These guidelines provide an up-date of previous IFCN report on "Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application" (Rossini et al., 1994). A new Committee, composed of international experts, some of whom were in the panel of the 1994 "Report", was selected to produce a current state-of-the-art review of non-invasive stimulation both for clinical application and research in neuroscience. Since 1994, the international scientific community has seen a rapid increase in non-invasive brain stimulation in studying cognition, brain-behavior relationship and pathophysiology of various neurologic and psychiatric disorders. New paradigms of stimulation and new techniques have been developed. Furthermore, a large number of studies and clinical trials have demonstrated potential therapeutic applications of non-invasive brain stimulation, especially for TMS. Recent guidelines can be found in the literature covering specific aspects of non-invasive brain stimulation, such as safety (Rossi et al., 2009), methodology (Groppa et al., 2012) and therapeutic applications (Lefaucheur et al., 2014). This up-dated review covers theoretical, physiological and practical aspects of non-invasive stimulation of brain, spinal cord, nerve roots and peripheral nerves in the light of more updated knowledge, and include some recent extensions and developments.

Transcranial electrical stimulation (tES), including transcranial direct and alternating current stimulation (tDCS, tACS) are non-invasive brain stimulation techniques increasingly used for modulation of central nervous system excitability in humans. Here we address methodological issues required for tES application. This review covers technical aspects of tES, as well as applications like exploration of brain physiology, modelling approaches, tES in cognitive neurosciences, and interventional approaches. It aims to help the reader to appropriately design and conduct studies involving these brain stimulation techniques, understand limitations and avoid shortcomings, which might hamper the scientific rigor and potential applications in the clinical domain.

Low intensity transcranial electrical stimulation (TES) in humans, encompassing transcranial direct current (tDCS), transcutaneous spinal Direct Current Stimulation (tsDCS), transcranial alternating current (tACS), and transcranial random noise (tRNS) stimulation or their combinations, appears to be safe. No serious adverse events (SAEs) have been reported so far in over 18,000 sessions administered to healthy subjects, neurological and psychiatric patients, as summarized here. Moderate adverse events (AEs), as defined by the necessity to intervene, are rare, and include skin burns with tDCS due to suboptimal electrode-skin contact. Very rarely mania or hypomania was induced in patients with depression (11 documented cases), yet a causal relationship is difficult to prove because of the low incidence rate and limited numbers of subjects in controlled trials. Mild AEs (MAEs) include headache and fatigue following stimulation as well as prickling and burning sensations occurring during tDCS at peak-to-baseline intensities of 1–2 mA and during tACS at higher peak-to-peak intensities above 2 mA. The prevalence of published AEs is different in studies specifically assessing AEs vs. those not assessing them, being higher in the former. AEs are frequently reported by individuals receiving placebo stimulation. The profile of AEs in terms of frequency, magnitude and type is comparable in healthy and clinical populations, and this is also the case for more vulnerable populations, such as children, elderly persons, or pregnant women. Combined interventions (e.g., co-application of drugs, electrophysiological measurements, neuroimaging) were not associated with further safety issues. Safety is established for low-intensity ‘conventional’ TES defined as <4 mA, up to 60 min duration per day. Animal studies and modeling evidence indicate that brain injury could occur at predicted current densities in the brain of 6.3–13 A/m2 that are over an order of magnitude above those produced by tDCS in humans. Using AC stimulation fewer AEs were reported compared to DC. In specific paradigms with amplitudes of up to 10 mA, frequencies in the kHz range appear to be safe. In this paper we provide structured interviews and recommend their use in future controlled studies, in particular when trying to extend the parameters applied. We also discuss recent regulatory issues, reporting practices and ethical issues. These recommendations achieved consensus in a meeting, which took place in Göttingen, Germany, on September 6–7, 2016 and were refined thereafter by email correspondence.

SummaryBackgroundNeuronal elements underlying perception, cognition, and action exhibit distinct oscillatory phenomena, measured in humans by electro- or magnetoencephalography (EEG/MEG). So far, the correlative or causal nature of the link between brain oscillations and functions has remained elusive. A compelling demonstration of causality would primarily generate oscillatory signatures that are known to correlate with particular cognitive functions and then assess the behavioral consequences. Here, we provide the first direct evidence for causal entrainment of brain oscillations by transcranial magnetic stimulation (TMS) using concurrent EEG.ResultsWe used rhythmic TMS bursts to directly interact with an MEG-identified parietal α-oscillator, activated by attention and linked to perception. With TMS bursts tuned to its preferred α-frequency (α-TMS), we confirmed the three main predictions of entrainment of a natural oscillator: (1) that α-oscillations are induced during α-TMS (reproducing an oscillatory signature of the stimulated parietal cortex), (2) that there is progressive enhancement of this α-activity (synchronizing the targeted, α-generator to the α-TMS train), and (3) that this depends on the pre-TMS phase of the background α-rhythm (entrainment of natural, ongoing α-oscillations). Control conditions testing different TMS burst profiles and TMS-EEG in a phantom head confirmed specificity of α-boosting to the case of synchronization between TMS train and neural oscillator.ConclusionsThe periodic electromagnetic force that is generated during rhythmic TMS can cause local entrainment of natural brain oscillations, emulating oscillatory signatures activated by cognitive tasks. This reveals a new mechanism of online TMS action on brain activity and can account for frequency-specific behavioral TMS effects at the level of biologically relevant rhythms.

Non-invasive brain stimulation (NIBS) is a method for the study of cognitive function that is quickly gaining popularity. It bypasses the correlative approaches of other imaging techniques, making it possible to establish a causal relationship between cognitive processes and the functioning of specific brain areas. Like lesion studies, NIBS can provide information about where a particular process occurs. However, NIBS offers the opportunity to study brain mechanisms beyond process localisation, providing information about when activity in a given brain region is involved in a cognitive process, and even how it is involved. When using NIBS to explore cognitive processes, it is important to understand not only how NIBS functions but also the functioning of the neural structures themselves. We know that NIBS techniques have the potential to transiently influence behaviour by altering neuronal activity, which may have facilitatory or inhibitory behavioural effects, and these alterations can be used to understand how the brain works. Given that NIBS necessarily involves the relatively indiscriminate activation of large numbers of neurons, its impact on a neural system can be easily understood as modulation of neural activity that changes the relation between noise and signal. In this review, we describe the mutual interactions between NIBS and brain activity and provide an updated and precise perspective on the theoretical frameworks of NIBS and their impact on cognitive neuroscience. By transitioning our discussion from one aspect (NIBS) to the other (cognition), we aim to provide insights to guide future research.

Perceptual learning is considered a manifestation of neural plasticity in the human brain. We investigated brain plasticity mechanisms in a learning task using noninvasive transcranial electrical stimulation (tES). We hypothesized that different types of tES would have varying actions on the nervous system, which would result in different efficacies of neural plasticity modulation. Thus, the principal goal of the present study was to verify the possibility of inducing differential plasticity effects using two tES approaches [i.e., direct current stimulation (tDCS) and random noise stimulation (tRNS)] during the execution of a visual perceptual learning task.One hundred seven healthy volunteers participated in the experiment. High-frequency tRNS (hf-tRNS, 100 -640 Hz), low-frequency tRNS (lf-tRNS, 0.1-100 Hz), anodal-tDCS (a-tDCS), cathodal-tDCS (c-tDCS), and sham stimulation were applied to the visual areas of the brain in a group of volunteers while they performed an orientation discrimination task. Furthermore, a control group was stimulated on the vertex (Cz). The analysis showed a learning effect during task execution that was differentially modulated according to the stimulation conditions. Post hoc comparisons revealed that hf-tRNS significantly improved performance accuracy compared with a-tDCS, c-tDCS, sham, and Cz stimulations.Our results confirmed the efficacy of hf-tRNS over the visual cortex in improving behavioral performance and showed its superiority in comparison to others tES. We concluded that the mechanism of action of tRNS was based on repeated subthreshold stimulations, which may prevent homeostasis of the system and potentiate task-related neural activity. This result highlights the potential of tRNS and advances our knowledge on neuroplasticity induction approaches.

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The present functional data on large populations support the 'transitional hypothesis' of a shadow zone across normality, pre-clinical stage of dementia (MCI), and AD.