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The analysis of co-citations, which occurs when two publications or authors are mentioned together in the same text, has long been established as a practice within scientometrics, particularly in the field of “science mapping”. However, historiography has shown less openness to utilizing co-citation analysis for distant reading purposes. To address this gap, this article presents a comprehensive methodology for applying co-citation analysis to extensive collections of historical documents, specifically 17th-century letters indexed in the ePistolarium database. In science mapping, co-citation serves as an indicator for tracking the development of scientific fields. Similarly, I employ co-citation to map the Dutch socio-intellectual landscape during the Scientific Revolution period (1623–87) and evaluate the strengths and limitations of this approach.

Stroke is a severe medical condition which may lead to permanent disability conditions. The initial 8 weeks following a stroke are crucial for rehabilitation, as most recovery occurs during this period. Personalized approaches and predictive biomarkers are needed for tailored rehabilitation. In this context, EEG brain connectivity and Artificial Intelligence (AI) can play a crucial role in diagnosing and predicting stroke outcomes efficiently. In the present study, 127 patients with subacute ischemic lesions and 90 age- and gender-matched healthy controls were enrolled. EEG recordings were obtained from each participant within 15 days of stroke onset. Clinical evaluations were performed at baseline and at 40-days follow-up using the National Institutes of Health Stroke Scale (NIHSS). Functional connectivity analysis was conducted using Total Coherence (TotCoh) and Small Word (SW). Quadratic support vector machines (SVM) algorithms were implemented to classify healthy subjects compared to stroke patients (Healthy vs Stroke), determine the affected hemisphere (Left vs Right Hemisphere), and predict functional recovery (Functional Recovery Prediction). In the classification for Functional Recovery Prediction, an accuracy of 94.75%, sensitivity of 96.27% specificity of 92.33%, and AUC of 0.95 were achieved; for Healthy vs Stroke,an accuracy of 99.09%, sensitivity of 100%, specificity of 98.46%, and AUC of 0.99 were achieved. For Left vs Right Hemisphereclassification, accuracy was 86.77%, sensitivity was 91.44%, specificity was 80.33%, and AUC was 0.87. These findings highlight the potential of utilizing functional connectivity measures based on EEG in combination with AI algorithms to improve patient outcomes by targeted rehabilitation interventions.

In recent decades, entropy measures have gained prominence in neuroscience due to the nonlinear behaviour exhibited by neural systems. This rationale justifies the application of methods from the theory of nonlinear dynamics to cerebral activity, aiming to detect and quantify its variability more effectively. In the context of electroencephalogram (EEG) signals, entropy analysis offers valuable insights into the complexity and irregularity of electromagnetic brain activity. By moving beyond linear analyses, entropy measures provide a deeper understanding of neural dynamics, particularly pertinent in elucidating the mechanisms underlying brain aging and various acute/chronic-progressive neurological disorders. Indeed, various pathologies can disrupt nonlinear structuring in neural activity, which may remain undetected by linear methods such as power spectral analysis. Consequently, the utilization of nonlinear tools, including entropy analysis, becomes crucial for capturing these alterations. To establish the relevance of entropy analysis and its potential to discern between physiological and pathological conditions, this review discusses its diverse applications in studying healthy brain aging and neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). Various entropy parameters, such as approximate entropy (ApEn), sample entropy (SampEn), multiscale entropy (MSE), and permutation entropy (PermEn), are analysed within this context. By quantifying the complexity and irregularity of EEG signals, entropy analysis may serve as a valuable biomarker for early diagnosis, treatment monitoring, and disease management. Such insights offer clinicians crucial information for devising personalized treatment and rehabilitation plans tailored to individual patients.

Moving from the hypothesis that aging processes modulate brain connectivity networks, 170 healthy elderly volunteers were submitted to EEG recordings in order to define age-related normative limits. Graph theory functions were applied to exact low-resolution electromagnetic tomography on cortical sources in order to evaluate the small-world parameter as a representative model of network architecture. The analyses were carried out in the whole brain—as well as for the left and the right hemispheres separately—and in three specific resting state subnetworks defined as follows: attentional network (AN), frontal network (FN), and default mode network (DMN) in the EEG frequency bands (delta, theta, alpha 1, alpha 2, beta 1, beta 2, gamma). To evaluate the stability of the investigated parameters, a subgroup of 32 subjects underwent three separate EEG recording sessions in identical environmental conditions after a few days interval. Results showed that the whole right/left hemispheric evaluation did not present side differences, but when individual subnetworks were considered, AN and DMN presented in general higher SW in low (delta and/or theta) and high (gamma) frequency bands in the left hemisphere, while for FN, the alpha 1 band was lower in the left with respect to the right hemisphere. It was also evident the test-retest reliability and reproducibility of the present methodology when carried out in clinically stable subjects.

Hyperventilation (HV) is a voluntary activity that causes changes in the neuronal firing characteristics noticeable in the electroencephalogram (EEG) signals. HV-related changes have been scribed to modulation of pO2/pCO2 blood contents. Therefore, an HV test is routinely used for highlighting brain abnormalities including those depending to neurobiological mechanisms at the basis of neurodegenerative disorders. The main aim of the present paper is to study the effectiveness of HV test in modifying the functional connectivity from the EEG signals that can be typical of a prodromal state of Alzheimer’s disease (AD), the Mild Cognitive Impairment prodromal to Alzheimer condition. MCI subjects and a group of age-matched healthy elderly (Ctrl) were enrolled and subjected to EEG recording during HV, eyes-closed (EC), and eyes-open (EO) conditions. Since the cognitive decline in MCI seems to be a progressive disconnection syndrome, the approach we used in the present study is the graph theory, which allows to describe brain networks with a series of different parameters. Small world (SW), modularity (M), and global efficiency (GE) indexes were computed among the EC, EO, and HV conditions comparing the MCI group to the Ctrl one. All the three graph parameters, computed in the typical EEG frequency bands, showed significant changes among the three conditions, and more interestingly, a significant difference in the GE values between the MCI group and the Ctrl one was obtained, suggesting that the combination of HV test and graph theory parameters should be a powerful tool for the detection of possible cerebral dysfunction and alteration.

Aging is the inevitable biological process that results in a progressive structural and functional decline associated with alterations in the resting/task-related brain activity, morphology, plasticity, and functionality. In the present study, we analyzed the effects of physiological aging on the human brain through entropy measures of electroencephalographic (EEG) signals. One hundred sixty-one participants were recruited and divided according to their age into young (n= 72) and elderly (n= 89) groups. Approximate entropy (ApEn) values were calculated in each participant for each EEG recording channel and both for the total EEG spectrum and for each of the main EEG frequency rhythms: delta (2–4 Hz), theta (4–8 Hz), alpha 1 (8–11 Hz), alpha 2 (11–13 Hz), beta 1 (13–20 Hz), beta 2 (20–30 Hz), and gamma (30–45 Hz), to identify eventual statistical differences between young and elderly. To demonstrate that the ApEn represents the age-related brain changes, the computed ApEn values were used as features in an age-related classification of subjects (young vs elderly), through linear, quadratic, and cubic support vector machine (SVM). Topographic maps of the statistical results showed statistically significant difference between the ApEn values of the two groups found in the total spectrum and in delta, theta, beta 2, and gamma. The classifiers (linear, quadratic, and cubic SVMs) revealed high levels of accuracy (respectively 93.20 ± 0.37, 93.16 ± 0.30, 90.62 ± 0.62) and area under the curve (respectively 0.95, 0.94, 0.93). ApEn seems to be a powerful, very sensitive–specific measure for the study of cognitive decline and global cortical alteration/degeneration in the elderly EEG activity.

Objective:Hemianopia after occipital stroke is believed to be mainly due to local damage at or near the lesion site. However, magnetic resonance imaging studies suggest functional connectivity network (FCN) reorganization also in distant brain regions. Because it is unclear whether reorganization is adaptive or maladaptive, compensating for, or aggravating vision loss, we characterized FCNs electrophysiologically to explore localand globalbrain plasticity and correlated FCN reorganization with visual performance.Methods:Resting-state electroencephalography (EEG) was recorded in chronic, unilateral stroke patients and healthy age-matched controls (n= 24 each). This study was approved by the local ethics committee. The correlation of oscillating EEG activity was calculated with the imaginary part of coherence between pairs of regions of interest, and FCN graph theory metrics (degree, strength, clustering coefficient) were correlated with stimulus detection and reaction time.Results:Stroke brains showed altered FCNs in the alpha- and low beta-band in numerous occipital, temporal brain structures. On a globallevel, FCN had a less efficient network organization whereas on the locallevel node networks were reorganized especially in the intact hemisphere. Here, the occipital network was 58% more rigid (with a more “regular” network structure) whereas the temporal network was 32% more efficient (showing greater “small-worldness”), both of which correlated with worse or better visual processing, respectively.Conclusions:Occipital stroke is associated with both localand globalFCN reorganization, but this can be both adaptive and maladaptive. We propose that the more “regular” FCN structure in the intact visual cortex indicates maladaptiveplasticity, where less processing efficacy with reduced signal/noise ratio may cause the perceptual deficits in the intact visual field (VF). In contrast, reorganization in intact temporal brain regions is presumably adaptive, possibly supporting enhanced peripheral movement perception.

Most studies of René Descartes’s legacy have focused on the novelty of his ideas, but little has been done to uncover the conditions that allowed these ideas to spread. Seventeenth-century Europe was already a small world—it presented a high degree of connectedness with a few brokers bridging otherwise disparate regions. A communication network known as the Republic of Letters enabled scholars to trade ideas—including Descartes’s—by means of correspondence. This article offers an analysis—both qualitative and quantitative—of a corpus of letters written during Descartes’s lifetime and mentioning his name. The aim is to unveil the factors that drove the diffusion of Descartes’s ideas. The results are twofold. First, a close reading of the letters reveals that they were not used to create awareness about Descartes and his works but rather to discuss his ideas. Second, a network analysis of the letters shows that ideas do not spread like viruses, thus undermining the ‘social contagion’ model, and that weak ties are not as effective in promoting innovations as they are in circulating information.

We tested the hypothesis that functional cortico-muscular coupling of brain rhythms is implied in the control of lower limb muscles for upright standing. Electroencephalographic (EEG; Be-plus Eb-Neuro) and electromyographic (EMG) data were recorded in 18 fencing and 19 karate elite athletes, 14 karate amateurs, and 9 non-athletes, during quiet upright standing with open and closed eyes conditions. Cortico-muscular coupling was evaluated by computing EEG-EMG spectral coherence and directed transfer function (DTF). Body sway area did not differ among the groups. In non-athletes, the EEG-EMG coherence (gastrocnemius lateralis) at centro-parietal and parasylvian alpha rhythms (about 8-12 Hz) was higher during the open than closed eyes condition. This was not true in the elite athletes. At the same alpha rhythms, the sport amateurs presented values halfway between the non-athletes and elite athletes. Finally, the DTF was higher for cortico-muscular than muscular-cortical direction. These results suggest that visual information affects cortico-muscular coherence at 8-12 Hz in non-athletes and amateur athletes but not in elite athletes. In elite athletes, this might be due to a long training for the control of equilibrium based on proprioceptive and tactile inputs. Keywords: electroencephalographic rhythms, electromyogram, stabilogram, spectral coherence, sport science

Previous evidence relating to somatosensory-evoked magnetic fields has shown that the human parasylvian cortex (PC) is affected by ongoing painful sensorimotor interactions. In the present magnetoencephalographic study, the activity of the PC was investigated to evaluate the hypothesis of anticipatory processes preceding painful sensorimotor interactions. Sensorimotor interactions were induced by warned painful electrical stimulations at the left hand concomitant with a motor task of the right hand. The anticipatory activity of the PC was probed via contingent negative variation. Compared with the control nonpainful condition, the anticipation of the painful sensorimotor interactions increased the PC activity over the hemisphere ipsilateral to the stimulation. Dipole modeling indicated that the center of gravity of the anticipatory activity in the PC was located in the secondary somatosensory cortex. These results suggest that anticipation of painful sensorimotor interactions engages the human PC. especially in the hemisphere ipsilateral to upcoming painful stimuli and contralateral to preparatory motor commands.

This high-resolution electroencephalographic (EEG) study on alpha event-related desynchronization (ERD) evaluated whether anticipatory activity precedes a sensorimotor interaction induced by concomitant painful stimuli and sensorimotor demand. An omitted-stimulus paradigm induced the expectancy of the painful stimulation at the left hand. In the experimental condition, the painful stimulation was associated with a visual go/no-go task triggering right-hand movements. Two control conditions manipulated the painful sensorimotor interaction variable. Compared with the control conditions, the expectancy of the painful sensorimotor interaction increased the high-band alpha EEG oscillations over the right primary sensorimotor cortex contralateral to the nociceptive stimuli and, to a lesser extent, over the centroparietal midline. These findings suggest that concomitant painful stimuli and simple sensorimotor go/no-go demands affect anticipatory activity as revealed by alpha ERD. Keywords: electroencephalography, alpha rhythms, event-related desynchronization/synchronization, primary sensorimotor cortex, central midline

The intent of this electroencephalography study was to investigate the competition between cortical nociceptive and cognitive motor processes preceding sensorimotor interactions. Sensorimotor expectancy processes to painful stimulation and motor go/no-go demands were indexed over primary sensorimotor and midline cortical areas by contingent negative variation (CNV). Before the sensorimotor interaction, CNV was observed over midline posterior and bilateral central areas. Early expectancy of painful stimulation and the go/no-go task induced an evident midline posterior CNV. During the late expectancy period, CNV extended to the right central area contralateral to the stimulation. These findings suggest a sequential activation of midline posterior and primary sensorimotor areas contralateral to the painful stimulation as a reflection of the enhanced nociceptive processes preceding painful sensorimotor interactions.

Patients with mild Alzheimer's disease (AD) present with abnormally strong values of frontal and ipsilateral central sensorimotor rhythms. The authors tested 2 working hypotheses of the related electroencephalographic (EEG) coherence: disconnection, defined as a sign of a reduced coordination within the frontoparietal and interhemispheric networks, and cooperation, defined as a reflection of the reorganization of the brain sensorimotor networks. Results showed that, compared with healthy controls, patients with mild AD had an unreactive and abnormally low interhemispheric EEG coherence and an unreactive and abnormally high frontoparietal EEG coherence. These findings support the hypothesis of an impaired mechanism of sensorimotor cortical coupling (disconnection) in mild AD.

In this electroencephalographic study, the authors modeled the functional connectivity between frontal and parietal areas during short-term memory (STM) processes by spectral coherence analysis and the directed transfer function, that is, for the estimation of coherence 'direction.' A no-STM task was used as a reference. STM was characterized by an increased frontoparietal electroencephalograph coherence at high frequencies (beta and gamma, 14-45 Hz). In the control task, parietal-to-frontal flow prevailed at those frequencies. However, the STM task showed a bidirectional frontoparietal flow at the gamma band. In conclusion, frontoparietal connectivity would optimize 'representational' memory during STM. In this context, the frontal areas would increase their influence on parietal areas for memory retention.

Alzheimer’s disease (AD) is the most common neurodegenerative disorder in elderly subjects. Recent studies verified the effects of cognitive training combined with repetitive transcranial magnetic stimulation (rTMS-COG) in AD patients. Here, we analyzed neuropsychological and neurophysiological data, derived from electroencephalography (EEG), to evaluate the effects of a 6-week protocol of rTMS-COG in 72 AD. We designed a randomized, double-blind, sham-controlled trial to evaluate efficacy of rTMS on 6 brain regions obtained by an individual MRI combined with COG related to brain areas to stimulate (i.e., syntax and grammar tasks, comprehension of lexical meaning and categorization tasks, action naming, object naming, spatial memory, spatial attention). Patients underwent neuropsychological and EEG examination before (T0), after treatment (T1), and after 40 weeks (T2), to evaluate the effects of rehabilitation therapy. “Small World” (SW) graph approach was introduced allowing us to model the architecture of brain connectivity in order to correlate it with cognitive improvements. We found that following 6 weeks of intensive daily treatment the immediate results showed an improvement in cognitive scales among AD patients. SW present no differences before and after the treatment, whereas a crucial SW modulation emerges at 40-week follow-up, emphasizing the importance of rTMS-COG rehabilitation treatment for AD. Additional results demonstrated that the delta and alpha1 SW seem to be diagnostic biomarkers of AD, whereas alpha2 SW might represent a prognostic biomarker of cognitive recovery. Derived EEG parameters can be awarded the role of diagnostic and predictive biomarkers of AD progression, and rTMS-COG can be regarded as a potentially useful treatment for AD.

The objective of the present study is to explore the brain resting state differences between Parkinson’s disease (PD) patients and age- and gender-matched healthy controls (elderly) in terms of complexity of electroencephalographic (EEG) signals. One non-linear approach to determine the complexity of EEG is the entropy.In this pilot study, 28 resting state EEGs were analyzed from 13 PD patients and 15 elderly subjects, applying approximate entropy (ApEn) analysis to EEGs in ten regions of interest (ROIs), five for each brain hemisphere (frontal, central, parietal, occipital, temporal). Results showed that PD patients presented statistically higher ApEn values than elderly confirming the hypothesis that PD is characterized by a remarkable modification of brain complexity and globally modifies the underlying organization of the brain. The higher-than-normal entropy of PD patients may describe a condition of low order and consequently low information flow due to an alteration of cortical functioning and processing of information. Understanding the dynamics of brain applying ApEn could be a useful tool to help in diagnosis, follow the progression of Parkinson’s disease, and set up personalized rehabilitation programs.

Supplemental Digital Content is Available in the Text.A comparative study to assess outcomes of vitrectomy with and without internal limiting membrane peeling about formation of macular pucker.

Research indicates that a warning range exists within the normal interval of Mini-Mental State Examination (MMSE) responses for diagnosing early dementia in old age. The role of the long-term memory test in the MMSE for determining early dementia is discussed.

Supplemental Digital Content is Available in the Text.Modification of Adjustable Macular Buckle (AMB) by illuminating its terminal plate allows the visualization of the macular area and improves the accuracy of its positioning in the treatment of highly myopic macular hole.

The brain has a high level of complexity and needs continuous oxygen supply. So it is clear that any pathological condition, or physiological (aging) change, in the cardiovascular system affects functioning of the central nervous system. We evaluated linear aspects of the relationship between the slowness of cortical rhythms, as revealed by the modulation of a graph connectivity parameter, and congestive heart failure (CHF), as a reflection of neurodegenerative processes. Eyes-closed resting electroencephalographic (EEG) data of 10 patients with CHF were recorded by 19 electrodes positioned according the international 10-20 system. Graph theory function (normalized characteristic path length λ) was applied to the undirected and weighted networks obtained by lagged linear coherence evaluated by eLORETA software, therefore getting rid of volumetric propagation influences. The EEG frequency bands of interest were: delta (2-4 Hz), theta (4-8 Hz), alpha 1 (8-10.5 Hz), alpha 2 (10.5-13 Hz), beta 1 (13-20 Hz), beta 2 (20-30 Hz), and gamma (30-40 Hz). The analysis between B-type natriuretic peptide (BNP) values and λ showed positive correlation in delta, associated with a negative correlation in alpha 2 band. Namely, the higher the severity of the disease (as revealed by the BNP vales), the higher the λ in delta, and lower in alpha 2 band. Results suggest that delta and alpha λ indices are good markers of the severity of CHF.

Non-Communicable Diseases (NCDs) are among the most pressing global health problems of the twenty-first century. Their rising incidence and prevalence is linked to severe morbidity and mortality, and they are putting economic and managerial pressure on healthcare systems around the world. Moreover, NCDs are impeding healthy aging by negatively affecting the quality of life of a growing number of the global population. NCDs result from the interaction of various genetic, environmental and habitual factors, and cluster in complex ways, making the complex identification of resulting phenotypes not only difficult, but also a top research priority. The degree of complexity required to interpret large patient datasets generated by advanced high-throughput functional genomics assays has now increased to the point that novel computational biology approaches are essential to extract information that is relevant to the clinical decision-making process. Consequently, system-level models that interpret the interactions between extensive tissues, cellular and molecular measurements and clinical features are also being created to identify new disease phenotypes, so that disease definition and treatment are optimized, and novel therapeutic targets discovered. Likewise, Systems Medicine (SM) platforms applied to extensively-characterized patients provide a basis for more targeted clinical trials, and represent a promising tool to achieve better prevention and patient care, thereby promoting healthy aging globally. The present paper: (1) reviews the novel systems approaches to NCDs; (2) discusses how to move efficiently from Systems Biology to Systems Medicine; and (3) presents the scientific and clinical background of the San Raffaele Systems Medicine Platform.

In phase II clinical trial, fingolimod at a dose of 5.0mg (ten times higher than the currently approved dose) induced dyspnoea and decreased forced expiratory flow in some patients, probably trought an airways constriction S1P4-mediated. In phase III trials, respiratory adverse events associated with fingolimod treatment as dyspnoea, cough, oropharingeal pain and nasal congestion are reported with the same incidence of placebo. Here we report two cases of severe dyspnoea with alteration of the diffusion capacity of the lung associated with fingolimod treatment, which led to permanent treatment withdrawal.

In this paper, we review the contribution of our research group to the study of human consciousness by quantitative electroencephalographic (EEG) techniques. We posit that EEG techniques can be extremely useful for a direct measurement of brain electrophysiological activity related to human consciousness for their unsurpassable high temporal resolution (milliseconds). This activity can be expressed in terms of event-related potentials as well as changes of EEG rhythms of interest, for example the dominant alpha rhythms (about 8-12 Hz). The results of our studies, and those of several independent groups, lead support to the hypothesis that these techniques provide important insights about the neurophysiologic mechanisms underlying cortical neural synchronization/desynchronization and the regulation of neuromodulatory systems (e.g. dopaminergic, noradrenergic, cholinergic, etc.) at the basis of brain arousal and consciousness in healthy subjects and in patients with impairment of the consciousness. A possible interaction of these mechanisms and the drugs administered to patients with consciousness disorders is discussed.

Different kinds of challenge can alter cognitive process and electroencephalographic (EEG) rhythms in humans. This can provide an alternative paradigms to evaluate treatment effects in drug discovery. Here, we report recent findings on the effects of challenges represented by sleep deprivation (SD), transient hypoxia, and transcranial magnetic stimulation (TMS) in healthy volunteers on cognitive processes and EEG rhythms to build a knowledge platform for novel research for drug discovery in AD Alzheimers disease (AD). Sleep pressure enhanced frontal delta rhythms (< 4 Hz) during the night, while SD increased slow rhythms in the theta range (4-7 Hz), and reduced resting state alpha rhythms (8-12 Hz) after the following day. Furthermore, SD transiently affected cognitive performance. In contrast, transient experimental hypoxia induced abnormal posterior resting state delta and alpha rhythms in healthy volunteers that resemble the abnormal EEG rhythms typically recorded in AD patients. However, the relationship between the cognitive and EEG effects of such challenges is poorly understood. TMS reversibly interfered with higher brain functions during EEG recordings, but few studies have investigated the relationship between the cognitive and EEG effects of TMS. In conclusion, SD is the most mature challenge model for testing new drugs for AD. Future investigation is needed to better understand the opportunities offered by TMS and hypoxia challenges.

Subjects with Mild Cognitive Impairment (MCI) are normally classified according to the presence of episodic memory deficits associated or not to disturbances of other cognitive domains. The present study had two aims: to identify discrete subtypes of amnestic MCI (a-MCI) with hippocampal atrophy; and to assess if the identified subtypes show different rates of progression to dementia. Sixty-seven a-MCI subjects were enrolled, all showing significant hippocampal atrophy on MRI. The subjects underwent at baseline and at follow-up a comprehensive neuropsychological examination, and were followed-up for five years to detect the conversion to dementia. An exploratory factor analysis on neuropsychological performances at baseline identified three main factors that were subsequently used to perform a k-means cluster analysis. Three cluster of a-MCI subjects were identified: “pure amnestic” (N=29), “multiple domain”(N=16), and “amnestic/semantic”(N=22). The successive discriminant functions were able to correctly classify 88% of the subjects. During the follow-up, 33 subjects converted to dementia (49.2%), 14 “pure amnestic” (48.3%), 11 “multiple domain” (68.5%) and 8 “amnestic/semantic” (36.4%; log-rank: p=0.016); median survival was respectively 36, 22, and 39 months. On Cox proportional hazard model, baseline MMSE (HR=0,709; p=0.006), education (HR=1,115; p=0.011) and belonging to the “multiple domain” subgroup (HR=2,706; p=0.013) were significantly associated to higher rate of conversion to dementia. Our findings confirm the tendency to worst outcome of subjects with multiple domain MCI, and show that the association of episodic and semantic memory deficits, without other cognitive disturbances, could identify a specific cognitive pattern associated to slower cognitive decline, as previously reported in Alzheimer’s Disease.

Background: Mild Cognitive Impairment (MCI) and REM Behavior Disorder (RBD) are both associated with a degeneration of ponto-medullary cholinergic pathways. Methods: We conducted a placebo-controlled, cross-over pilot trial of Rivastigmine (RVT) in 25 consecutive patients with MCI, who presented RBD refractory to conventional first-line treatments (melatonin up to 5 mg/day and clonazepam up to 2 mg/day). Results: RVT treatment was followed by a significant reduction of RBD episodes when compared with placebo. Conclusions: Our data suggest that, in MCI patients with RBD resistant to conventional therapies (muscle relaxants benzodiazepines or melatonin,) treatment with RVT may induce a reduction in the frequency of RBD episodes compared to placebo.

To report successful treatment of refractive glaucoma in a patient submitted to osteo-odonto-keratoprosthesis surgery for Stevens–Johnson syndrome.

The pathophysiological mechanisms underlying normal aging and neurodegenerative disorders represent the focus of a bulk of recent research. Physiological brain aging is characterized by a progressive dysfunction and loss of synaptic contacts and neuronal abnormal apoptosis. Neural and synaptic redundancy as well as functional and structural plastic remodeling of brain networking promote maintenance of brain activity in healthy elderly for everyday life but are not sufficient to face the pathologic scenario of excessive synaptic/ neuronal loss as in dementias. It is, then, important to implement techniques that are able to measure changes in normal aging brain and to discriminate the threshold from neurodegenerative processes. Rhythmic electromagnetic brain oscillatory activity is a hallmark of neuronal function and it contains relevant traces of neuronal assemblies cooperation across different brain functions; an integrated approach utilizing modern neurophysiological techniques, including electroencephalography (EEG), event-related potentials (ERPs), and transcranial magnetic stimulation (TMS), together with biological markers and structural and functional imaging is promising for largescale, affordable, and non-invasive intercept of at-risk populations both at a group and probably also at a single-subject level. This approach might also guarantee the possibility of studying drug-induced changes in the electrical properties of the human cortex, developing and testing models of brain connectivity and treating neuropsychiatric diseases. In this paper some neurophysiological cutting-edge techniques will be presented that provide innovative information and deal with the broad issue of the role of neurophysiology for the assessment of patho-physiological aging and dementia also providing new insight to the actions of central nervous system drugs at the cortical level.

AbstractIncreasing evidence supports the notion that brain plasticity involves distinct functional and structural components, each entailing a number of cellular mechanisms operating at different time scales, synaptic loci, and developmental phases within an extremely complex framework. However, the exact relationship between functional and structural components of brain plasticity/connectivity phenomena is still unclear and its explanation is a major challenge within modern neuroscience. Transcranial magnetic stimulation (TMS), with or without electroencephalography (EEG), is a sensitive and objective measure of the effect of different kinds of noninvasive manipulation of the brain’s activity, particularly of the motor cortex. Moreover, the key feature of TMS and TMS-EEG coregistration is their crucial role in tracking temporal dynamics and inner hierarchies of brain functional and effective connectivities, possibly clarifying some essential issues underlying brain plasticity. All together, the findings presented here are significant for the adoption of the TMS and TMS-EEG coregistration techniques as a tool for basic neurophysiologic research and, in the future, even for clinical diagnostics purposes.

The link between biometals and Alzheimers disease (AD) has been investigated with a focus on local metal accumulations. In this work, we have looked at systemic metal changes and computed a score (M-score) based on metal disarrangements to discriminate patients with AD from patients with vascular dementia (VaD) and from controls. We measured serum levels of iron, copper, ceruloplasmin, transferrin, and total antioxidant capacity (TAS), performed Apolipoprotein E (APOE) genotyping and calculated non-ceruloplasmin copper (‘free’ copper) levels, transferrin saturation, total iron binding capacity, and ceruloplasmin-transferrin ratio (Cp/Tf) in 93 patients with AD, 45 patients with VaD, and 48 controls. All subjects underwent biochemical, neuroimaging and cognitive evaluations. Significant differences were observed among the tested groups for the levels of copper, free copper, peroxides, and TAS and for the Cp/Tf with disparity in couple comparison. On this basis we created the M-score as linear combination of biometal variables and APOE genotype. Besides its ability to discriminate AD patients vs. controls (ROC AUC=90), M-score was able to distinguish AD vs. VaD (ROC AUC=79). Moreover, we calculated the sensitivity and the specificity for M-score and for the other significant variables: M-score reached the highest sensitivity without a relevant loss in terms of specificity. When we compared M-score with APOE genotype and Medial Temporal Atrophy score, it resulted statistically better than these diagnostic markers. In conclusion, we confirm the link between biometals and AD and suggest its potential as diagnostic tool. Further studies may elucidate its potential role as reliable diagnostic test.

To quantify the overall contribution of mutations in the currently known amyotrophic lateral sclerosis (ALS) genes in a large cohort of sporadic patients and to make genotype–phenotype correlations.

Here we describe a methodological approach for the simultaneous electroencephalographic (EEG) recording in musicians playing in ensemble. Four professional saxophonists wore pre-wired EEG caps (30 electrodes placed according to an augmented 10–20 system; cephalic reference and ground). Each cap was connected to a single multi-channel amplifier box [Brain Explorer (BE), EB-Neuro©]. The four boxes converged to a single workstation equipped with a software (GALILEO NT, EB-Neuro©) allowing the simultaneous recording of sounds, digital trigger, and EEG–electrooculographic (EOG)–electromyographic (EMG) data, and providing a separate output file for each individual. Noteworthy, the subjects were electrically decoupled to satisfy international safety guidelines. The quality of the EEG data was confirmed by the rate of artifact-free EEG epochs (about 80%) and by EEG spectral features. During the resting state, dominant EEG power density values were observed at alpha band (8–12Hz) in posterior cortex. The quality of EMG can be used to identify “on” and “off” states of the musicians’ motor performance, thus potentially allowing the investigation of the relationships between EEG dynamics and different characteristics of the specific performance. During the music performance, alpha power density values decreased in amplitude in several cortical regions, whereas power density values enhanced within narrow high-frequency bands. In conclusion, the present methodological approach appeared to be suitable for simultaneous EEG recordings in musicians playing in ensemble.

Cerebral vasomotor reactivity (VMR) is a capability of cerebral vessels to dilate in response to hypercapnia. Transcranial direct current stimulation (tDCS) effects on cerebral hemodynamics have been poorly studied.

In acute stroke, Iron (Fe) may amplify reperfusion injury by catalyzing the conversion of superoxide and hydrogen peroxide into highly reactive radicals. Transferrin (Tf) is the main protein regulating Fe homeostasis, whereas Ceruplasmin (CP) is a circulating ferroxidase enzyme able to oxidize ferrous ions to less toxic ferric forms. This study aims at investigating whether CP, Copper (Cu), Tf, and Fe play a role in the pathophysiology of acute stroke.

Background and aims: Epidemiological studies have examined the association between the use of non-steroidal anti-inflammatory drugs (NSAIDs) and the risk of Alzheimer’s disease (AD). Recently, a variety of experimental studies indicates that a subset of NSAIDs, such as ibuprofen or flurbiprofen, also have Aβ-lowering properties in both AD transgenic mice and cell cultures of peripheral, glial and neuronal origin. In this trial, we evaluated whether the non-selective NSAID ibuprofen slows disease progression in patients with mild to moderate AD. Methods: This was a 12-month multicenter, randomized, double-blind, placebo-controlled, parallel group trial. Participants with mild-moderate AD (Mini-Mental State Examination score >15, <26; Clinical Dementia Rating= 0.5–1), 65 years or older, with reliable caregivers, were recruited between April 2003 and September 2004. Seven AD Outpatient Treatment Centers screened 530 patients, 132 of whom were enrolled. Interventionconsisted of 400 mg ibuprofen twice a day or placebo, together with 20 mg once a day of esomeprazol, or placebo. The primary measure was any one-year change in the Alzheimer Disease Assessment Scale-Cognitive (ADAS-Cog) subscale score. Secondary measures included changes in MMSE, CDR, Basic and Instrumental Activities of Daily Living scales, and Neuropsychiatry Inventory (NPI). Results: Fifty-one patients (77%) in the ibuprofen vs 46 (70%) in the placebo group completed the protocol (p>0.20). In intention-to-treat analysis, ADAS-Cog score worsening was similar in the two groups (p=0.951, treatment difference= 0.1, CI-2.7; 2.9). No differences were found for any secondary outcomes. In a subsample of genotyped patients, ApoE ε4 carriers treated with ibuprofen (n=27) were the only group without significant cognitive decline. Conclusions: Ibuprofen, if used for relatively short periods of time and although well tolerated thanks to gastroprotection, does not seem to be effective in tertiary prevention of mild-moderate AD. Our results suggest the need to examine whether differences in the response to NSAIDs exist, based on ApoE ε4 carrier status.

Alzheimer’s disease (AD) is typically associated with an impairment of brain networks and global cognitive function in aging. In this vein, the present study tested the hypothesis that the functional coupling of resting cortical electroencephalographic (EEG) rhythms is progressively abnormal in amnesic mild cognitive impairment (MCI) and AD subjects. Eyes-closed resting EEG data were recorded (10–20 system) in 33 mild AD, 52 amnesic MCI, and 47 normal elderly subjects (Nold). EEG rhythms of interest were delta (2–4 Hz), theta (4–8 Hz), alpha1 (8–10 Hz), alpha2 (10–13 Hz), beta1 (13–20 Hz), beta2 (20–30 Hz), and gamma (30–40 Hz). The global functional coupling of the EEG rhythms was indexed by means of spectral coherence for all combinations of electrode pairs (i.e., total coherence). The main results showed that the total coherence of delta rhythms was higher in the AD than the MCI group. It was also higher in the MCI than the Nold group. Furthermore, the delta total coherence was negatively correlated with global cognition (Mini Mental State Examination score) across the Nold, MCI, and AD subjects. Finally, the alpha1 total coherence was lower in the AD group than in the MCI and Nold groups. These results suggest that in the AD process an impairment of brain networks and global cognition is associated with a frequency-specific modulation of the global functional coupling of resting EEG rhythms.

Mugil cephalushas been identified as a suitable species for feeding populations in developing countries, and it represents a traditionally harvested and consumed species in various European countries. A decline in wild populations and a growing demand have promoted new interest in mullet production in hatcheries, considered imperative for the production of a steady supply of fry and the expansion of M. cephalusaquaculture. In the present study, wild adults collected in Sardinian lagoons were induced to spawn during their natural reproductive period by treating them with a single dose of a slow release GnRHa preparation (200µgkgbw-1). In 2016, a protocol for reducing stress in capturing, transporting and selecting wild adults was set up, and 64% of the females with an oocyte diameter larger than 550µm were successfully induced to spawn. Five spawning induction trials were carried out in the period 2016–2019. The mean fertilization rate and the mean hatching rate obtained were 83±14% and 76±13%, respectively. The individuals obtained were reared indoor in a recirculating aquaculture system (RAS) at a density of 40 individuals L-1for 60 days, and their survival ranged from 10±2 to 19±1%. During the whole larval rearing phase, from 0 to 34 days post hatching (dph), the mean standard growth rates recorded were 5.0±0.7% in total length and 14.4±3.9% in body weight. The rearing density used resulted in an average survival rate comparable or even better than those obtained by other authors, thus indicating the possibility of producing M. cephalusfries in captivity from sexually mature adults captured in Sardinian lagoons, reducing the costs and optimizing the production.

Using repetitive transcranial magnetic stimulation (rTMS), we investigated the role of the left and right dorsolateral prefrontal cortex (DLPFC) in sentence comprehension. Subjects were required to judge which of the two pictures correctly matched the meaning of active and passive semantically reversible sentences (subject–verb–object); the incorrect picture did not match the sentence in term of lexical items (semantic task) or agent–patient structure (syntactic task). The subjects performed the task while a series of magnetic stimuli were applied to the left or right DLPFC. When rTMS was applied to the left DLPFC, the subjects' performance was delayed only for the semantic task, while rTMS applied to the right DLPFC slowed the processing of syntactic information. The results of this experiment provide direct evidence of a double dissociation between the rTMS effects and the type of task, which may reflect a differential hemispheric involvement of working memory resources during sentence comprehension.

A dysfunction in copper homeostasis seems to occur in Alzheimer’s disease (AD). We recently demonstrated that an excess of non-ceruloplasmin-copper (i.e. ‘free’ copper) correlates with the main functional and anatomical deficits as well as the cerebrospinal markers of the disease, thus suggesting that copper contributes to AD neurodegeneration. Aim of this study was to investigate the profile of serum ceruloplasmin isoforms immunoreactive protein in relation to copper dysfunction in AD. Twenty-five AD patients and 25 controls were included in the study. All subjects underwent individual measurements of serum ceruloplasmin and copper concentrations, and the amount of ‘free’ copper was computed for each copper and ceruloplasmin pair. Serum samples were also pooled and analyzed by two dimensional polyacrylamide gel electrophoresis (2-D PAGE) and western blot analysis. The mean concentration of ’free’ copper resulted higher in AD patients than in controls. Ceruloplasmin 2-D PAGE western blot analysis of pooled sera showed in the AD samples low-molecular-weight spots in the &lt;50 kDa range that were not detected in controls’ pooled sera (p &lt; 0.029). Our data indicate a ceruloplasmin fragmentation in the serum of AD patients, possibly related to ‘free’ copper deregulation in this disease.

In the immune system, extracellular ATP functions as a “natural adjuvant” that exhibits multiple proinflammatory effects. It is released by damaged cells as an indicator of trauma and cell death but can be inactivated by CD39 (nucleoside triphosphate diphosphohydrolase-1 [NTPDase 1]), an ectoenzyme that degrades ATP to AMP. Here, we show that CD39 is expressed primarily by immune-suppressive Foxp3+regulatory T (Treg) cells. In mice, the enzyme is present on virtually all CD4+CD25+cells. CD39 expression is driven by the Treg-specific transcription factor Foxp3 and its catalytic activity is strongly enhanced by T-cell receptor (TCR) ligation. Activated Treg cells are therefore able to abrogate ATP-related effects such as P2 receptor-mediated cell toxicity and ATP-driven maturation of dendritic cells. Also, human Treg cells express CD39. In contrast to mice, CD39 expression in man is restricted to a subset of Foxp3+regulatory effector/memory-like T (TREM) cells. Notably, patients with the remitting/relapsing form of multiple sclerosis (MS) have strikingly reduced numbers of CD39+Treg cells in the blood. Thus, in humans CD39 is a marker of a Treg subset likely involved in the control of the inflammatory autoimmune disease.

In the immune system, extracellular ATP functions as a “natural adjuvant” that exhibits multiple proinflammatory effects. It is released by damaged cells as an indicator of trauma and cell death but can be inactivated by CD39 (nucleoside triphosphate diphosphohydrolase-1 [NTPDase 1]), an ectoenzyme that degrades ATP to AMP. Here, we show that CD39 is expressed primarily by immune-suppressive Foxp3+ regulatory T (Treg) cells. In mice, the enzyme is present on virtually all CD4+CD25+ cells. CD39 expression is driven by the Treg-specific transcription factor Foxp3 and its catalytic activity is strongly enhanced by T-cell receptor (TCR) ligation. Activated Treg cells are therefore able to abrogate ATP-related effects such as P2 receptor-mediated cell toxicity and ATP-driven maturation of dendritic cells. Also, human Treg cells express CD39. In contrast to mice, CD39 expression in man is restricted to a subset of Foxp3+ regulatory effector/memory-like T (TREM) cells. Notably, patients with the remitting/relapsing form of multiple sclerosis (MS) have strikingly reduced numbers of CD39+ Treg cells in the blood. Thus, in humans CD39 is a marker of a Treg subset likely involved in the control of the inflammatory autoimmune disease.

Transcranial magnetic stimulation (TMS) is a 20-year-old technique originally introduced to noninvasively investigate nervous propagation along the corticospinal tract, spinal roots, and peripheral nerves in humans. TMS is extensively used in clinical neurophysiology, including rehabilitation and intraoperative monitoring. Single-pulse TMS and other more recent versions (paired-pulse TMS, repetitive TMS, integration with structural and functional MRI, and neuronavigation) allow motor output to be mapped precisely to a given body district. Moreover, TMS can be used to evaluate excitatory/inhibitory intracortical circuits and to provide information on brain physiology and pathophysiology of various neuropsychiatric diseases as well as on the mechanisms of brain plasticity and of neuroactive drugs. TMS applied over nonmotor areas made it possible to extend research applications (often complementary with other functional neuroimaging techniques) in several fields of psychophysiology, causally testing brain–behavior relationships. Being able to induce relatively long-lasting excitability changes, repetitive TMS has made the treatment of neuropsychiatric diseases linked with brain excitability dysfunctions possible. These uses, however, warrant further large-scale studies. In emerging fields of research, TMS-EEG co-registration is considered a promising approach to evaluate corticocortical connectivity and brain reactivity with high temporal resolution. However, safety and ethical limitations of TMS technique need a high level of vigilance.

The rupture of posterior capsule during cataract surgery is always the cause of potential severe complications for the patient. This paper reports the use of triamcinolone acetonide crystal powder injected into the anterior chamber in the management of cataract surgery complications, when posterior capsule rupture occurred. The corticosteroid powder is useful in these situations because of its capability to link prolapsed vitreous fibrils in the anterior chamber and so helping to remove those radically. Triamcinolone is a valid aid in the postsurgical time because of its antiphlologistic and antiedemigenous properties. Aside from these, a new personal surgical technique, with a 25-gauge infusion into the anterior chamber (reflow technique), will be shown to better manage this event.

Relationships between the apolipoprotein E ε4 allele and electroencephalographic (EEG) rhythmicity have been demonstrated in Alzheimer's disease (AD) patients but not in the preclinical stage prodromic to it, namely, mild cognitive impairment (MCI). The present multicentric EEG study tested the hypothesis that presence of ε4 affects sources of resting EEG rhythms in both MCI and AD subjects. We enrolled 89 MCI subjects (34.8% with ε4) and 103 AD patients (50.4% with ε4). Resting eyes‐closed EEG data were recorded for all subjects. EEG rhythms of interest were delta (2—4Hz), theta (4–8Hz), alpha 1 (8–10.5Hz), alpha 2 (10.5–13Hz), beta 1 (13–20Hz), and beta 2 (20–30Hz). EEG cortical sources were estimated by low‐resolution brain electromagnetic tomography. Results showed that amplitude of alpha 1 and 2 sources in occipital, temporal, and limbic areas was lower in subjects carrying the ε4 allele than in those not carrying the ε4 allele (p< 0.01). This was true for both MCI and AD. For the first time to our knowledge, a relationship was shown between ApoE genotype and global neurophysiological phenotype (ie, cortical alpha rhythmicity) in a preclinical AD condition, MCI, in addition to clinically manifest AD. Such a demonstration motivates future genotype–EEG phenotype studies for the early prediction of AD conversion in individual MCI subjects. Ann Neurol 2005

Background and aims:Substantial evidence supports the hypothesis that impairment of mitochondrial function and increased oxidative damage are involved in the pathogenesis of several neurodegenerative disorders including Alzheimer’s disease (AD). Manganese Superoxide dismutase (MnSOD) plays a major role in protecting the mitochondrion from oxidative damage due to Superoxide radicals and other excited oxygen species. Recent studies have indicated that MnSOD mRNA levels are significantly increased in the lymphocytes of AD patients, supporting the role of oxidative alterations in the pathogenetic mechanism underlying this neurodegeneration. A potentially functional amino acid polymorphism (Ala-9Val) has been described in the signal sequence of enzymes associated with decreased defense capacity against oxidative stress. The object of this study was to investigate the association between this polymorphism of the MnSOD gene and AD in the Italian population. Methods:The Ala-9Val polymorphism was genotyped by PCR amplification and SSCP analysis in 227 AD patients and 198 healthy controls. Results:No significant differences in genotype or allele frequencies between cases and controls, even after stratification for APOE carrier status, were observed. Conclusions:Our data suggest that the Ala-9Val polymorphism in the MnSOD gene is not associated with genetic susceptibility in AD patients.