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As the field of noninvasive brain stimulation (NIBS) expands, there is a growing need for comprehensive guidelines on training practitioners in the safe and effective administration of NIBS techniques in their various research and clinical applications. This article provides recommendations on the structure and content of this training. Three different types of practitioners are considered (Technicians, Clinicians, and Scientists), to attempt to cover the range of education and responsibilities of practitioners in NIBS from the laboratory to the clinic. Basic or core competencies and more advanced knowledge and skills are discussed, and recommendations offered regarding didactic and practical curricular components. We encourage individual licensing and governing bodies to implement these guidelines.

International audience; Background: Early Alzheimer's disease (AD) detection using cerebrospinal fluid (CSF) biomarkers has been recommended as enrichment strategy for trials involving mild cognitive impairment (MCI) patients.Objective: To model a prodromal AD trial for identifying MRI structural biomarkers to improve subject selection and to be used as surrogate outcomes of disease progression.Methods: APOE ɛ4 specific CSF Aβ42/P-tau cut-offs were used to identify MCI with prodromal AD (Aβ42/P-tau positive) in the WP5-PharmaCog (E-ADNI) cohort. Linear mixed models were performed 1) with baseline structural biomarker, time, and biomarker×time interaction as factors to predict longitudinal changes in ADAS-cog13, 2) with Aβ42/P-tau status, time, and Aβ42/P-tau status×time interaction as factors to explain the longitudinal changes in MRI measures, and 3) to compute sample size estimation for a trial implemented with the selected biomarkers.Results: Only baseline lateral ventricle volume was able to identify a subgroup of prodromal AD patients who declined faster (interaction, p = 0.003). Lateral ventricle volume and medial temporal lobe measures were the biomarkers most sensitive to disease progression (interaction, p≤0.042). Enrichment through ventricular volume reduced the sample size that a clinical trial would require from 13 to 76%, depending on structural outcome variable. The biomarker needing the lowest sample size was the hippocampal subfield GC-ML-DG (granule cells of molecular layer of the dentate gyrus) (n = 82 per arm to demonstrate a 20% atrophy reduction).Conclusion: MRI structural biomarkers can enrich prodromal AD with fast progressors and significantly decrease group size in clinical trials of disease modifying drugs.

The use of inferior alveolar nerve (IAN) somatosensory evoked potentials (SEPs) may represent a non-invasive method to evaluate the sensory nerve function in the maxillofacial region. The aim of this work is to confirm the feasibility of a technique, previously reported in the literature, and the data previously obtained.SEPs were obtained following electrical stimulation (square wave pulses 0.2 millisecond [ms] in duration, 4 to 6.5 mA, 0.7/second repetition rate, 200 averages) of the gum at the mental foramen level, in the IAN region, via a new designed type of intraoral surface electrodes and recorded from the contralateral central scalp sites.We recognized waveforms of sufficient quality and consistently recorded a "W"-shaped response. Peak latencies of waves were at 14, 20, 27, 34 and 43 ms respectively. One side of the lower lip can be compared with the contralateral side.IAN SEPs, obtained with the present technique, may represent an objective, non-invasive, and reliable way of testing sensory nerve function in the maxillofacial region.

[Image: see text] COVER ILLUSTRATION: Brain connectivity in pre and post sleep onset conditions at sigma band.

Cortical sources of resting state electroencephalographic (EEG) rhythms are abnormal in subjects with mild cognitive impairment (MCI). Here, we tested the hypothesis that these sources in amnesic MCI subjects further deteriorate over 1 year. To this aim, the resting state eyes-closed EEG data were recorded in 54 MCI subjects at baseline (Mini Mental State Examination I ¼ 26.9; standard error [SE], 0.2) and at approximately 1-year follow-up (13.8 months; SE, 0.5; Mini Mental State Examination II ¼ 25.8; SE, 0.2). As a control, EEG recordings were also performed in 45 normal elderly and in 50 mild Alzheimer’s disease subjects. EEG rhythms of interest were delta (2e4 Hz), theta (4e8 Hz), alpha1 (8e10.5 Hz), alpha2 (10.5e13 Hz), beta1 (13e20 Hz), and beta2 (20e30 Hz). Cortical EEG sources were estimated using low-resolution brain electromagnetic tomography. Compared with the normal elderly and mild Alzheimer’s disease subjects, the MCI subjects were characterized by an intermediate power of posterior alpha1 sources. In the MCI subjects, the follow-up EEG recordings showed a decreased power of posterior alpha1 and alpha2 sources. These results suggest that the resting state EEG alpha sources were sensitivedat least at the group leveldto the cognitive decline occurring in the amnesic MCI group over 1 year, and might represent cost-effective, noninvasive and widely available markers to follow amnesic MCI populations in large clinical trials.

Human brain contains an intricate network of about 100 billion neurons. Aging of the brain is characterized by a combination of synaptic pruning, loss of cortico-cortical connections and neuronal apoptosis that provoke an age-dependent decline of cognitive functions. Neural/synaptic redundancy and plastic remodeling of brain networking, also secondary to mental and physical training, promotes maintenance of brain activity and cognitive status in healthy elderly for everyday life. However, age is the main risk factor for neurodegenerative disorders such as Alzheimer's disease (AD) that impact on cognition. Growing evidence supports the idea that AD targets specific and functionally connected neuronal networks and that oscillatory electromagnetic brain activity might be a hallmark of the disease. In this line, digital electroencephalography (EEG) allows non-invasive analysis cortical neuronal synchronization as revealed by resting state brain rhythms. This review provides an overview of the studies on resting state eyes closed EEG rhythms recorded in amnesic mild cognitive impairment (MCI) and AD subjects. Several studies support the idea that spectral markers of these EEG rhythms such as power density, spectral coherence, and other quantitative features differ among normal elderly, MCI, and AD subjects, at least at group level. Regarding the classification of these subjects at individual level, most of the studies showed a moderate accuracy (70-80%) in the classification of EEG markers relative to normal and AD subjects. In conclusion, resting state EEG makers are promising for large-scale, low-cost, fully non-invasive screening of elderly subjects at risk of AD.

Questo manuale nasce da un'intuizione, quella di poter utilizzare un sistema per trascrivere la Lingua dei Segni Italiana (LIS), adattando ai segni italiani il Sign Writing, ideato nel 1995 da Valerie Sutton (1995) e proposto come "un alfabeto per scrivere le lingue dei segni". La LIS infatti, come le altre lingue dei segni, non ha una corrispettiva forma scritta ed è stata tramandata di generazione in generazione dalla comunità sorda. La mancanza di una forma scritta, del resto comune a molte altre lingue, ha avuto tutta una serie di implicazioni nella storia della comunità sorda e la possibilità di utilizzare un sistema di trascrizione - come ha detto Valerie Sutton - può aprire nuove frontiere della comunicazione per i segnanti. L'attuale generazione di persone sorde adulte, che sta imparando a leggere e a scrivere le lingue segnate per la prima volta, sta creando la base per il lavoro delle generazioni future.

Objective.Micro-fabricated neural interfaces based on polyimide (PI) are achieving increasing importance in translational research. The ability to produce well-defined micro-structures with properties that include chemical inertness, mechanical flexibility and low water uptake are key advantages for these devices.Approach.This paper reports the development of the transverse intrafascicular multichannel electrode (TIME) used to deliver intraneural sensory feedback to an upper-limb amputee in combination with a sensorized hand prosthesis. A failure mode analysis on the explanted devices was performed after a first-in-human study limited to 30 d.Main results.About 90% of the stimulation contact sites of the TIMEs maintained electrical functionality and stability during the full implant period. However, optical analysis post-explantation revealed that 62.5% of the stimulation contacts showed signs of delamination at the metallization-PI interface. Such damage likely occurred due to handling during explantation and subsequent analysis, since a significant change in impedance was not observedin vivo. Nevertheless, whereas device integrity is mandatory for long-term functionality in chronic implantation, measures to increase the bonding strength of the metallization-PI interface deserve further investigation. We report here that silicon carbide (SiC) is an effective adhesion-promoting layer resisting heavy electrical stimulation conditions within a rodent animal trial. Optical analysis of the new electrodes revealed that the metallization remained unaltered after delivering over 14 million pulsesin vivowithout signs of delamination at the metallization-PI interface.Significance.Failure mode analysis guided implant stability optimization. Reliable adhesion of thin-film metallization to substrate has been proven using SiC, improving the potential transfer of micro-fabricated neural electrodes for chronic clinical applications. (Document number of Ethical Committee: P/905/CE/2012; Date of approval: 2012-10-04)

Objective. Recent results have shown the potentials of neural interfaces to provide sensory feedback to subjects with limb amputation increasing prosthesis usability. However, their advantages for decoding motor control signals over current methods based on electromyography (EMG) are still debated. In this study we compared a standard EMG-based method with approaches that use peripheral intraneural data to infer distinct levels of grasping force and velocity in a trans-radial amputee. Approach. Surface EMG (three channels) and intraneural signals (collected with transverse intrafascicular multichannel electrodes, TIMEs, 56 channels) were simultaneously recorded during the amputee's intended grasping movements. We sorted single unit activity (SUA) from each neural signal and then we identified the most informative units. EMG envelopes were extracted from the recorded EMG signals. A reference support vector machine (SVM) classifier was used to map EMG envelopes into desired force and velocity levels. Two decoding approaches using SUA were then tested and compared to the EMG-based reference classifier: (a) SVM classification of firing rates into desired force and velocity levels; (b) reconstruction of covariates (the grasp cue level or EMG envelopes) from neural data and use of covariates for classification into desired force and velocity levels. Main results. Using EMG envelopes as reconstructed covariates from SUA yielded significantly better results than the other approaches tested, with performance similar to that of the EMG-based reference classifier, and stable over three different recording days. Of the two reconstruction algorithms used in this approach, a linear Kalman filter and a nonlinear point process adaptive filter, the nonlinear filter gave better results. Significance. This study presented a new effective approach for decoding grasping force and velocity from peripheral intraneural signals in a trans-radial amputee, which relies on using SUA to reconstruct EMG envelopes. Being dependent on EMG recordings only for the training phase, this approach can fully exploit the advantages of implanted neural interfaces and potentially overcome, in the medium to long term, current state-of-the-art methods. (Clinical trial's registration number: NCT02848846).

Alzheimer's disease is the most common age-related neurodegenerative disorder and its burden on patients, families, and society grows significantly with lifespan. Early modifications of risk-enhancing lifestyles and treatment initiation expand personal autonomy and reduce management costs. Many clinical trials with potentially disease-modifying drugs are devoted to mild cognitive impairment (MCI) prodromal-to-Alzheimer's disease. The identification of biomarkers for early diagnosis may thus be crucial for early intervention and identification of high-risk subjects, the most appropriate target of new drugs as soon as they will be discovered. INTERCEPTOR is a strategic project by the Italian Ministry of Health and the Italian Medicines Agency (AIFA), aiming to validate the best combination (highly accurate, non-invasive, available on the whole national territory and financially sustainable) of biomarkers and organizational model for early diagnosis. 500 MCI subjects will be enrolled at baseline and followed-up for 3 years for at least 400 of them in order to define a "hub & spoke" nationwide model with recruiting (spokes) centers for MCI identification and expert (hubs) centers for risk diagnosis.

The aim of this article is to shed light on an understudied aspect of Giordano Bruno's intellectual biography, namely, his career as a mathematical practitioner. Early interpreters, especially, have criticized Bruno's mathematics for being "outdated" or too "concrete". However, thanks to developments in the study of early modern mathematics and the rediscovery of Bruno's first mathematical writings (four dialogues on Fabrizio's Mordente proportional compass), we are in a position to better understand Bruno's mathematics. In particular, this article aims to reopen the question of whether Bruno anticipated the concept of infinitesimal quantity. It does so by providing an analysis of the dialogues on Mordente's compass and of the historical circumstances under which those dialogues were written.

At the turn of the seventeenth century, Bruno and Cavalieri independently developed two theories, central to which was the concept of the geometrical indivisible. The introduction of indivisibles had significant implications for geometry – especially in the case of Cavalieri, for whom indivisibles provided a forerunner of the calculus. But how did this event occur? What can we learn from the fact that two theories of indivisibles arose at about the same time? These are the questions addressed in this paper. Relying on the methodology of “historical epistemology”, this paper asserts that the similarities and differences between the theories of Bruno and Cavalieri can be explained in terms of “shared knowledge”. The paper shows that the idea – on which both Bruno and Cavalieri build – that geometrical objects are generated by motion was part of the mathematical culture of the time. Tracing this idea back to its Pythagorean origins thus sheds light on the relationship between motion and continuum in mathematics.

Multiple sclerosis is an autoimmune disease predominantly affecting the white matter of the CNS, causing--among functional sequelae-cortico--cortical partial or total disconnection. Since functional connectivity linking cerebral regions is reliably reflected by synchronization of their neuronal firing, in this study an electrophysiological parameter measured by magnetoencephalography was used to quantify an intra-cortical connectivity (ICC) index focused on the primary somatosensory cortical areas (S1). Twenty-one patients affected by mild (Extended Disability Scale Score, median 1,5) relapsing-remitting (RR) multiple sclerosis in the remitting phase without clinically evident sensory impairment were evaluated. Three dimensional MRI was used to quantify the lesion load, discriminating black hole and non-black hole portions, normalized by individual brain volumes. When matched with a control population, multiple sclerosis patients showed a reduced ICC combined with the complete loss of the finger-dependent functional specialization in S1 cortex of the dominant hemisphere. No association was found between ICC impairment and disease duration, or prolongation of the central sensory conduction time, presence of spinal cord lesions and ongoing disease modifying therapy. The ICC index slightly correlated with the lesion load. A local index of ICC in a circumscribed brain primary area was altered in mildly disabled RR-multiple sclerosis patients, also in absence of any impairment of central sensory conduction. In conclusion, the diffuse damage influencing the multi-nodal network subtending complex cerebral functions also affects intrinsic cortical connectivity. The S1 ICC index is proposed as a highly sensitive and simple-to-test functional measure for the evaluation of intra-cortical synchronization mechanisms in RR-multiple sclerosis.

Background: Alterations of synaptic transmission induced by inflammatory activity have been linked to the pathogenic mechanisms of multiple sclerosis (MS). Regulated upon activation, normal T-cell expressed, and secreted (RANTES) is a pro-inflammatory chemokine involved in MS pathophysiology, potentially able to regulate glutamate release and plasticity in MS brains, with relevant consequences on the clinical manifestations of the disease. Objective: To assess the role of RANTES in the regulation of cortical excitability. Methods: We explored the association of RANTES levels in the cerebrospinal fluid (CSF) of newly diagnosed MS patients with magnetic resonance imaging (MRI) and laboratory measures of inflammatory activity, as well its role in the control of cortical excitability and plasticity explored by means of transcranial magnetic stimulation (TMS), and in hippocampal mouse slices in vitro. Results: CSF levels of RANTES were remarkably high only in active MS patients and were correlated with the concentrations of interleukin-1β. RANTES levels were associated with TMS measures of cortical synaptic excitability, but not with long-term potentiation (LTP)-like plasticity. Similar findings were obtained in mouse hippocampal slices in vitro, where we observed that RANTES enhanced basal excitatory synaptic transmission with no effect on LTP. Conclusion: RANTES correlates with inflammation and synaptic excitability in MS brains.

Transcranial magnetic stimulation (TMS) is a recently established technique in the neurosciences that allows the non-invasive assessment, among other parameters, of the excitability of motor cortex. Up to now, its application to sleep research has been very scarce and because of technical problems it provided contrasting results. In fact delivering one single suprathreshold magnetic stimulus easily awakes subjects, or lightens their sleep. For this reason, in the present study we assessed motor thresholds (MTs) upon rapid eye movement (REM) and non-rapid eye movement (NREM) sleep awakenings, both in the first and in the last part of the night. Taking into account that a full re-establishment of wake regional brain activity patterns upon awakening from sleep needs up to 20-30 min, it is possible to make inferences about the neurophysiological characteristics of the different sleep stages by analyzing the variables of interest immediately after provoked awakenings. Ten female volunteers slept in the lab for four consecutive nights. During the first night the MTs were collected, following a standardized procedure: 5 min before lights off, upon stage 2 awakening (second NREM period), upon REM sleep awakening (second REM period), upon the final morning awakening (always from stage 2). Results showed that MTs increased linearly from presleep wakefulness to REM sleep awakenings, and from the latter to stage 2 awakenings. There was also a time-of-night effect on MTs upon awakening from stage 2, indicating that MTs decreased from the first to the second part of the night. The increase in corticospinal excitability across the night, which parallels the fulfillment of sleep need, is consistent with the linear decrease of auditory arousal thresholds during the night. The maximal reduction of corticospinal excitability during early NREM sleep can be related to the hyperpolarization of thalamocortical neurons, and is in line with the decreased metabolic activity of motor cortices during this sleep stage. On the contrary, the increase of MTs upon REM sleep awakenings should reflect peripheral factors. We conclude that our findings legitimate the introduction of the TMS technique as a new proper tool in sleep research.