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.

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Axonal excitability studies allow deductions about membrane and ion channel properties in vivo. Excitability studies have investigated nerve function and pathophysiology in neurological disease. Guidelines summarise physiological basis, methodology and interpretation of excitability studies.

SUMMARY1. In micro-electrode recordings from the human peroneal and tibial nerves, the responses of thirty-two primary spindle endings, thirteen secondary spindle endings and three Golgi tendon organs were studied during vibration of the tendons of the receptor-bearing muscles in the leg. The amplitude of the applied vibration was 1-5 mm and the frequency was varied from 20 to 220 Hz. As checked with e.m.g. and torque measurements, the muscles of the leg were relaxed during the sequences analysed.2. Providing that the vibrator was accurately applied, all endings responded with discharges phase-locked to the vibration cycles, the discharge rates being at the vibration frequency or at subharmonics of that frequency. The response to vibration was of abrupt onset and offset, was maintained for the duration of vibration, and was not subject to fluctuation with changes in attention or with remote muscle contraction.3. The maximal discharge rate that could be achieved varied from one ending to the next, and increased with the length of the receptor-bearing muscle. For endings driven at their maximal rate an increase in vibration frequency produced a decrease in discharge rate as the ending changed to a subharmonic pattern of response. The converse occurred on decreasing vibration frequency.' 4. For any given muscle length, primary endings could generally be driven to higher rates than secondary endings but there was a wide range of responsiveness within each group and a significant overlap between the groups. At medium muscle length, the most responsive primary endings could be driven up to 220 Hz but secondary endings did not reach discharge rates higher than 100 Hz. 5. With combined vibration and passive movements, primary endings

The strength-duration time constant (tau SD) is a property of nodal membrane and, while it depends on a number of factors, its measurement may shed light on axonal properties when taken in conjunction with measurements of axonal excitability. For example, tau SD increases with demyelination as the exposed membrane is enlarged by inclusion of paranodal and internodal membrane, it decreases with hyperpolarization and it increases with depolarization. The present study was undertaken in 20 normal volunteers to compare strength-duration curves for compound sensory and muscle action potentials, to determine the most appropriate curve fitting equation for the data, and to examine the reproducibility of the calculated time constant on different days, for potentials of different amplitude and at different sites along the nerve. Using a computerized threshold-tracking system, stimulus intensity was adjusted to produce an antidromic compound sensory action potential (CSAP) or an orthodromic muscle action potential of 30% of maximum. Stimulus duration was increased every minute in 20 microseconds steps from 20 microseconds to 1 ms. The time constant for compound sensory potentials (665 +/- 182 microsecond) was longer than that for compound EMG potentials (459 +/- 126 microseconds). Weiss's formula, which relates threshold charge to stimulus duration, provided an accurate fit for the experimental data, and the study validated that, using it, relatively few experimental measurements were required to calculate the time constant. In repeated studies on the same subject, time constants usually differed by < 400 microseconds for sensory axons and < 250 microseconds for motor axons. They were identical at different sites along the nerve and did not alter with the size of the compound action potential. These characteristics suggest that the determinations of strength-duration time constant could be suitable for clinical usage.

1. To identify the vestibular contribution to human standing, responses in leg muscles evoked by galvanic vestibular stimulation were studied.Step impulses of current were applied between the mastoid processes of normal subjects and the effects on the soleus and tibialis anterior electromyograms (EMGs), ankle torque, and body sway were identified by post-stimulus averaging.

Electrical stimulation over human muscle can generate force directly by activation of motor axons and indirectly by ‘reflex’ recruitment of spinal motoneurones. These experiments were designed to define the properties of the centrally generated ‘reflex’ force, including the optimal stimulus conditions for producing it in tibialis anterior (TA) and triceps surae (TS), and its interaction with volition. Subjects (n= 21) were seated with their foot strapped to an isometric myograph. Surface EMG was recorded from TS and TA. High‐frequency electrical stimulation (100 Hz) of TS and TA with wide pulse widths (1 ms) was most effective to evoke the sustained centrally generated forces. The maximal force evoked by this mechanism during stimulation of TA for 40 s was ∼42 % of that produced by a maximal voluntary contraction. For both muscle groups, ramp increases and decreases in stimulus frequency (from ∼4 to 100 Hz and back to 4 Hz over 6 s) resulted in marked hysteresis in the force‐frequency plot. After a single ‘burst’ of 100 Hz stimulation during prolonged stimulation at 25 Hz, force remained elevated. Repeated bursts often generated progressively larger force increments. These behaviours were abolished by an anaesthetic nerve block proximal to the stimulation site, confirming the central origin for the ‘extra’ force. After a brief voluntary contraction was performed during 25 Hz stimulation, force remained elevated, and this showed some gradation with voluntary contraction amplitude. Sometimes voluntary contractions alone initiated the sustained central motor output. Involuntary contractions often persisted for many seconds after electrical stimulation ceased. These were not terminated by brief inhibitory inputs to the active motoneurones but could be stopped by the voluntary command to ‘relax completely’. Overall, these centrally generated contractions are consistent with activation of plateau potentials in motoneurones innervating the ankle dorsiflexors and plantarflexors. Large forces can be produced through this mechanism. The interaction with volitional drives suggests that plateau behaviour may contribute significantly to the normal output of human motoneurones.

When electrical stimulation is applied over human muscle, the evoked force is generally considered to be of peripheral origin. However, in relaxed humans, stimulation (1 msec pulses, 100 Hz) over the muscles that plantarflex the ankle produced more than five times more force than could be accounted for by peripheral properties. This additional force was superimposed on the direct response to motor axon stimulation, produced up to 40% of the force generated during a maximal voluntary contraction, and was abolished during anesthesia of the tibial nerve proximal to the stimulation site. It therefore must have resulted from the activation of motoneurons within the spinal cord. The additional force could be initiated by stimulation of low-threshold afferents, distorted the classical relationship between force and stimulus frequency, and often outlasted the stimulation. The mean firing rate of 27 soleus motor units recorded during the sustained involuntary activity after the stimulation was 5.8 Ϯ 0.2 Hz. The additional force increments were not attributable to voluntary intervention because they were present in three sleeping subjects and in two subjects with lesions of the thoracic spinal cord. The phenomenon is consistent with activation of plateau potentials within motoneurons and, if so, the present findings imply that plateau potentials can make a large contribution to forces produced by the human nervous system.