent increase in learning. Detrimental effects on behaviour could result from the interaction between AtDCS- and task-mediated cortical activation. This interaction might enhance cortical excitability and hinder normal task-related neuroplastic phenomena subtending learning.
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http://dx.doi.org/10.1016/j.brainres.2020.147227DOI Listing
February 2021

Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: Expert Guidelines.

Clin Neurophysiol 2021 Jan 24;132(1):269-306. Epub 2020 Oct 24.

Human Motor Control Section, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, MD, USA. Electronic address:

This article is based on a consensus conference, promoted and supported by the International Federation of Clinical Neurophysiology (IFCN), which took place in Siena (Italy) in October 2018. The meeting intended to update the ten-year-old safety guidelines for the application of transcranial magnetic stimulation (TMS) in research and clinical settings (Rossi et al., 2009). Therefore, only emerging and new issues are covered in detail, leaving still valid the 2009 recommendations regarding the description of conventional or patterned TMS protocols, the screening of subjects/patients, the need of neurophysiological monitoring for new protocols, the utilization of reference thresholds of stimulation, the managing of seizures and the list of minor side effects. New issues discussed in detail from the meeting up to April 2020 are safety issues of recently developed stimulation devices and pulse configurations; duties and responsibility of device makers; novel scenarios of TMS applications such as in the neuroimaging context or imaging-guided and robot-guided TMS; TMS interleaved with transcranial electrical stimulation; safety during paired associative stimulation interventions; and risks of using TMS to induce therapeutic seizures (magnetic seizure therapy). An update on the possible induction of seizures, theoretically the most serious risk of TMS, is provided. It has become apparent that such a risk is low, even in patients taking drugs acting on the central nervous system, at least with the use of traditional stimulation parameters and focal coils for which large data sets are available. Finally, new operational guidelines are provided for safety in planning future trials based on traditional and patterned TMS protocols, as well as a summary of the minimal training requirements for operators, and a note on ethics of neuroenhancement.
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http://dx.doi.org/10.1016/j.clinph.2020.10.003DOI Listing
January 2021

Enhancing cognitive training effects in Alzheimer's disease: rTMS as an add-on treatment.

Brain Stimul 2020 Nov - Dec;13(6):1655-1664. Epub 2020 Sep 28.

Fondazione Europea Ricerca Biomedica, Ospedale Sant'Isidoro, 24069, Trescore Balneario, Bergamo, Italy.

The treatment of Alzheimer's disease (AD) in the field of non-pharmacological interventions is a challenging issue, given the limited benefits of the available drugs. Cognitive training (CT) represents a commonly recommended strategy in AD. Recently, repetitive transcranial magnetic stimulation (rTMS) has gained increasing attention as a promising therapeutic tool for the treatment of AD, given its ability of enhancing neuroplasticity. In the present randomized, double-blind, sham-controlled study, we aimed at investigating the add-on effect of a high frequency rTMS protocol applied over the left dorsolateral prefrontal cortex (DLPFC) combined with a face-name associative memory CT in the continuum of AD pathology. Fifty patients from a very early to a moderate phase of dementia were randomly assigned to one of two groups: CT plus real rTMS or CT plus placebo rTMS. The results showed that the improvement in the trained associative memory induced with rTMS was superior to that obtained with CT alone. Interestingly, the extent of the additional improvement was affected by disease severity and levels of education, with less impaired and more educated patients showing a greater benefit. When testing for generalization to non-trained cognitive functions, results indicated that patients in CT-real group showed also a greater improvement in visuospatial reasoning than those in the CT-sham group. Interestingly, this improvement persisted over 12 weeks after treatment beginning. The present study provides important hints on the promising therapeutic use of rTMS in AD.
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http://dx.doi.org/10.1016/j.brs.2020.09.010DOI Listing
September 2020

Transcranial electric stimulation as a neural interface to gain insight on human brain functions: current knowledge and future perspective.

Soc Cogn Affect Neurosci 2020 Aug 5. Epub 2020 Aug 5.

UniCamillus - Saint Camillus International University of Health Sciences, via di Sant'Alessandro 8, 00131, Rome, Italy.

The use of brain-stimulation approaches in social and affective science has greatly increased over the last two decades. The interest in social factors has grown along with technological advances in brain research. Transcranial electric stimulation (tES) is a research tool that allows scientists to establish contributory causality between brain functioning and social behaviour, therefore deepening our understanding of the social mind. Preliminary evidence is also starting to demonstrate that tES, either alone or in combination with pharmacological or behavioural interventions, can alleviate the symptomatology of individuals with affective or social cognition disorders. This review offers an overview of the application of tES in the field of social and affective neuroscience. We discuss issues and challenges related to this application and suggest avenue for future basic and translational research.
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http://dx.doi.org/10.1093/scan/nsaa099DOI Listing
August 2020

Pearl and pitfalls in brain functional analysis by event-related potentials: a narrative review by the Italian Psychophysiology and Cognitive Neuroscience Society on methodological limits and clinical reliability-part II.

Neurol Sci 2020 Dec 18;41(12):3503-3515. Epub 2020 Jul 18.

Neurology Unit, Bambino Gesù Hospital, Rome, Italy.

This review focuses on new and/or less standardized event-related potentials methods, in order to improve their knowledge for future clinical applications. The olfactory event-related potentials (OERPs) assess the olfactory functions in time domain, with potential utility in anosmia and degenerative diseases. The transcranial magnetic stimulation-electroencephalography (TMS-EEG) could support the investigation of the intracerebral connections with very high temporal discrimination. Its application in the diagnosis of disorders of consciousness has achieved recent confirmation. Magnetoencephalography (MEG) and event-related fields (ERF) could improve spatial accuracy of scalp signals, with potential large application in pre-surgical study of epileptic patients. Although these techniques have methodological limits, such as high inter- and intraindividual variability and high costs, their diffusion among researchers and clinicians is hopeful, pending their standardization.
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http://dx.doi.org/10.1007/s10072-020-04527-xDOI Listing
December 2020

tDCS effects on brain network properties during physiological aging.

Pflugers Arch 2020 Jul 4. Epub 2020 Jul 4.

Cognitive Neuroscience Section, IRCCS Istituto Centro San Giovanni di Dio, Fatebenefratelli, Brescia, Italy.

Brain neural networks undergo relevant changes during physiological aging, which affect cognitive and behavioral functions. Currently, non-invasive brain stimulation techniques, such as transcranial direct current stimulation (tDCS), are proposed as tools able to modulate cognitive functions in brain aging, acting on networks properties and connectivity. Segregation and integration measures are used and evaluated by means of local clustering (segregation) and path length (integration). Moreover, to assess the balancing between them, the Small World (SW) parameter is employed, evaluating functional coupling in normal brain aging and in pathological conditions including neurodegeneration. The aim of this study was to systematically investigate the tDCS-induced effects on brain network proprieties in physiological aging. In order to reach this aim, cortical activity was acquired from healthy young and elderly subjects by means of EEG recorded before, during, and after anodal, cathodal, and sham tDCS sessions. Specifically, the aim to exploring tDCS polarity-dependent changes in the age-dependent network dynamics was based on a network graph theory application on two groups divided in young and elderly subjects. Eighteen healthy young (9 females; mean age = 24.7, SD = 3.2) and fifteen elderly subjects (9 females; mean = 70.1, SD = 5.1) were enrolled. Each participant received anodal, cathodal, or sham tDCS over the left prefrontal cortex (PFC) in three separate experimental sessions performed 1 week apart. SW was computed to evaluate brain network organization. The present study demonstrates that tDCS delivered in PFC can change brain network dynamics, and tDCS-EEG coregistration data can be analyzed using graph theory to understand the induced effects of different tDCS polarities in physiological and pathological brain aging.
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http://dx.doi.org/10.1007/s00424-020-02428-8DOI Listing
July 2020

Integrating TMS, EEG, and MRI as an Approach for Studying Brain Connectivity.

Neuroscientist 2020 Oct-Dec;26(5-6):471-486. Epub 2020 May 9.

Center for Mind/Brain Sciences-CIMeC, University of Trento, Rovereto, Italy.

The human brain is a complex network in which hundreds of brain regions are interconnected via thousands of axonal pathways. The capability of such a complex system emerges from specific interactions among smaller entities, a set of events that can be described by the activation of interconnections between brain areas. Studies that focus on brain connectivity have the aim of understanding and modeling brain function, taking into account the spatiotemporal dynamics of neural communication between brain regions. Much of the current knowledge regarding brain connectivity has been obtained from stand-alone neuroimaging methods. Nevertheless, the use of a multimodal approach seems to be a powerful way to investigate effective brain connectivity, overcoming the limitations of unimodal approaches. In this review, we will present the advantages of an integrative approach in which transcranial magnetic stimulation-electroencephalography coregistration is combined with magnetic resonance imaging methods to explore effective neural interactions. Moreover, we will describe possible implementations of the integrative approach in open- and closed-loop frameworks where real-time brain activity becomes a contributor to the study of cognitive brain networks.
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http://dx.doi.org/10.1177/1073858420916452DOI Listing
May 2020

Pearls and pitfalls in brain functional analysis by event-related potentials: a narrative review by the Italian Psychophysiology and Cognitive Neuroscience Society on methodological limits and clinical reliability-part I.

Neurol Sci 2020 Oct 9;41(10):2711-2735. Epub 2020 May 9.

Neurology Ward Unit, Bambino Gesù Hospital, Rome, Italy.

Event-related potentials (ERPs) are obtained from the electroencephalogram (EEG) or the magnetoencephalogram (MEG, event-related fields (ERF)), extracting the activity that is time-locked to an event. Despite the potential utility of ERP/ERF in cognitive domain, the clinical standardization of their use is presently undefined for most of procedures. The aim of the present review is to establish limits and reliability of ERP medical application, summarize main methodological issues, and present evidence of clinical application and future improvement. The present section of the review focuses on well-standardized ERP methods, including P300, Contingent Negative Variation (CNV), Mismatch Negativity (MMN), and N400, with a chapter dedicated to laser-evoked potentials (LEPs). One section is dedicated to proactive preparatory brain activity as the Bereitschaftspotential and the prefrontal negativity (BP and pN). The P300 and the MMN potentials have a limited but recognized role in the diagnosis of cognitive impairment and consciousness disorders. LEPs have a well-documented usefulness in the diagnosis of neuropathic pain, with low application in clinical assessment of psychophysiological basis of pain. The other ERP components mentioned here, though largely applied in normal and pathological cases and well standardized, are still confined to the research field. CNV, BP, and pN deserve to be largely tested in movement disorders, just to explain possible functional changes in motor preparation circuits subtending different clinical pictures and responses to treatments.
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http://dx.doi.org/10.1007/s10072-020-04420-7DOI Listing
October 2020

Effects of different transcranial direct current stimulation protocols on visuo-spatial contextual learning formation: evidence of homeostatic regulatory mechanisms.

Sci Rep 2020 03 12;10(1):4622. Epub 2020 Mar 12.

Centre for Mind/Brain Sciences - CIMeC, University of Trento, Rovereto, TN, Italy.

In the present study we tested the effects of different transcranial direct current stimulation (tDCS) protocols in the formation of visuo-spatial contextual learning (VSCL). The study comprised three experiments designed to evaluate tDCS-induced changes in VSCL measures collected during the execution of a visual search task widely used to examine statistical learning in the visuo-spatial domain. In Experiment 1, we probed for the effects of left-posterior parietal cortex (PPC) anodal-tDCS (AtDCS) at different timings (i.e. offline and online) and intensities (i.e. 3 mA and 1.5 mA). The protocol producing the more robust effect in Experiment 1 was used in Experiment 2 over the right-PPC, while in Experiment 3, cathodal-tDCS (CtDCS) was applied over the left-PPC only at a high intensity (i.e. 3 mA) but varying timing of application (offline and online). Results revealed that high intensity offline AtDCS reduced VSCL regardless of the stimulation side (Experiment 1 and 2), while no significant behavioral changes were produced by both online AtDCS protocols (Experiment 1) and offline/online CtDCS (Experiment 3). The reduced VSCL could result from homeostatic regulatory mechanisms hindering normal task-related neuroplastic phenomena.
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http://dx.doi.org/10.1038/s41598-020-61626-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067887PMC
March 2020

Touch anticipation mediates cross-modal Hebbian plasticity in the primary somatosensory cortex.

Cortex 2020 05 30;126:173-181. Epub 2020 Jan 30.

Department of Psychology & NeuroMi - Milan Center for Neuroscience, University of Milano-Bicocca, Milan, Italy; Laboratory of Neuropsychology, IRCCS Istituto Auxologico Italiano, Milan, Italy. Electronic address:

Paired associative stimulation (PAS) protocols can be used to induce Hebbian plasticity in the human brain. A modified, cross-modal version, of the PAS (cross-modal PAS, cm-PAS) has been recently developed. The cm-PAS consists in the repetitive pairings of a transcranial magnetic stimulation (TMS) pulse over the primary somatosensory cortex (S1) and a visual stimulus depicting a hand being touched; a 20 ms of inter-stimulus interval (ISI) is required to affect S1 plasticity, in turn modulating tactile acuity and somatosensory evoked potentials. The present study explores the role of anticipatory simulation in the cm-PAS efficacy, which could be responsible for such a short ISI. To this aim, we compared the effect of the original, fixed-frequency, cm-PAS to that of a jittered version, in which the time interval between trials was not steady but jittered, hence avoiding the anticipation of the upcoming visual-touch stimulus. Moreover, in the jittered PAS, the ISI between the paired stimulations was varied: it could match the early, somatosensory-driven, activation of S1 (20 ms), or the mirror recruitment of S1 by touch observation (150 ms). Results showed that tactile acuity is enhanced by the fixed-frequency cm-PAS, with an ISI of 20 ms between paired stimulation (visual-touch stimulus and TMS pulse over S1), and also by the jittered cm-PAS but only if the ISI is of 150 ms. These findings suggest that the cm-PAS with a jittered frequency, by preventing an anticipatory pre-activation of S1, delays the timing of the interaction between the visual-touch stimulus and the cortical pulse. On a broader perspective, our study highlights the possible involvement of sensory anticipation, likely through mirror-like simulation mechanisms, in tactile mirroring, as well as its influence of the optimal interval between the afferent and the magnetic pulse during PAS protocols.
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http://dx.doi.org/10.1016/j.cortex.2020.01.008DOI Listing
May 2020

Modelling the effects of ongoing alpha activity on visual perception: The oscillation-based probability of response.

Neurosci Biobehav Rev 2020 05 2;112:242-253. Epub 2020 Feb 2.

Cognitive Neuroscience Section, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.

Substantial evidence has shown that ongoing neural activity significantly contributes to how the brain responds to upcoming stimuli. In visual perception, a considerable portion of trial-to-trial variability can be accounted for by prestimulus magneto/electroencephalographic (M/EEG) alpha oscillations, which play an inhibitory function by means of cross-frequency interactions with gamma-band oscillations. Despite the fundamental theories on the role of oscillations in perception and cognition, the current literature lacks a clear theorization of the neural mechanisms underlying the effects of prestimulus activity, including electrophysiological phenomena at different scales (e.g., local field potentials and macro-scale M/EEG). Here, we present a model called the oscillation-based probability of response (OPR), which directly assesses the link between meso-scale neural mechanisms, macro-scale M/EEG, and behavioural outcome. The OPR includes distinct meso-scale mechanisms through which alpha oscillations modulate M/EEG gamma activity, namely, by decreasing a) the amplitude and/or b) neural synchronization of gamma oscillations. Crucially, the OPR makes specific predictions on the effects of these mechanisms on visual perception, as assessed through the psychometric function. SIGNIFICANCE STATEMENT: The oscillation-based probability of response (OPR) is grounded on a psychophysical approach focusing on the psychometric function estimation and may be highly informative in the study of ongoing brain activity, because it provides a tool for distinguishing different neural mechanisms of alpha-driven modulation of sensory processing.
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http://dx.doi.org/10.1016/j.neubiorev.2020.01.037DOI Listing
May 2020

State-dependent TMS reveals the differential contribution of ATL and IPS to the representation of abstract concepts related to social and quantity knowledge.

Cortex 2020 02 24;123:30-41. Epub 2019 Oct 24.

University School for Advanced Studies, Pavia, Italy; IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy. Electronic address:

The neural representation of abstract concepts is a current matter of debate. While social concepts have been associated to superior anterior temporal lobe (sATL), the neural correlates of quantity-related concepts have seldom been investigated. The right intraparietal sulcus (IPS) is known to be involved in the processing of numerical information and of quantifiers. In the present study, we investigated the causal role of right sATL and right IPS in representing social and quantity-related concepts, using a state-dependent transcranial magnetic stimulation (TMS)-priming paradigm. We modulated the neural activation by priming to a category label (either SOCIAL or QUANTITY), before applying TMS and presenting the target (i.e., an exemplar of one of the two abstract classes). When the target word belonged to the quantity category, TMS applied over the IPS (but not sATL) abolished the expected priming effect by speeding up reaction times (RTs) in incongruent trials. For the social category, both IPS and sATL stimulation abolished the priming effect, by reducing RTs in incongruent trials. Our results suggest a specialization of distinct brain areas in processing different classes of abstract concepts. The right IPS contains neuronal representations tuned to quantity-related concepts, in line with its well-known role in numerical and magnitude representation. Social concepts, in contrast, are represented in both the right sATL and the right IPS, known to be involved in social cognition and person-related knowledge.
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http://dx.doi.org/10.1016/j.cortex.2019.09.018DOI Listing
February 2020

Dependence of connectivity on geometric distance in brain networks.

Sci Rep 2019 09 16;9(1):13412. Epub 2019 Sep 16.

Department of Physics, University of Trento, 38123, Trento, Italy.

In any network, the dependence of connectivity on physical distance between nodes is a direct consequence of trade-off mechanisms between costs of establishing and sustaining links, processing rates, propagation speed of signals between nodes. Despite its universality, there are still few studies addressing this issue. Here we apply a recently-developed method to infer links between nodes, and possibly subnetwork structures, to determine connectivity strength as a function of physical distance between nodes. The model system we investigate is brain activity reconstructed on the cortex out of magnetoencephalography recordings sampled on a set of healthy subjects in resting state. We found that the dependence of the time scale of observability of a link on its geometric length follows a power-law characterized by an exponent whose extent is inversely proportional to connectivity. Our method provides a new tool to highlight and investigate networks in neuroscience.
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http://dx.doi.org/10.1038/s41598-019-50106-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746748PMC
September 2019

Age-related changes in cortical connectivity influence the neuromodulatory effects of transcranial electrical stimulation.

Neurobiol Aging 2019 10 23;82:77-87. Epub 2019 Jul 23.

Cognitive Neuroscience Section, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Brescia, Italy. Electronic address:

Transcranial electrical stimulation (tES) is a potentially viable tool for boosting cognitive performance in aging. However, most knowledge on tES effects is based on studies involving young adults. Here, we applied tES (transcranial random noise stimulation [tRNS] as an effective stimulation and anodal transcranial direct current stimulation [atDCS] as a "control" stimulation) to the visual cortex during visual perceptual learning (VPL) in healthy young and older individuals. Moreover, we measured transcranial magnetic stimulation-evoked potentials to investigate the neurophysiological underpinnings of tES effects. We found that only the tRNS in the young, but not in the older, subjects modulated VPL, by decreasing performance. Transcranial magnetic stimulation-evoked potentials revealed age-related changes in connectivity, that is, a stronger activation of the prefrontal cortex after visual cortex stimulation, and a stronger modulation of the prefrontal cortex after VPL in the older subjects. These results may indicate that task performance in older adults relies on the recruitment of a wider network and a crucial contribution of the anterior portion of the brain, which may dramatically influence tES effects in aging.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.07.009DOI Listing
October 2019

Hebbian associative plasticity in the visuo-tactile domain: A cross-modal paired associative stimulation protocol.

Neuroimage 2019 11 17;201:116025. Epub 2019 Jul 17.

Department of Psychology & NeuroMi - Milan Center for Neuroscience, University of Milano-Bicocca, Milano, Italy; Laboratory of Neuropsychology, IRCCS Istituto Auxologico Italiano, Milano, Italy. Electronic address:

We developed and assessed the effects of a novel cross-modal protocol aimed at inducing associative (Hebbian-like) plasticity in the somatosensory cortical system through vision. Associative long-term potentiation can be induced in the primary somatosensory cortex (S1) by means of paired associative stimulation (PAS), in which a peripheral electrical stimulation of the median nerve is repeatedly paired with a transcranial magnetic stimulation (TMS) pulse over S1. Considering the mirror proprieties of S1, the cross-modal PAS (cm-PAS) consists of repetitive observation of bodily tactile stimulations, paired with TMS pulses over the contralateral S1. Through three experiments in healthy participants, we demonstrate that the cm-PAS is able to induce excitatory plastic effects with functional significance in S1, improving somatosensory processing at both behavioral (tactile acuity) and neurophysiological (somatosensory-evoked potentials) levels. The plastic effects induced by cm-PAS depend on the interval (20 ms) between the visual stimulus and the magnetic pulse, the targeted cortical site (S1), and the tactile content of the visual stimulus, which must represent a touch event. Such specificity implies the involvement of cross-modal, mirror-like, mechanisms in S1, which are able to visually promote associative synaptic plasticity in S1 likely through the recruitment of predictive coding processes.
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http://dx.doi.org/10.1016/j.neuroimage.2019.116025DOI Listing
November 2019

Predicting Alzheimer's disease severity by means of TMS-EEG coregistration.

Neurobiol Aging 2019 08 13;80:38-45. Epub 2019 Apr 13.

Cognitive Neuroscience Section, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.

Clinical manifestations of Alzheimer's disease (AD) are associated with a breakdown in large-scale communication, such that AD may be considered as a "disconnection syndrome." An established method to test effective connectivity is the combination of transcranial magnetic stimulation with electroencephalography (TMS-EEG) because the TMS-induced cortical response propagates to distant anatomically connected regions. To investigate whether prefrontal connectivity alterations may predict disease severity, we explored the relationship of dorsolateral prefrontal cortex connectivity (derived from TMS-EEG) with cognitive decline (measured with Mini Mental State Examination and a face-name association memory task) in 26 patients with AD. The amplitude of TMS-EEG evoked component P30, which was found to be generated in the right superior parietal cortex, predicted Mini Mental State Examination and face-name memory scores: higher P30 amplitudes predicted poorer cognitive and memory performances. The present results indicate that advancing disease severity might be associated with effective connectivity increase involving long-distance frontoparietal connections, which might represent a maladaptive pathogenic mechanism reflecting a damaged excitatory-inhibitory balance between anterior and posterior regions.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.04.008DOI Listing
August 2019

Perceptual and Physiological Consequences of Dark Adaptation: A TMS-EEG Study.

Brain Topogr 2019 09 10;32(5):773-782. Epub 2019 May 10.

Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, UK.

Existing literature on sensory deprivation suggests that short-lasting periods of dark adaptation (DA) can cause changes in visual cortex excitability. DA cortical effects have previously been assessed through phosphene perception, i.e., the ability to report visual sensations when a transcranial magnetic stimulation (TMS) pulse is delivered over the visual cortex. However, phosphenes represent an indirect measure of visual cortical excitability which relies on a subjective report. Here, we aimed at overcoming this limitation by assessing visual cortical excitability by combining subjective (i.e., TMS-induced phosphenes) and objective (i.e., TMS-evoked potentials - TEPs) measurements in a TMS-EEG protocol after 30 min of DA. DA effects were compared to a control condition, entailing 30 min of controlled light exposure. TMS was applied at 11 intensities in order to estimate the psychometric function of phosphene report and explore the relationship between TEPs and TMS intensity. Compared to light adaptation, after DA the slope of the psychometric function was significantly steeper, and the amplitude of a TEP component (P60) was lower, only for high TMS intensities. The perceptual threshold was not affected by DA. These results support the idea that DA leads to a change in the excitability of the visual cortex, accompanied by a behavioral modification of visual perception. Furthermore, this study provides a first valuable description of the relationship between TMS intensity and visual TEPs.
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http://dx.doi.org/10.1007/s10548-019-00715-xDOI Listing
September 2019

Transcranial Direct Current Stimulation in Neurodegenerative Disorders.

J ECT 2018 09;34(3):193-202

Cortical excitability modulation and neuroplasticity are considered essential mechanisms for improving clinical and cognitive abilities in neurodegenerative disorders (NDDs). In such context, transcranial direct current stimulation (tDCS) shows great promise for facilitating remodeling of neurosynaptic organization. The aim of this review was to provide an overview of how tDCS is currently used as a neurorehabilitation strategy in some NDDs. We describe results from studies in which tDCS was applied in mild cognitive impairment, Alzheimer's disease, and primary progressive aphasia. Currently, findings related to the ability of tDCS to restore cognitive dysfunctions and behavioral impairments in these NDDs do not seem to support the notion that tDCS shows clear therapeutic efficacy in patients with mild cognitive impairment, Alzheimer disease, and primary progressive aphasia. This is probably because tDCS research in this area is still in its early stages. Methodological concerns, such as differences in tDCS parameters (eg, intensity or duration), target sites, and study design (eg, the relationship between tDCS and the rehabilitation strategy), or the use of underpowered sample sizes may also contribute to these outcomes. Nevertheless, it is important to note that almost no studies have evaluated how the underlying neurophysiological state of patients should guide the application of tDCS. These results should not prevent the use of tDCS in these NDDs, but they should trigger a deeper evaluation of how tDCS should be used. Transcranial direct current stimulation cannot be considered a neurorehabilitation apparatus by itself but should be instead viewed as a method for weakly modulating existing brain excitability. Future studies should aim to improve our understanding of the neurophysiological mechanisms that underlie the clinical effects of tDCS with the final goal of designing and performing individualized stimulation protocols that can be tailored for each NDD patient and combined with other appropriate neurorehabilitation strategies.
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http://dx.doi.org/10.1097/YCT.0000000000000539DOI Listing
September 2018

Interventional programmes to improve cognition during healthy and pathological ageing: Cortical modulations and evidence for brain plasticity.

Ageing Res Rev 2018 May 6;43:81-98. Epub 2018 Mar 6.

Cognitive Neuroscience Section, IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.

A growing body of evidence suggests that healthy elderly individuals and patients with Alzheimer's disease retain an important potential for neuroplasticity. This review summarizes studies investigating the modulation of neural activity and structural brain integrity in response to interventions involving cognitive training, physical exercise and non-invasive brain stimulation in healthy elderly and cognitively impaired subjects (including patients with mild cognitive impairment (MCI) and Alzheimer's disease). Moreover, given the clinical relevance of neuroplasticity, we discuss how evidence for neuroplasticity can be inferred from the functional and structural brain changes observed after implementing these interventions. We emphasize that multimodal programmes, which combine several types of interventions, improve cognitive function to a greater extent than programmes that use a single interventional approach. We suggest specific methods for weighting the relative importance of cognitive training, physical exercise and non-invasive brain stimulation according to the functional and structural state of the brain of the targeted subject to maximize the cognitive improvements induced by multimodal programmes.
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http://dx.doi.org/10.1016/j.arr.2018.03.001DOI Listing
May 2018

Noninvasive brain stimulation of the parietal lobe for improving neurologic, neuropsychologic, and neuropsychiatric deficits.

Handb Clin Neurol 2018 ;151:427-446

Center for Mind/Brain Sciences - CIMeC, University of Trento and IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.

Transcranial magnetic stimulation (TMS) and transcranial electric stimulation (tES) are noninvasive brain stimulation (NIBS) tools that are now widely used in neuroscientific research in humans. The fact that both TMS and tES are able to modulate brain plasticity and, in turn, affect behavior is opening up new horizons in the treatment of brain circuit and plasticity disorders. In the present chapter, we will first provide the reader with a brief background on the basic principles of NIBS, describing the electromagnetic and physical foundations of TMS and tES, as well as the current knowledge of the neurophysiologic basis of their effects on brain activity and plasticity. In the main part, we will outline studies aimed at improving persistent symptoms and deficits in patients suffering from neurologic and neuropsychiatric disorders featured by dysfunction of the parietal lobe. The emerging view is that NIBS of parietal areas holds the promise to overcome various sensory, motor, and cognitive disorders that are often refractory to standard medical or behavioral therapies. The chapter closes with an outlook on further developments in this realm, discussing novel therapeutic approaches that could lead to more effective rehabilitation procedures, better suited for the specific parietal lobe dysfunction.
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http://dx.doi.org/10.1016/B978-0-444-63622-5.00022-XDOI Listing
August 2018

Anodal Transcranial Direct Current Stimulation Promotes Frontal Compensatory Mechanisms in Healthy Elderly Subjects.

Front Aging Neurosci 2017 18;9:420. Epub 2017 Dec 18.

Cognitive Neuroscience Section, Istituto di Ricovero e Cura a Carattere Scientifico Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.

Recent studies have demonstrated that transcranial direct current stimulation (tDCS) is potentially useful to improve working memory. In the present study, young and elderly subjects performed a working memory task (-back task) during an electroencephalogram recording before and after receiving anodal, cathodal, and sham tDCS over the left dorsolateral prefrontal cortex (DLPFC). We investigated modulations of behavioral performance and electrophysiological correlates of working memory processes (frontal and parietal P300 event-related potentials). A strong tendency to modulated working memory performance was observed after the application of tDCS. In detail, young, but not elderly, subjects benefited from additional practice in the absence of real tDCS, as indicated by their more accurate responses after sham tDCS. The cathodal tDCS had no effect in any group of participants. Importantly, anodal tDCS improved accuracy in elderly. Moreover, increased accuracy after anodal tDCS was correlated with a larger frontal P300 amplitude. These findings suggest that, in elderly subjects, improved working memory after anodal tDCS applied over the left DLPFC may be related to the promotion of frontal compensatory mechanisms, which are related to attentional processes.
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http://dx.doi.org/10.3389/fnagi.2017.00420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741680PMC
December 2017

Clinical neurophysiology of prolonged disorders of consciousness: From diagnostic stimulation to therapeutic neuromodulation.

Clin Neurophysiol 2017 09 29;128(9):1629-1646. Epub 2017 Jun 29.

Department of Medicine, Surgery and Neuroscience, Section of Human Physiology, University of Siena, Italy; Department of Medicine, Surgery and Neuroscience, Section of Neurology and Clinical Neurophysiology, Brain Investigation & Neuromodulation Lab (Si-BIN Lab), University of Siena, Italy.

The identification of signs of awareness in patients with prolonged disorders of consciousness (DoC) after severe brain injury is a challenging task for clinicians. Differentiating on behavioural examination the vegetative state (VS) from the minimally conscious state (MCS) can lead to a high misdiagnosis rate. Advanced neuroimaging and neurophysiological techniques can supplement clinical evaluation by providing physiological evidence of brain activity. However, an open issue remains whether these empirical results are directly or indirectly associated with covert consciousness and limitations emerge for their diagnostic application at the single-patient level. On the therapeutic side, the efficacy of both non-invasive and invasive brain stimulation/modulation trials is matter of debate. The present review provides an updated analysis of the diagnostic and prognostic impact that the different neurophysiological techniques of stimulation [including short-latency evoked potentials, long-latency event related potentials (ERPs), transcranial magnetic stimulation (TMS), TMS-EEG co-registration] offer in prolonged DoC. The results of the therapeutic stimulation techniques are also evaluated. It is concluded that TMS-EEG emerges as the most promising tool for differentiating VS from MCS whereas ERPs allow neurophysiologists to probe covert cognitive capacities of each patient. Significant behavioural improvements in prolonged DoC with brain stimulation techniques are still anecdotical and further treatment options are awaited.
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http://dx.doi.org/10.1016/j.clinph.2017.06.037DOI Listing
September 2017

Characterizing the Cortical Oscillatory Response to TMS Pulse.

Front Cell Neurosci 2017 27;11:38. Epub 2017 Feb 27.

Cognitive Neuroscience Section, IRCCS Centro San Giovanni di Dio FatebenefratelliBrescia, Italy; Center for Mind/Brain Sciences - CIMeC, University of TrentoRovereto, Italy.

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http://dx.doi.org/10.3389/fncel.2017.00038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5326778PMC
February 2017

Guiding transcranial brain stimulation by EEG/MEG to interact with ongoing brain activity and associated functions: A position paper.

Clin Neurophysiol 2017 05 29;128(5):843-857. Epub 2017 Jan 29.

Experimental Psychology Lab, Department of Psychology, Center for Excellence "Hearing4all", European Medical School, Carl von Ossietzky University & Research Center Neurosensory Science, University of Oldenburg, Oldenburg, Germany.

Non-invasive transcranial brain stimulation (NTBS) techniques have a wide range of applications but also suffer from a number of limitations mainly related to poor specificity of intervention and variable effect size. These limitations motivated recent efforts to focus on the temporal dimension of NTBS with respect to the ongoing brain activity. Temporal patterns of ongoing neuronal activity, in particular brain oscillations and their fluctuations, can be traced with electro- or magnetoencephalography (EEG/MEG), to guide the timing as well as the stimulation settings of NTBS. These novel, online and offline EEG/MEG-guided NTBS-approaches are tailored to specifically interact with the underlying brain activity. Online EEG/MEG has been used to guide the timing of NTBS (i.e., when to stimulate): by taking into account instantaneous phase or power of oscillatory brain activity, NTBS can be aligned to fluctuations in excitability states. Moreover, offline EEG/MEG recordings prior to interventions can inform researchers and clinicians how to stimulate: by frequency-tuning NTBS to the oscillation of interest, intrinsic brain oscillations can be up- or down-regulated. In this paper, we provide an overview of existing approaches and ideas of EEG/MEG-guided interventions, and their promises and caveats. We point out potential future lines of research to address challenges.
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http://dx.doi.org/10.1016/j.clinph.2017.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385293PMC
May 2017

The mismatch negativity as an index of cognitive decline for the early detection of Alzheimer's disease.

Sci Rep 2016 09 12;6:33167. Epub 2016 Sep 12.

Cognitive Neuroscience Section, IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.

Evidence suggests that Alzheimer's disease (AD) is part of a continuum, characterized by long preclinical phases before the onset of clinical symptoms. In several cases, this continuum starts with a syndrome, defined as mild cognitive impairment (MCI), in which daily activities are preserved despite the presence of cognitive decline. The possibility of having a reliable and sensitive neurophysiological marker that can be used for early detection of AD is extremely valuable because of the incidence of this type of dementia. In this study, we aimed to investigate the reliability of auditory mismatch negativity (aMMN) as a marker of cognitive decline from normal ageing progressing from MCI to AD. We compared aMMN elicited in the frontal and temporal locations by duration deviant sounds in short (400 ms) and long (4000 ms) inter-trial intervals (ITI) in three groups. We found that at a short ITI, MCI showed only the temporal component of aMMN and AD the frontal component compared to healthy elderly who presented both. At a longer ITI, aMMN was elicited only in normal ageing subjects at the temporal locations. Our study provides empirical evidence for the possibility to adopt aMMN as an index for assessing cognitive decline in pathological ageing.
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http://dx.doi.org/10.1038/srep33167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5018736PMC
September 2016

Assessing cortical synchronization during transcranial direct current stimulation: A graph-theoretical analysis.

Neuroimage 2016 Oct 4;140:57-65. Epub 2016 Jun 4.

Cognitive Neuroscience Section, IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy. Electronic address:

Transcranial direct current stimulation (tDCS) is a neuromodulation technique that can alter cortical excitability and modulate behaviour in a polarity-dependent way. Despite the widespread use of this method in the neuroscience field, its effects on ongoing local or global (network level) neuronal activity are still not foreseeable. A way to shed light on the neuronal mechanisms underlying the cortical connectivity changes induced by tDCS is provided by the combination of tDCS with electroencephalography (EEG). In this study, twelve healthy subjects underwent online tDCS-EEG recording (i.e., simultaneous), during resting-state, using 19 EEG channels. The protocol involved anodal, cathodal and sham stimulation conditions, with the active and the reference electrodes in the left frontocentral area (FC3) and on the forehead over the right eyebrow, respectively. The data were processed using a network model, based on graph theory and the synchronization likelihood. The resulting graphs were analysed for four frequency bands (theta, alpha, beta and gamma) to evaluate the presence of tDCS-induced differences in synchronization patterns and graph theory measures. The resting state network connectivity resulted altered during tDCS, in a polarity-specific manner for theta and alpha bands. Anodal tDCS weakened synchronization with respect to the baseline over the fronto-central areas in the left hemisphere, for theta band (p<0.05). In contrast, during cathodal tDCS a significant increase in inter-hemispheric synchronization connectivity was observed over the centro-parietal, centro-occipital and parieto-occipital areas for the alpha band (p<0.05). Local graph measures showed a tDCS-induced polarity-specific differences that regarded modifications of network activities rather than specific region properties. Our results show that applying tDCS during the resting state modulates local synchronization as well as network properties in slow frequency bands, in a polarity-specific manner.
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http://dx.doi.org/10.1016/j.neuroimage.2016.06.003DOI Listing
October 2016

On the Functional Equivalence of Electrodes in Transcranial Random Noise Stimulation.

Brain Stimul 2016 Jul-Aug;9(4):621-2. Epub 2016 Apr 11.

Cognitive Neuroscience Section, IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; Neuroscience Section, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

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http://dx.doi.org/10.1016/j.brs.2016.04.005DOI Listing
April 2016

Acute effects of aerobic exercise promote learning.

Sci Rep 2016 05 5;6:25440. Epub 2016 May 5.

Department of Clinical and Experimental Sciences, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.

The benefits that physical exercise confers on cardiovascular health are well known, whereas the notion that physical exercise can also improve cognitive performance has only recently begun to be explored and has thus far yielded only controversial results. In the present study, we used a sample of young male subjects to test the effects that a single bout of aerobic exercise has on learning. Two tasks were run: the first was an orientation discrimination task involving the primary visual cortex, and the second was a simple thumb abduction motor task that relies on the primary motor cortex. Forty-four and forty volunteers participated in the first and second experiments, respectively. We found that a single bout of aerobic exercise can significantly facilitate learning mechanisms within visual and motor domains and that these positive effects can persist for at least 30 minutes following exercise. This finding suggests that physical activity, at least of moderate intensity, might promote brain plasticity. By combining physical activity-induced plasticity with specific cognitive training-induced plasticity, we favour a gradual up-regulation of a functional network due to a steady increase in synaptic strength, promoting associative Hebbian-like plasticity.
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http://dx.doi.org/10.1038/srep25440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4857085PMC
May 2016