Publications by authors named "Tommaso Gili"

27 Publications

  • Page 1 of 1

SARS-COV-2 comorbidity network and outcome in hospitalized patients in Crema, Italy.

PLoS One 2021 25;16(3):e0248498. Epub 2021 Mar 25.

Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milan, Italy.

We report onset, course, correlations with comorbidities, and diagnostic accuracy of nasopharyngeal swab in 539 individuals suspected to carry SARS-COV-2 admitted to the hospital of Crema, Italy. All individuals underwent clinical and laboratory exams, SARS-COV-2 reverse transcriptase-polymerase chain reaction on nasopharyngeal swab, and chest X-ray and/or computed tomography (CT). Data on onset, course, comorbidities, number of drugs including angiotensin converting enzyme (ACE) inhibitors and angiotensin-II-receptor antagonists (sartans), follow-up swab, pharmacological treatments, non-invasive respiratory support, ICU admission, and deaths were recorded. Among 411 SARS-COV-2 patients (67.7% males) median age was 70.8 years (range 5-99). Chest CT was performed in 317 (77.2%) and showed interstitial pneumonia in 304 (96%). Fatality rate was 17.5% (74% males), with 6.6% in 60-69 years old, 21.1% in 70-79 years old, 38.8% in 80-89 years old, and 83.3% above 90 years. No death occurred below 60 years. Non-invasive respiratory support rate was 27.2% and ICU admission 6.8%. Charlson comorbidity index and high C-reactive protein at admission were significantly associated with death. Use of ACE inhibitors or sartans was not associated with outcomes. Among 128 swab negative patients at admission (63.3% males) median age was 67.7 years (range 1-98). Chest CT was performed in 87 (68%) and showed interstitial pneumonia in 76 (87.3%). Follow-up swab turned positive in 13 of 32 patients. Using chest CT at admission as gold standard on the entire study population of 539 patients, nasopharyngeal swab had 80% accuracy. Comorbidity network analysis revealed a more homogenous distribution 60-40 aged SARS-COV-2 patients across diseases and a crucial different interplay of diseases in the networks of deceased and survived patients. SARS-CoV-2 caused high mortality among patients older than 60 years and correlated with pre-existing multiorgan impairment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248498PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993836PMC
April 2021

Evaluation of denoising strategies for task-based functional connectivity: Equalizing residual motion artifacts between rest and cognitively demanding tasks.

Hum Brain Mapp 2021 Apr 2;42(6):1805-1828. Epub 2021 Feb 2.

MARBILab, CREF - Centro Ricerche Enrico Fermi, Roma, 00184, Italy.

In-scanner head motion represents a major confounding factor in functional connectivity studies and it raises particular concerns when motion correlates with the effect of interest. One such instance regards research focused on functional connectivity modulations induced by sustained cognitively demanding tasks. Indeed, cognitive engagement is generally associated with substantially lower in-scanner movement compared with unconstrained, or minimally constrained, conditions. Consequently, the reliability of condition-dependent changes in functional connectivity relies on effective denoising strategies. In this study, we evaluated the ability of common denoising pipelines to minimize and balance residual motion-related artifacts between resting-state and task conditions. Denoising pipelines-including realignment/tissue-based regression, PCA/ICA-based methods (aCompCor and ICA-AROMA, respectively), global signal regression, and censoring of motion-contaminated volumes-were evaluated according to a set of benchmarks designed to assess either residual artifacts or network identifiability. We found a marked heterogeneity in pipeline performance, with many approaches showing a differential efficacy between rest and task conditions. The most effective approaches included aCompCor, optimized to increase the noise prediction power of the extracted confounding signals, and global signal regression, although both strategies performed poorly in mitigating the spurious distance-dependent association between motion and connectivity. Censoring was the only approach that substantially reduced distance-dependent artifacts, yet this came at the great cost of reduced network identifiability. The implications of these findings for best practice in denoising task-based functional connectivity data, and more generally for resting-state data, are discussed.
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http://dx.doi.org/10.1002/hbm.25332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978116PMC
April 2021

Brain Connectivity Changes after Osteopathic Manipulative Treatment: A Randomized Manual Placebo-Controlled Trial.

Brain Sci 2020 Dec 11;10(12). Epub 2020 Dec 11.

Networks Unit, IMT School for Advanced Studies Lucca, 55100 Lucca, Italy.

The effects of osteopathic manipulative treatment (OMT) on functional brain connectivity in healthy adults is missing in the literature. To make up for this lack, we applied advanced network analysis methods to analyze resting state functional magnetic resonance imaging (fMRI) data, after OMT and Placebo treatment (P) in 30 healthy asymptomatic young participants randomized into OMT and placebo groups (OMTg; Pg). fMRI brain activity measures, performed before (T0), immediately after (T1) and three days after (T2) OMT or P were used for inferring treatment effects on brain circuit functional organization. Repeated measures ANOVA and post-hoc analysis demonstrated that Right Precentral Gyrus (F (2, 32) = 5.995, < 0.005) was more influential over the information flow immediately after the OMT, while decreased betweenness centrality in Left Caudate (F (2, 32) = 6.496, < 0.005) was observable three days after. Clustering coefficient showed a distinct time-point and group effect. At T1, reduced neighborhood connectivity was observed after OMT in the Left Amygdala (L-Amyg) (F (2, 32) = 7.269, < 0.005) and Left Middle Temporal Gyrus (F (2, 32) = 6.452, < 0.005), whereas at T2 the L-Amyg and Vermis-III (F (2, 32) = 6.772, < 0.005) increased functional interactions. Data demonstrated functional connectivity re-arrangement after OMT.
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http://dx.doi.org/10.3390/brainsci10120969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764238PMC
December 2020

Network Analysis of Gut Microbiome and Metabolome to Discover Microbiota-Linked Biomarkers in Patients Affected by Non-Small Cell Lung Cancer.

Int J Mol Sci 2020 Nov 19;21(22). Epub 2020 Nov 19.

Department of Diagnostic and Laboratory Medicine, Unit of Parasitology and Area of Genetics and Rare Diseases, Unit of Human Microbiome, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy.

Several studies in recent times have linked gut microbiome (GM) diversity to the pathogenesis of cancer and its role in disease progression through immune response, inflammation and metabolism modulation. This study focused on the use of network analysis and weighted gene co-expression network analysis (WGCNA) to identify the biological interaction between the gut ecosystem and its metabolites that could impact the immunotherapy response in non-small cell lung cancer (NSCLC) patients undergoing second-line treatment with anti-PD1. Metabolomic data were merged with operational taxonomic units (OTUs) from 16S RNA-targeted metagenomics and classified by chemometric models. The traits considered for the analyses were: (i) condition: disease or control (CTRLs), and (ii) treatment: responder (R) or non-responder (NR). Network analysis indicated that indole and its derivatives, aldehydes and alcohols could play a signaling role in GM functionality. WGCNA generated, instead, strong correlations between short-chain fatty acids (SCFAs) and a healthy GM. Furthermore, commensal bacteria such as , Rikenellaceae, , Peptostreptococcaceae, Mogibacteriaceae and Clostridiaceae were found to be more abundant in CTRLs than in NSCLC patients. Our preliminary study demonstrates that the discovery of microbiota-linked biomarkers could provide an indication on the road towards personalized management of NSCLC patients.
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http://dx.doi.org/10.3390/ijms21228730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699235PMC
November 2020

Sense of external agency is sustained by multisensory functional integration in the somatosensory cortex.

Hum Brain Mapp 2020 Oct 15;41(14):4024-4040. Epub 2020 Jul 15.

Department of Clinical and Behavioral Neurology, Neuropsychiatry Laboratory, IRCCS Santa Lucia Foundation, Rome, Italy.

"Sense of agency" (SoA), the feeling of control for events caused by one's own actions, is deceived by visuomotor incongruence. Sensorimotor networks are implicated in SoA, however little evidence exists on brain functionality during agency processing. Concurrently, it has been suggested that the brain's intrinsic resting-state (rs) activity has a preliminary influence on processing of agency cues. Here, we investigated the relation between performance in an agency attribution task and functional interactions among brain regions as derived by network analysis of rs functional magnetic resonance imaging. The action-effect delay was adaptively increased (range 90-1,620 ms) and behavioral measures correlated to indices of cognitive processes and appraised self-concepts. They were then regressed on local metrics of rs brain functional connectivity as to isolate the core areas enabling self-agency. Across subjects, the time window for self-agency was 90-625 ms, while the action-effect integration was impacted by self-evaluated personality traits. Neurally, the brain intrinsic organization sustaining consistency in self-agency attribution was characterized by high connectiveness in the secondary visual cortex, and regional segregation in the primary somatosensory area. Decreased connectiveness in the secondary visual area, regional segregation in the superior parietal lobule, and information control within a primary visual cortex-frontal eye fields network sustained self-agency over long-delayed effects. We thus demonstrate that self-agency is grounded on the intrinsic mode of brain function designed to organize information for visuomotor integration. Our observation is relevant for current models of psychopathology in clinical conditions in which both rs activity and sense of agency are altered.
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http://dx.doi.org/10.1002/hbm.25107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469779PMC
October 2020

Brain Network Modularity During a Sustained Working-Memory Task.

Front Physiol 2020 8;11:422. Epub 2020 May 8.

Centro Fermi-Museo Storico della Fisica e Centro di Studi e Ricerche Enrico Fermi, Rome, Italy.

Spontaneous oscillations of the blood oxygenation level-dependent (BOLD) signal are spatially synchronized within specific brain networks and are thought to reflect synchronized brain activity. Networks are modulated by the performance of a task, even if the exact features and degree of such modulations are still elusive. The presence of networks showing anticorrelated fluctuations lend initially to suppose that a competitive relationship between the default mode network (DMN) and task positive networks (TPNs) supports the efficiency of brain processing. However, more recent results indicate that cooperative and competitive dynamics between networks coexist during task performance. In this study, we used graph analysis to assess the functional relevance of the topological reorganization of brain networks ensuing the execution of a steady state working-memory (WM) task. Our results indicate that the performance of an auditory WM task is associated with a switching between different topological configurations of several regions of specific networks, including frontoparietal, ventral attention, and dorsal attention areas, suggesting segregation of ventral attention regions in the presence of increased overall integration. However, the correct execution of the task requires integration between components belonging to all the involved networks.
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http://dx.doi.org/10.3389/fphys.2020.00422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227445PMC
May 2020

Mild Propofol Sedation Reduces Frontal Lobe and Thalamic Cerebral Blood Flow: An Arterial Spin Labeling Study.

Front Physiol 2019 18;10:1541. Epub 2019 Dec 18.

Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology, Cardiff University, Cardiff, United Kingdom.

Mechanisms of anesthetic drug-induced sedation and unconsciousness are still incompletely understood. Functional neuroimaging modalities provide a window to study brain function changes during anesthesia allowing us to explore the sequence of neuro-physiological changes associated with anesthesia. Cerebral perfusion change under an assumption of intact neurovascular coupling is an indicator of change in large-scale neural activity. In this experiment, we have investigated resting state cerebral blood flow (CBF) changes in the human brain during mild sedation, with propofol. Arterial spin labeling (ASL) provides a non-invasive, reliable, and robust means of measuring cerebral blood flow (CBF) and can therefore be used to investigate central drug effects. Mild propofol sedation-related CBF changes were studied at rest ( = 15), in a 3 T MR scanner using a PICORE-QUIPSS II ASL technique. CBF was reduced in bilateral paracingulate cortex, premotor cortex, Broca's areas, right superior frontal gyrus and also the thalamus. This cerebral perfusion study demonstrates that propofol induces suppression of key cortical (frontal lobe) and subcortical (thalamus) regions during mild sedation.
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http://dx.doi.org/10.3389/fphys.2019.01541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930185PMC
December 2019

Stairways to the brain: Transcutaneous spinal direct current stimulation (tsDCS) modulates a cerebellar-cortical network enhancing verb recovery.

Brain Res 2020 01 22;1727:146564. Epub 2019 Nov 22.

IMT Scuola Alti Studi Lucca, 55100, Lucca, Italy. Electronic address:

It has long been assumed that the language function is hierarchically organized into specific cortical areas. Here, for the first time, we present direct evidence that the spinal cord takes part in language processing. In a randomized-double blind design, sixteen aphasics underwent a language treatment combined with transcutaneous spinal direct current stimulation (tsDCS). During the treatment, each subject received tsDCS (20 min, 2 mA) over the thoracic vertebrae (IX-X vertebrae) in two different conditions: (1) anodal, and (2) sham while performing a verb naming task. Each experimental condition was run in five consecutive daily sessions over two weeks. Before and after each condition, all patients underwent a resting state functional magnetic resonance imaging (rs-fMRI). After anodal tsDCS, significant functional connectivity changes were found in a cerebellar-cortical network recruiting regions such as the left cerebellum, the right parietal and premotor cortex known to be also involved in action-related verb processing. Indeed, this increase of connectivity significantly correlated with the greatest amount of improvement found in verb naming. In line with our experimental data, we also found a greater improvement after anodal tsDCS also on untreated items of the language test but only on tasks which required the use of verbs, such as verb naming and picture description. No significant changes were found in noun naming. Thus, this evidence emphasizes, for the first time, that the neural response due to tsDCS combined with language treatment changes during the course of recovery by enhancing activity into cortical regions which influence verb processing.
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http://dx.doi.org/10.1016/j.brainres.2019.146564DOI Listing
January 2020

Cerebral Perfusion Changes After Osteopathic Manipulative Treatment: A Randomized Manual Placebo-Controlled Trial.

Front Physiol 2019 5;10:403. Epub 2019 Apr 5.

IMT School for Advanced Studies Lucca, Lucca, Italy.

Osteopathic Manipulative Treatment (OMT) is a therapeutic approach aimed at enhancing the body's self-regulation focusing on somatic dysfunctions correction. Despite evidence of OMT effectiveness, the underlying neurophysiological mechanisms, as well as blood perfusion effects, are still poorly understood. The study aim was to address OMT effects on cerebral blood flow (CBF) in asymptomatic young volunteers as measured by Magnetic Resonance Arterial Spin Labeling (ASL) method. Thirty blinded participants were randomized to OMT or placebo, and evaluated with an MRI protocol before manual intervention (T0), immediately after (T1), and 3 days later (T2). After T0 MRI, participants received 45 min of OMT, focused on correcting whole body somatic dysfunctions, or placebo manual treatment, consisting of passive touches in a protocolled order. After treatment, participants completed a de-blinding questionnaire about treatment perception. Results show significant differences due to treatment only for the OMT group (OMTg): perfusion decreased (compared to T0) in a cluster comprising the left posterior cingulate cortex (PCC) and the superior parietal lobule, while increased at T2 in the contralateral PCC. Furthermore, more than 60% of participants believed they had undergone OMT. The CBF modifications at T2 suggest that OMT produced immediate but reversible effects on CBF.
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http://dx.doi.org/10.3389/fphys.2019.00403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460882PMC
April 2019

Metastable States of Multiscale Brain Networks Are Keys to Crack the Timing Problem.

Front Comput Neurosci 2018 11;12:75. Epub 2018 Sep 11.

Laboratory of Neuropsychiatry, IRCCS Santa Lucia Foundation, Rome, Italy.

The dynamics of the environment where we live in and the interaction with it, predicting events, provided strong evolutionary pressures for the brain functioning to process temporal information and generate timed responses. As a result, the human brain is able to process temporal information and generate temporal patterns. Despite the clear importance of temporal processing to cognition, learning, communication and sensory, motor and emotional processing, the basal mechanisms of how animals differentiate simple intervals or provide timed responses are still under debate. The lesson we learned from the last decade of research in neuroscience is that functional and structural brain connectivity matter. Specifically, it has been accepted that the organization of the brain in interacting segregated networks enables its function. In this paper we delineate the route to a promising approach for investigating timing mechanisms. We illustrate how novel insight into timing mechanisms can come by investigating brain functioning as a multi-layer dynamical network whose clustered dynamics is bound to report the presence of metastable states. We anticipate that metastable dynamics underlie the real-time coordination necessary for the brain's dynamic functioning associated to time perception. This new point of view will help further clarifying mechanisms of neuropsychiatric disorders.
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http://dx.doi.org/10.3389/fncom.2018.00075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6141745PMC
September 2018

Scale-invariant rearrangement of resting state networks in the human brain under sustained stimulation.

Neuroimage 2018 10 5;179:570-581. Epub 2018 Jul 5.

Centro Fermi - Museo storico della fisica e Centro di studi e ricerche Enrico Fermi, Roma, Italy; Fondazione Santa Lucia IRCCS, Roma, Italy. Electronic address:

Brain activity at rest is characterized by widely distributed and spatially specific patterns of synchronized low-frequency blood-oxygenation level-dependent (BOLD) fluctuations, which correspond to physiologically relevant brain networks. This network behaviour is known to persist also during task execution, yet the details underlying task-associated modulations of within- and between-network connectivity are largely unknown. In this study we exploited a multi-parametric and multi-scale approach to investigate how low-frequency fluctuations adapt to a sustained n-back working memory task. We found that the transition from the resting state to the task state involves a behaviourally relevant and scale-invariant modulation of synchronization patterns within both task-positive and default mode networks. Specifically, decreases of connectivity within networks are accompanied by increases of connectivity between networks. In spite of large and widespread changes of connectivity strength, the overall topology of brain networks is remarkably preserved. We show that these findings are strongly influenced by connectivity at rest, suggesting that the absolute change of connectivity (i.e., disregarding the baseline) may not be the most suitable metric to study dynamic modulations of functional connectivity. Our results indicate that a task can evoke scale-invariant, distributed changes of BOLD fluctuations, further confirming that low frequency BOLD oscillations show a specialized response and are tightly bound to task-evoked activation.
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http://dx.doi.org/10.1016/j.neuroimage.2018.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538940PMC
October 2018

Segregation of Brain Structural Networks Supports Spatio-Temporal Predictive Processing.

Front Hum Neurosci 2018 24;12:212. Epub 2018 May 24.

Neuropsychiatry Laboratory, Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation, Rome, Italy.

The ability to generate probabilistic expectancies regarding when and where sensory stimuli will occur, is critical to derive timely and accurate inferences about updating contexts. However, the existence of specialized neural networks for inferring predictive relationships between events is still debated. Using graph theoretical analysis applied to structural connectivity data, we tested the extent of brain connectivity properties associated with spatio-temporal predictive performance across 29 healthy subjects. Participants detected visual targets appearing at one out of three locations after one out of three intervals; expectations about stimulus location (spatial condition) or onset (temporal condition) were induced by valid or invalid symbolic cues. Connectivity matrices and centrality/segregation measures, expressing the relative importance of, and the local interactions among specific cerebral areas respect to the behavior under investigation, were calculated from whole-brain tractography and cortico-subcortical parcellation. Response preparedness to cued stimuli relied on different structural connectivity networks for the temporal and spatial domains. Significant covariance was observed between centrality measures of regions within a subcortical-fronto-parietal-occipital network -comprising the left putamen, the right caudate nucleus, the left frontal operculum, the right inferior parietal cortex, the right paracentral lobule and the right superior occipital cortex-, and the ability to respond after a short cue-target delay suggesting that the local connectedness of such nodes plays a central role when the source of temporal expectation is explicit. When the potential for functional segregation was tested, we found highly clustered structural connectivity across the right superior, the left middle inferior frontal gyrus and the left caudate nucleus as related to explicit temporal orienting. Conversely, when the interaction between explicit and implicit temporal orienting processes was considered at the long interval, we found that explicit processes were related to centrality measures of the bilateral inferior parietal lobule. Degree centrality of the same region in the left hemisphere covaried with behavioral measures indexing the process of attentional re-orienting. These results represent a crucial step forward the ordinary predictive processing description, as we identified the patterns of connectivity characterizing the brain organization associated with the ability to generate and update temporal expectancies in case of contextual violations.
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http://dx.doi.org/10.3389/fnhum.2018.00212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5978278PMC
May 2018

Moving Beyond the Brain: Transcutaneous Spinal Direct Current Stimulation in Post-Stroke Aphasia.

Front Neurol 2017 8;8:400. Epub 2017 Aug 8.

Clinica Neurologica III, Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy.

Over the last 20 years, major advances in cognitive neuroscience have clearly shown that the language function is not restricted into the classical language areas but it involves brain regions, which had never previously considered. Indeed, recent lines of evidence have suggested that the processing of words associated to motor schemata, such as action verbs, modulates the activity of the sensorimotor cortex, which, in turn, facilitates its retrieval. To date, no studies have investigated whether the spinal cord, which is functionally connected to the sensorimotor system, might also work as an auxiliary support for language processing. We explored the combined effect of transcutaneous spinal direct current stimulation (tsDCS) and language treatment in a randomized double-blind design for the recovery of verbs and nouns in 14 chronic aphasics. During each treatment, each subject received tsDCS (20 min, 2 mA) over the thoracic vertebrae (10th vertebra) in three different conditions: (1) anodic, (2) cathodic and (3) sham, while performing a verb and noun naming tasks. Each experimental condition was run in five consecutive daily sessions over 3 weeks. Overall, a significant greater improvement in verb naming was found during the anodic condition with respect to the other two conditions, which persisted at 1 week after the end of the treatment. No significant differences were present for noun naming among the three conditions. The hypothesis is advanced that anodic tsDCS might have influenced activity along the ascending somatosensory pathways, ultimately eliciting neurophysiological changes into the sensorimotor areas which, in turn, supported the retrieval of verbs. These results further support the evidence that action words, due to their sensorimotor semantic properties, are partly represented into the sensorimotor cortex. Moreover, they also document, for the first time, that tsDCS enhances verb recovery in chronic aphasia and it may represent a promising new tool for language treatment.
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http://dx.doi.org/10.3389/fneur.2017.00400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550684PMC
August 2017

Task-Related Modulations of BOLD Low-Frequency Fluctuations within the Default Mode Network.

Front Phys 2017 Jul 25;5. Epub 2017 Jul 25.

MARBILab, Centro Fermi-Museo Storico Della fisica e Centro Studi e Ricerche Enrico Fermi, Rome, Italy.

Spontaneous low-frequency Blood-Oxygenation Level-Dependent (BOLD) signals acquired during resting state are characterized by spatial patterns of synchronous fluctuations, ultimately leading to the identification of robust brain networks. The resting-state brain networks, including the Default Mode Network (DMN), are demonstrated to persist during sustained task execution, but the exact features of task-related changes of network properties are still not well characterized. In this work we sought to examine in a group of 20 healthy volunteers (age 33 ± 6 years, 8 F/12 M) the relationship between changes of spectral and spatiotemporal features of one prominent resting-state network, namely the DMN, during the continuous execution of a working memory n-back task. We found that task execution impacted on both functional connectivity and amplitude of BOLD fluctuations within large parts of the DMN, but these changes correlated between each other only in a small area of the posterior cingulate. We conclude that combined analysis of multiple parameters related to connectivity, and their changes during the transition from resting state to continuous task execution, can contribute to a better understanding of how brain networks rearrange themselves in response to a task.
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http://dx.doi.org/10.3389/fphy.2017.00031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568127PMC
July 2017

Organization and hierarchy of the human functional brain network lead to a chain-like core.

Sci Rep 2017 07 7;7(1):4888. Epub 2017 Jul 7.

Enrico Fermi Center, Piazza del Viminale 1, 00184, Rome, Italy.

The brain is a paradigmatic example of a complex system: its functionality emerges as a global property of local mesoscopic and microscopic interactions. Complex network theory allows to elicit the functional architecture of the brain in terms of links (correlations) between nodes (grey matter regions) and to extract information out of the noise. Here we present the analysis of functional magnetic resonance imaging data from forty healthy humans at rest for the investigation of the basal scaffold of the functional brain network organization. We show how brain regions tend to coordinate by forming a highly hierarchical chain-like structure of homogeneously clustered anatomical areas. A maximum spanning tree approach revealed the centrality of the occipital cortex and the peculiar aggregation of cerebellar regions to form a closed core. We also report the hierarchy of network segregation and the level of clusters integration as a function of the connectivity strength between brain regions.
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http://dx.doi.org/10.1038/s41598-017-04716-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501790PMC
July 2017

Modafinil-Induced Changes in Functional Connectivity in the Cortex and Cerebellum of Healthy Elderly Subjects.

Front Aging Neurosci 2017 30;9:85. Epub 2017 Mar 30.

Department of Neurosciences, Imaging and Clinical Sciences, "G. d'Annunzio" University of Chieti-PescaraChieti, Italy.

In the past few years, cognitive enhancing drugs (CEDs) have gained growing interest and the focus of investigations aimed at exploring their use to potentiate the cognitive performances of healthy individuals. Most of this exploratory CED-related research has been performed on young adults. However, CEDs may also help to maintain optimal brain functioning or compensate for subtle and or subclinical deficits associated with brain aging or early-stage dementia. In this study, we assessed effects on resting state brain activity in a group of healthy elderly subjects undergoing acute administration of modafinil, a wakefulness-promoting agent. To that aim, participants ( = 24) were investigated with resting state functional Magnetic Resonance Imaging (rs-fMRI) before and after the administration of a single dose (100 mg) of modafinil. Effects were compared to age and size-matched placebo group. Rs-fMRI effects were assessed, employing a graph-based approach and Eigenvector Centrality (EC) analysis, by taking in account topological changes occurring in functional brain networks. The main finding of the study is that modafinil promotes enhanced centrality, a measure of the importance of nodes within functional networks, of the bilateral primary visual (V1) cortex. EC analysis also revealed that modafinil-treated subjects show increased functional connectivity between the V1 and specific cerebellar (Crus I, Crus II, VIIIa lobule) and frontal (right inferior frontal sulcus and left middle frontal gyrus) regions. Present findings provide functional data supporting the hypothesis that modafinil can modulate the cortico-cerebellar connectivity of the aging brain.
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http://dx.doi.org/10.3389/fnagi.2017.00085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5371677PMC
March 2017

Right sensory-motor functional networks subserve action observation therapy in aphasia.

Brain Imaging Behav 2017 Oct;11(5):1397-1411

IRCCS Fondazione Santa Lucia, Rome, Italy.

Recent studies have shown that the systematic and repetitive observation of actions belonging to the experiential human motor repertoire without verbal facilitation enhances the recovery of verbs in non fluent aphasia. However, it is still an open question whether this approach extends its efficacy also on discourse productivity by improving the retrieval of other linguistic units (i.e. nouns, sentences, content words). Moreover, nothing is known regarding the neural substrates which support the language recovery process due to action observation treatment.In the present study, ten non fluent aphasics were presented with two videoclips (real everyday life context vs. familiar pantomimed context), each video for six consecutive weeks (Monday to Friday, weekend off). During the treatment, they were asked to observe each video and to describe it without verbal facilitation from the therapist. In all patients, language measures were collected before and at the end of treatment. Before and after each treatment condition (real vs. pantomimed context), each subject underwent a resting state fMRI. After the treatment, significant changes in functional connectivity were found in right sensory-motor networks which were accompanied by a significant improvement for the different linguistic units in the real context condition. On the contrary, the language recovery obtained in the pantomimed context did not match any functional modification. The evidence for a recruitment of the sensory-motor cortices during the observation of actions embedded in real context suggests to potentially enhance language recovery in non fluent aphasia through a simulation process related to the sensory-motor properties of actions.
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http://dx.doi.org/10.1007/s11682-016-9635-1DOI Listing
October 2017

Bilateral Transcranial Direct Current Stimulation Language Treatment Enhances Functional Connectivity in the Left Hemisphere: Preliminary Data from Aphasia.

J Cogn Neurosci 2016 May 25;28(5):724-38. Epub 2016 Jan 25.

IRCCS Fondazione Santa Lucia, Rome, Italy.

Several studies have already shown that transcranial direct current stimulation (tDCS) is a useful tool for enhancing recovery in aphasia. However, no reports to date have investigated functional connectivity changes on cortical activity because of tDCS language treatment. Here, nine aphasic persons with articulatory disorders underwent an intensive language therapy in two different conditions: bilateral anodic stimulation over the left Broca's area and cathodic contralesional stimulation over the right homologue of Broca's area and a sham condition. The language treatment lasted 3 weeks (Monday to Friday, 15 sessions). In all patients, language measures were collected before (T0) and at the end of treatment (T15). Before and after each treatment condition (real vs. sham), each participant underwent a resting-state fMRI study. Results showed that, after real stimulation, patients exhibited the greatest recovery not only in terms of better accuracy in articulating the treated stimuli but also for untreated items on different tasks of the language test. Moreover, although after the sham condition connectivity changes were confined to the right brain hemisphere, real stimulation yielded to stronger functional connectivity increase in the left hemisphere. In conclusion, our data provide converging evidence from behavioral and functional imaging data that bilateral tDCS determines functional connectivity changes within the lesioned hemisphere, enhancing the language recovery process in stroke patients.
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http://dx.doi.org/10.1162/jocn_a_00927DOI Listing
May 2016

Unraveling predictors affecting compliance to MRI in Parkinson's disease.

Parkinsonism Relat Disord 2015 Aug 15;21(8):964-7. Epub 2015 May 15.

IRCCS Santa Lucia Foundation, Via Ardeatina 306, 00179 Rome, Italy; Beth K. and Stuart C. Yudofsky Division of Neuropsychiatry, Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, 1 Baylor Plaza, 77030 Houston, TX, USA. Electronic address:

Introduction: Magnetic resonance imaging (MRI) is a sensitive, noninvasive and widely available technique for studying Parkinson's disease (PD) from both research and clinical perspective. Several issues may physically impede execution of MRI. Moreover, the severity of motor or non-motor symptoms of PD might reduce compliance to MRI. Here we investigated predictors affecting compliance to MRI in PD patients.

Methods: Two-hundred-thirty-six PD patients underwent clinical, neuropsychological and neuropsychiatric investigations. Accordingly to their ability/inability to perform MRI scan, they were divided into 3 groups. Forty-two patients had physical incompatibility to MRI (PI); 51 patients refused to undergo scan during the MRI evaluation session (RR); 143 patients accepted to undergo and successfully completed MRI (SP). Multivariate/Univariate Analyses of Variance, followed by Bonferroni's post-hoc comparisons, were used to assess differences among groups. To identify predictors of compliance to MRI scan in the whole PD sample (SP vs. RR + PI) we carried out a logistic regression analysis.

Results: PI subjects were significantly older, had higher UPRDRS-III score, received lower daily dopamine agonist doses, and displayed worse cognitive performances than SP. RR subjects had significantly higher anxiety severity than SP. Lower daily dopamine agonist equivalents and higher anxiety scores were the significant whole predictors of not compliance to MRI in the logistic regression analysis.

Conclusions: These results show that demographic, neuropsychological and neuropsychiatric features may limit compliance to MRI in PD, and provide valuable aid for setting and interpreting research and clinical MRI studies in PD.
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http://dx.doi.org/10.1016/j.parkreldis.2015.05.009DOI Listing
August 2015

Intrinsic patterns of coupling between correlation and amplitude of low-frequency fMRI fluctuations are disrupted in degenerative dementia mainly due to functional disconnection.

PLoS One 2015 6;10(4):e0120988. Epub 2015 Apr 6.

Museo Storico della Fisica e Centro Studi e Ricerche Enrico Fermi, Rome, Italy; Fondazione Santa Lucia IRCCS, Rome, Italy.

Low frequency fluctuations (LFFs) of the BOLD signal are a major discovery in the study of the resting brain with functional magnetic resonance imaging (fMRI). Two fMRI-based measures, functional connectivity (FC), a measure of signal synchronicity, and the amplitude of LFFs (ALFF), a measure of signal periodicity, have been proved to be sensitive to changes induced by several neurological diseases, including degenerative dementia. In spite of the increasing use of these measures, whether and how they are related to each other remains to be elucidated. In this work we used voxel-wise FC and ALFF computed in different frequency bands (slow-5: 0.01-0.027 Hz; slow-4: 0.027-0.073 Hz; and full-band: 0.01-0.073 Hz), in order to assess their relationship in healthy elderly as well as the relevant changes induced by Alzheimer's Disease (AD) and Mild Cognitive Impairment (MCI). We found that in healthy elderly subjects FC and ALFF are positively correlated in anterior and posterior cingulate cortex (full-band, slow-4 and slow-5), temporal cortex (full-band and slow-5), and in a set of subcortical regions (full-band and slow-4). These correlation patterns between FC and ALFF were absent in either AD or MCI patients. Notably, the loss of correlation between FC and ALFF in the AD group was primarily due to changes in FC rather than in ALFF. Our results indicate that degenerative dementia is characterized by a loss of global connection rather than by a decrease of fluctuation amplitude.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0120988PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4386762PMC
April 2016

The thalamus and brainstem act as key hubs in alterations of human brain network connectivity induced by mild propofol sedation.

J Neurosci 2013 Feb;33(9):4024-31

Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, Cardiff, CF10 3AT, United Kingdom.

Despite their routine use during surgical procedures, no consensus has yet been reached on the precise mechanisms by which hypnotic anesthetic agents produce their effects. Molecular, animal and human studies have suggested disruption of thalamocortical communication as a key component of anesthetic action at the brain systems level. Here, we used the anesthetic agent, propofol, to modulate consciousness and to evaluate differences in the interactions of remote neural networks during altered consciousness. We investigated the effects of propofol, at a dose that produced mild sedation without loss of consciousness, on spontaneous cerebral activity of 15 healthy volunteers using functional magnetic resonance imaging (fMRI), exploiting oscillations (<0.1 Hz) in blood oxygenation level-dependent signal across functionally connected brain regions. We considered the data as a graph, or complex network of nodes and links, and used eigenvector centrality (EC) to characterize brain network properties. The EC mapping of fMRI data in healthy humans under propofol mild sedation demonstrated a decrease of centrality of the thalamus versus an increase of centrality within the pons of the brainstem, highlighting the important role of these two structures in regulating consciousness. Specifically, the decrease of thalamus centrality results from its disconnection from a widespread set of cortical and subcortical regions, while the increase of brainstem centrality may be a consequence of its increased influence, in the mildly sedated state, over a few highly central cortical regions key to the default mode network such as the posterior and anterior cingulate cortices.
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http://dx.doi.org/10.1523/JNEUROSCI.3480-12.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162411PMC
February 2013

Modeling the contribution of neuron-astrocyte cross talk to slow blood oxygenation level-dependent signal oscillations.

J Neurophysiol 2011 Dec 14;106(6):3010-8. Epub 2011 Sep 14.

Dipartimento di Fisica, Sapienza Università di Roma, Rome, Italy.

A consistent and prominent feature of brain functional magnetic resonance imaging (fMRI) data is the presence of low-frequency (<0.1 Hz) fluctuations of the blood oxygenation level-dependent (BOLD) signal that are thought to reflect spontaneous neuronal activity. In this report we provide modeling evidence that cyclic physiological activation of astroglial cells produces similar BOLD oscillations through a mechanism mediated by intracellular Ca(2+) signaling. Specifically, neurotransmission induces pulses of Ca(2+) concentration in astrocytes, resulting in increased cerebral perfusion and neuroactive transmitter release by these cells (i.e., gliotransmission), which in turn stimulates neuronal activity. Noticeably, the level of neuron-astrocyte cross talk regulates the periodic behavior of the Ca(2+) wave-induced BOLD fluctuations. Our results suggest that the spontaneous ongoing activity of neuroglial networks is a potential source of the observed slow fMRI signal oscillations.
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http://dx.doi.org/10.1152/jn.00416.2011DOI Listing
December 2011

Anatomical connectivity mapping: a new tool to assess brain disconnection in Alzheimer's disease.

Neuroimage 2011 Feb 7;54(3):2045-51. Epub 2010 Sep 7.

Neuroimaging Laboratory, Santa Lucia Foundation, Rome, Italy.

Previous studies suggest that the clinical manifestations of Alzheimer's disease (AD) are not only associated with regional gray matter damage but also with abnormal functional integration of different brain regions by disconnection mechanisms. A measure of anatomical connectivity (anatomical connectivity mapping or ACM) can be obtained by initiating diffusion tractography streamlines from all parenchymal voxels and then counting the number of streamlines passing through each voxel of the brain. In order to assess the potential of this parameter for the study of disconnection in AD, we computed it in a group of patients with AD (N=9), in 16 patients with amnestic mild cognitive impairment (a-MCI, which is considered the prodromal stage of AD) and in 12 healthy volunteers. All subjects had an MRI scan at 3T, and diffusion MRI data were analyzed to obtain fractional anisotropy (FA) and ACM. Two types of ACM maps, absolute count (ac-ACM) and normalized by brain size count (nc-ACM), were obtained. No between group differences in FA surviving correction for multiple comparison were found, while areas of both decreased (in the supramarginal gyrus) and increased (in the putamen) ACM were found in patients with AD. Similar results were obtained with ac-ACM and nc-ACM. ACM of the supramarginal gyrus was strongly associated with measures of short-term memory in healthy subjects. This study shows that ACM provides information that is complementary to that offered by FA and appears to be more sensitive than FA to brain changes in patients with AD. The increased ACM in the putamen was unexpected. Given the nature of ACM, an increase of this parameter may reflect a change in any of the areas connected to it. One intriguing possibility is that this increase of ACM in AD patients might reflect processes of brain plasticity driven by cholinesterase inhibitors.
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http://dx.doi.org/10.1016/j.neuroimage.2010.08.069DOI Listing
February 2011

Hemocompatibility of carotid artery stents: alterations of the electrical parameters of erythrocyte cell membrane--a word of caution.

Vasc Endovascular Surg 2010 Apr 11;44(3):190-7. Epub 2010 Feb 11.

Clinica Chirurgica II, Università di Roma La Sapienza, Rome, Italy.

The hemocompatibility of standard surgical treatment of carotid artery disease through the insertion of metallic stents is investigated by means of radio wave dielectric spectroscopy technique that allows the measurements of the electrical parameters of the red blood cell membrane. Our measurements suggest that both the membrane permittivity and the membrane conductivity, which characterize the overall electrical behavior of the cell membrane, undergo an appreciable alteration of their standard values as a consequence of the stent insertion. These alterations persist over long period of time, up to 4 weeks. Even if these effects could not cause any evident damage at physiological or clinical level to the patient, the presence of a host response to the stent implant suggests that a full hemocompatibility has not yet reached, and a word of caution is necessary.
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http://dx.doi.org/10.1177/1538574409359336DOI Listing
April 2010

Images-based suppression of unwanted global signals in resting-state functional connectivity studies.

Magn Reson Imaging 2009 Oct 19;27(8):1058-64. Epub 2009 Aug 19.

MARBILab, Museo storico della fisica e Centro di studi e ricerche "Enrico Fermi" Roma, Italy.

Correlated fluctuations of low-frequency fMRI signal have been suggested to reflect functional connectivity among the involved regions. However, large-scale correlations are especially prone to spurious global modulations induced by coherent physiological noise. Cardiac and respiratory rhythms are the most offending component, and a tailored preprocessing is needed in order to reduce their impact. Several approaches have been proposed in the literature, generally based on the use of physiological recordings acquired during the functional scans, or on the extraction of the relevant information directly from the images. In this paper, the performances of the denoising approach based on general linear fitting of global signals of noninterest extracted from the functional scans were assessed. Results suggested that this approach is sufficiently accurate for the preprocessing of functional connectivity data.
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http://dx.doi.org/10.1016/j.mri.2009.06.004DOI Listing
October 2009

L-DOPA preloading increases the uptake of borophenylalanine in C6 glioma rat model: a new strategy to improve BNCT efficacy.

Int J Radiat Oncol Biol Phys 2008 Oct;72(2):562-7

Physics Department, Sapienza University of Rome, Italy; Enrico Fermi Center, Rome, Italy.

Purpose: Boron neutron capture therapy (BNCT) is a radiotherapeutic modality based on (10)B(n,alpha)(7)Li reaction, for the treatment of malignant gliomas. One of the main limitations for BNCT effectiveness is the insufficient intake of (10)B nuclei in the tumor cells. This work was aimed at investigating the use of L-DOPA as a putative enhancer for (10)B-drug 4-dihydroxy-borylphenylalanine (BPA) uptake in the C6-glioma model. The investigation was first performed in vitro and then extended to the animal model.

Methods And Materials: BPA accumulation in C6-glioma cells was assessed using radiowave dielectric spectroscopy, with and without L-DOPA preloading. Two L-DOPA incubation times (2 and 4 hours) were investigated, and the corresponding effects on BPA accumulation were quantified. C6-glioma cells were also implanted in the brain of 32 rats, and tumor growth was monitored by magnetic resonance imaging. Rats were assigned to two experimental branches: (1) BPA administration; (2) BPA administration after pretreatment with L-DOPA. All animals were sacrificed, and assessments of BPA concentrations in tumor tissue, normal brain, and blood samples were performed using high-performance liquid chromatography.

Results: L-DOPA preloading induced a massive increase of BPA concentration in C6-glioma cells only after a 4-hour incubation. In the animal model, L-DOPA pretreatment produced a significantly higher accumulation of BPA in tumor tissue but not in normal brain and blood samples.

Conclusions: This study suggests the potential use of L-DOPA as enhancer for BPA accumulation in malignant gliomas eligible for BNCT. L-DOPA preloading effect is discussed in terms of membrane transport mechanisms.
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http://dx.doi.org/10.1016/j.ijrobp.2008.06.1493DOI Listing
October 2008

Are aortic endograft prostheses fully hemo-compatible? A dielectric spectroscopy investigation of the electrical alterations induced on erythrocyte cell membranes.

Biomed Mater 2007 Mar 12;2(1):26-31. Epub 2007 Jan 12.

Clinica Chirurgica II, Università di Roma La Sapienza, Rome, Italy.

In this paper we present a new approach directed to ascertain the full hemo-compatibility of aortic endograft prostheses based on the measurement of the passive electrical parameters of the erythrocyte cell membrane. The red blood cell membrane, from an electric point of view, is characterized by an electrical permittivity, (s), which takes into account the structural charged organization of the lipid double layer, and by the electrical conductivity, sigma(s), which accounts for the ionic transport processes across the membrane. These parameters can be easily measured by means of a radiowave dielectric spectroscopy technique, analyzing the dependence of the electrical impedance of an erythrocyte suspension on the frequency of the applied electric field. In this preliminary report, we investigate the alterations induced, at a membrane level, by two different devices commonly employed for endovascular abdominal aortic aneurysm exclusion, i.e., Excluder and Zenith devices, implanted in ten patients. We observe, in all the cases investigated, a statistically significant increase of both the permittivity (s) and electrical conductivity sigma(s) of the erythrocyte membrane upon the prosthesis implant, this increase being higher than about 20% of the un-treated values. Moreover, these alterations remain roughly unaffected 30 days after surgery. These findings suggest that a complete hemo-compatibility of these prostheses is lacking, even if the observed alterations may not have a clinical relevance.
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http://dx.doi.org/10.1088/1748-6041/2/1/005DOI Listing
March 2007