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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.

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.

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).

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.