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Several techniques and protocols of non-invasive transcranial brain stimulation (NIBS), including transcranial magnetic and electrical stimuli, have been developed in the past decades. Non-invasive transcranial brain stimulation may modulate cortical excitability outlasting the period of non-invasive transcranial brain stimulation itself from several minutes to more than one hour. Quite a few lines of evidence, including pharmacological, physiological and behavioral studies in humans and animals, suggest that the effects of non-invasive transcranial brain stimulation are produced through effects on synaptic plasticity. However, there is still a need for more direct and conclusive evidence. The fragility and variability of the effects are the major challenges that non-invasive transcranial brain stimulation currently faces. A variety of factors, including biological variation, measurement reproducibility and the neuronal state of the stimulated area, which can be affected by factors such as past and present physical activity, may influence the response to non-invasive transcranial brain stimulation. Work is ongoing to test whether the reliability and consistency of non-invasive transcranial brain stimulation can be improved by controlling or monitoring neuronal state and by optimizing the protocol and timing of stimulation., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

This study investigates the relationship between motor function and processing speed in preterm children. Processing speed was compared in 145 adolescents, born 25-41 weeks gestational age, utilizing tasks including differing motor demands. The influence of motor cortex excitability and functional motor skills on task performance was assessed. For tasks with motoric demands, differences in performance between preterm and term-born children were mediated by the relationship between gestational age, corticomotor excitability, and motor function. There were no differences in non-motor processing speed task performance between preterm and term-born children. Measures of processing speed may be confounded by a timed motor component.

Background/objectives: Over the last ten years, an increasing number of authors have used the theta burst stimulation (TBS) protocol to investigate long-term potentiation (LTP) and long-term depression (LTD)-like plasticity non-invasively in the primary motor cortex (M1) in healthy humans and in patients with various types of movement disorders. We here provide a comprehensive review of the LTP/LTD-like plasticity induced by TBS in the human M1., Methods: A workgroup of researchers expert in this research field review and discuss critically ten years of experimental evidence from TBS studies in humans and in animal models. The review also includes the discussion of studies assessing responses to TBS in patients with movement disorders., Main Findings/discussion: We discuss experimental studies applying TBS over the M1 or in other cortical regions functionally connected to M1 in healthy subjects and in patients with various types of movement disorders. We also review experimental evidence coming from TBS studies in animals. Finally, we clarify the status of TBS as a possible new non-invasive therapy aimed at improving symptoms in various neurological disorders., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Transcranial magnetic stimulation (TMS)-elicited motor-evoked potentials (MEPs) exhibit considerable trial-to-trial variability, potentially reducing the sensitivity and reproducibility of this measure. While increasing the number of trials will improve accuracy, prolonged recording blocks are not always feasible. In this study, we investigated the minimum number of trials required to provide a measure of human corticospinal excitability that is stable both within and between sessions. Single-pulse TMS was applied to the left primary motor cortex, and MEPs were recorded from the right first dorsal interosseous muscle. Approximately 20-30 trials were required to provide a stable measure of MEP amplitude with high within- and between-session reliability. Extending the number of trials beyond 30 provided no additional benefit. Collecting 30 trials may be optimal for reliably estimating corticospinal excitability using TMS. These findings may have significant implications for using TMS to measure corticospinal excitability in both basic and clinical research settings., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.)

Objective: Measures of short-interval intracortical inhibition (SICI) can be contaminated by excitatory influences of short-interval intracortical facilitation (SICF), unless examined at individually-optimized interstimulus intervals (ISIs). We hypothesized that age-related differences in SICF would explain previously reported reduced SICI in children and adolescents compared with adults., Methods: Fifty-one participants, aged 8-29years, underwent transcranial magnetic stimulation. SICF curves were constructed to determine the ISI at which SICF was minimal (i.e. the first trough). SICI curves were constructed at this individually-determined ISI with conditioning stimulus (S1) intensities of 60-110% of active motor threshold., Results: There was no effect of age on the ISI corresponding with the SICF trough. However, there was a main effect of age on the amplitude of the conditioned motor-evoked potential at the different ISIs, such that children aged 8-12years demonstrated greater SICF than those aged 16-18 and 19-21years. There was no effect of age on SICI, and no interaction between age group and S1 intensity., Conclusions: Compared with that in older adolescents and young adults, SICF is enhanced in children aged 8-12years. Surprisingly, this enhanced SICF does not appear to reduce the degree of SICI that can be evoked at the first trough in this age group., Significance: This is the first report of enhanced SICF in young children. It remains possible that enhanced SICF may have confounded earlier reports of reduced SICI in children less than 8years., (Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: The potential of non-invasive brain stimulation (NIBS) for studying, and inducing, functionally relevant neuroplasticity is dependent on protocols that can induce lasting, robust and reliable effects. A current limiting factor is the large inter- and intra-subject variability in NIBS-induced neuroplastic responses. There has been some study of inter-subject response variability and factors that contribute to it; however, intra-subject response variability has, so far, received little investigation., Objectives: By testing participants on multiple occasions we aimed to (1) compare inter- and intra-subject variability of neuroplastic responses induced by continuous theta-burst stimulation (cTBS); (2) determine whether the transcranial magnetic stimulation (TMS) intensity used to measure cTBS-induced neuroplastic responses contributes to response variability; (3) determine whether assessment of factors known to influence response variability can be used to explain some of the variability in cTBS-induced neuroplastic responses across experimental sessions., Methods: In three separate experimental sessions, motor-evoked potential (MEP) input-output (IO) curves were obtained before and after cTBS, and questionnaire-based assessments of physical activity and perceived stress were obtained., Results: cTBS-induced MEP suppression was greatest at the upper end of the IO curve (150-180% resting motor threshold; RMT) and most consistent across subjects and across experimental sessions when assessed with a TMS intensity of 150% RMT. The magnitude of cTBS-induced MEP suppression evoked at 150% RMT correlated with self-reported perceived stress, but not with self-reported physical activity., Conclusions: The most reliable TMS intensity to probe cTBS-induced long-term depression (LTD)-like neuroplastic responses is 150% RMT. This is unlikely to simply be a ceiling effect and, we suggest, may be due to changes in the descending volley evoked at higher stimulus intensities. The perceived stress scale appears to be sufficiently sensitive to measure the influence of subject stress on LTD-like neuroplastic responses., (Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.)

Synaptic weight changes induced by temporal correlations between the spikes of pre- and postsynaptic neurons are referred to as spike-timing-dependent plasticity (STDP). Transcranial magnetic stimulation (TMS) induces long-lasting effects on corticospinal excitability, if it is repetitively paired with stimulation of afferents from a corresponding contralateral hand region at short intervals (paired associative stimulation, PAS). PAS-induced plasticity has been linked with synaptic STDP. We aimed to investigate which elements of the cortical microcircuitry sustain and govern PAS-induced depression of corticospinal excitability in the target muscle representation (and enhancement of excitability in its functional surround). We show that the time window during which the interaction between both stimulus-induced cortical events leads to immediate post-interventional depression is short (<4.5 ms). The depressant PAS effects at the target representation were completely blocked by applying a subthreshold magnetic pulse 3 ms before the principal TMS pulse, even when the strength of the latter was adjusted to generate a motor-evoked potential of similar amplitude to that with the unconditioned magnetic pulse. Epidural recordings from the cervical cord of a patient showed that under this condition late TMS-evoked I-waves remain suppressed. When the intensity of the TMS component during PAS was lowered - sufficient to allow activation of inhibitory neurons, but insufficient to activate corticospinal neurons - excitability of short-latency intracortical inhibition remained unchanged. PAS-induced facilitation in the functional surround followed the same pattern as the centre-depressant effects. These findings may suggest that excitability-depressant PAS-induced effects are due to weakening of excitatory synapses between upper cortical layer principal neurons, but not those located on the corticospinal neuron, or inhibitory synapses. Inhibitory interneurons involved in short-latency intracortical inhibition are gate-keepers to producing centre-depressant/surround-facilitatory PAS effects. Based on these and earlier findings we propose a model specifying the composition and laminar location of the involved microcircuit of PAS-induced plasticity that may enhance its utility as a model of STDP in humans.

Transcranial electrical and magnetic stimulation techniques encompass a broad physical variety of stimuli, ranging from static magnetic fields or direct current stimulation to pulsed magnetic or alternating current stimulation with an almost infinite number of possible stimulus parameters. These techniques are continuously refined by new device developments, including coil or electrode design and flexible control of the stimulus waveforms. They allow us to influence brain function acutely and/or by inducing transient plastic after-effects in a range from minutes to days. Manipulation of stimulus parameters such as pulse shape, intensity, duration, and frequency, and location, size, and orientation of the electrodes or coils enables control of the immediate effects and after-effects. Physiological aspects such as stimulation at rest or during attention or activation may alter effects dramatically, as does neuropharmacological drug co-application. Non-linear relationships between stimulus parameters and physiological effects have to be taken into account., (© 2013 Elsevier B.V. All rights reserved.)

In the last decade transcranial magnetic stimulation (TMS) has been the subject of more than 20,000 original research articles. Despite this popularity, TMS responses are known to be highly variable and this variability can impact on interpretation of research findings. There are no guidelines regarding the factors that should be reported and/or controlled in TMS studies. This study aimed to develop a checklist to be recommended to evaluate the methodology and reporting of studies that use single or paired pulse TMS to study the motor system. A two round international web-based Delphi study was conducted. Panellists rated the importance of a number of subject, methodological and analytical factors to be reported and/or controlled in studies that use single or paired pulse TMS to study the motor system. Twenty-seven items for single pulse studies and 30 items for paired pulse studies were included in the final checklist. Eight items related to subjects (e.g. age, gender), 21 to methodology (e.g. coil type, stimulus intensity) and two to analysis (e.g. size of the unconditioned motor evoked potential). The checklist is recommended for inclusion when submitting manuscripts for publication to ensure transparency of reporting and could also be used to critically appraise previously published work. It is envisaged that factors could be added and deleted from the checklist on the basis of future research. Use of the TMS methodological checklist should improve the quality of data collection and reporting in TMS studies of the motor system., (Copyright © 2012 International Federation of Clinical Neurophysiology. All rights reserved.)

Non-invasive brain stimulation techniques, such as repetitive transcranial magnetic stimulation (rTMS), can modify cortical excitability in a lasting fashion. The modification can be bi-directional in nature and holds considerable therapeutic promise for a number of neurological conditions. However, the effectiveness of these techniques is currently limited by large intra- and inter-subject variability in the response. A number of factors that contribute to response variability have now been identified, with one of the most important being the history of synaptic activity within the cortical region being targeted by stimulation. In this review we discuss what is currently known about the influence of behaviourally, or experimentally, induced changes in synaptic activity in the cortical (or interconnected) region being targeted by stimulation on the response to rTMS techniques. Understanding such influences is a critical step in the development of effective therapeutic paradigms employing such techniques.

Human precision grip requires precise scaling of the grip force to match the weight and frictional conditions of the object. The ability to produce an accurately scaled grip force prior to lifting an object is thought to be the result of an internal feedforward model. However, relatively little is known about the roles of various brain regions in the control of such precision grip-lift synergies. Here we investigate the role of the primary motor (M1) and sensory (S1) cortices during a grip-lift task using inhibitory transcranial magnetic theta-burst stimulation (TBS). Fifteen healthy individuals received 40 s of either (i) M1 TBS, (ii) S1 TBS or (iii) sham stimulation. Following a 5-min rest, subjects lifted a manipulandum five times using a precision grip or completed a simple reaction time task. Following S1 stimulation, the duration of the pre-load phase was significantly longer than following sham stimulation. Following M1 stimulation, the temporal relationship between changes in grip and load force was altered, with changes in grip force coming to lag behind changes in load force. This result contrasts with that seen in the sham condition where changes in grip force preceded changes in load force. No significant difference was observed in the simple reaction task following either M1 or S1 stimulation. These results further quantify the contribution of the M1 to anticipatory grip-force scaling. In addition, they provide the first evidence for the contribution of S1 to object manipulation, suggesting that sensory information is not necessary for optimal functioning of anticipatory control.

Animal models reveal that correlated afferent inputs are a powerful driver of sensorimotor cortex reorganisation. Recently we developed a stimulation paradigm, which evokes convergent afferent input from two hand muscles and induces reorganisation within human motor cortex. Here we investigated whether this reorganisation is characterised by expansion and greater overlap of muscle representation zones, as reported in animal models. Using transcranial magnetic stimulation, we mapped the motor representation of the right first dorsal interosseous (FDI), abductor digiti minimi (ADM) and abductor pollicis brevis (APB) in 24 healthy subjects before and after 1 h of (1) associative stimulation to FDI and ADM motor points, (2) associative stimulation to digits II and V (3) a control condition employing non-correlated stimulation of FDI and ADM motor points. Motor point associative stimulation induced a significant increase in the number of active sites in all three muscles and volume in FDI and ADM. Additionally, the centre of gravity of the FDI and ADM maps shifted closer together. Similar changes were not observed following digital associative stimulation or motor point non-associative stimulation. These novel findings provide evidence that convergent input induces reorganisation of the human motor cortex characterised by expansion and greater overlap of representational zones.

Random number generation is an attention-demanding task that engages working memory and executive processes. Random number generation requires holding information 'on line', suppression of habitual counting, internally driven response generation and monitoring of responses. Evidence from PET studies suggests that the dorsolateral prefrontal cortex (DLPFC) is involved in the generation of random responses. We examined the effects of short trains of transcranial magnetic stimulation (TMS) over the left or right DLPFC or medial frontal cortex on random number generation in healthy normal participants. As in previous evidence, in control trials without stimulation participants performed poorly on the random number generation task, showing repetition avoidance and a tendency to count. Brief disruption of processing with TMS over the left DLPFC changed the balance of the individuals' counting bias, increasing the most habitual counting in ones and reducing the lower probability response of counting in twos. This differential effect of TMS over the left DLPFC on the balance of the subject's counting bias was not obtained with TMS over the right DLPFC or the medial frontal cortex. The results suggest that, with disruption of the left DLPFC with TMS, habitual counting in ones that has previously been suppressed is released from inhibition. From these findings a network modulation model of random number generation is proposed, whereby suppression of habitual responses is achieved through the modulatory influence of the left DLPFC over a number-associative network in the superior temporal cortex. To allow emergence of appropriate random responses, the left DLPFC inhibits the superior temporal cortex to prevent spreading activation and habitual counting in ones.

We assessed the safety of repeated short trains (4 stimuli) of rapid-rate transcranial magnetic stimulation (rrTMS) over the left motor cortex in 6 healthy normal subjects. rrTMS involved two separate blocks of 50 consecutive trains of 4 stimuli at a frequency of 20 Hz and an intensity of 5-10% above active motor threshold. We monitored EEG, and assessed aspects of neurological (balance, gait, two-point discrimination, blood pressure, pulse rate), cognitive (attention, memory, executive function) and motor function (speed of movement initiation and execution and manual dexterity) before and after the two blocks of rrTMS. EMG was also recorded from a number of hand, forearm and arm muscles contralateral to the site of stimulation. Two blocks of repeated rrTMS at 20 Hz and 5-10% above active motor threshold did not produce any adverse effects. Measures of neurological, cognitive and motor function showed no change following rrTMS. From the EMG recording there was evidence of increase in the amplitude of the motor evoked potentials (MEPs) recorded from the biceps in one subject during the first block of rrTMS, but this did not occur in the second block. A similar magnification of MEPs was also observed in another subject only during the second block of stimulation. When applied using parameters falling within published guidelines (Pascual-Leone et al., 1993; Pascual-Leone et al., 1994), repeated rrTMS is a relatively safe technique in healthy normal subjects. As rrTMS allows disruption of cortical function for a longer period, it has the potential of becoming a particularly useful tool for the study of cognitive function as well as sensory or motor function.

There have been conflicting reports over whether it is possible to stimulate the human cerebellum through the intact scalp using transcranial magnetic stimulation. Here we attempt to clarify the situation in normal subjects by comparing the various methods which have been used. EMG responses evoked by magnetic stimulation over the motor cortex could be suppressed by a prior magnetic stimulus over the cerebellum but the onset latency of the effect varied according to the type of magnetic coil used. Inhibition began at a latency which ranged from 5 to 9 msec in different subjects if conditioning stimuli were given through a flat figure-of-eight coil held horizontally over the basal occiput. The effect lasted a further 6-10 msec. With a larger double cone coil, held vertically over the basal occiput, inhibition began earlier and at a more constant latency of 5 msec. It lasted only 3 msec. Stimulation of the C6/7 nerve roots in the brachial plexus with either an electrical or magnetic stimulus also could suppress EMG responses evoked by cortical stimulation. This began at a conditioning-test interval of 7 or 8 msec and lasted for some 5 msec. We suggest that two types of motor cortical suppression may be elicited from stimulation over the posterior neck/skull: a cerebellar effect starting at 5 msec, and a peripheral nerve effect starting later at 7/8 msec. Stimulation with a horizontal large figure-of-eight coil may produce a mixture of effects because the lower wing of the coil overlaps the posterior neck and can activate peripheral nerve fibres in the brachial plexus.

Introduction: Intracortical inhibitory processes in the primary motor cortex (M1) play an important role in both the preparation and execution of motor tasks. Long-interval intracortical inhibition (LICI), measured with paired-pulse transcranial magnetic stimulation (TMS), is generally thought to reflect a single, long-lasting inhibitory process mediated by GABAB receptor activity. Recently, however, preliminary evidence has emerged to suggest that independent LICI processes with different time courses exist Chu et al., 2008. Furthermore, there is one report of long-lasting facilitation in response to paired-pulse TMS; the original work of Valls-Sole and colleagues Valls-Sole et al., 1992 showed that the conditioned MEP was facilitated when paired stimuli of sub-or near-threshold intensities were delivered. Objectives: Here, we were interested in Chu et al., 2008 investigating whether LICI measured with an inter-stimulus interval (ISI) of 100ms and LICI measured with an ISI of 150ms are independent processes, and Valls-Sole et al., 1992 characterising long-lasting facilitation evident with subthreshold CS intensities and a suprathreshold TS intensity. Materials and methods: Recruitment curves were obtained by delivering paired-pulse TMS with varying conditioning stimulus (CS) intensities. Single pulse test stimuli (TS) and paired-pulse stimuli were delivered to the left M1. CS intensity ranged from 50% to 100% resting motor threshold (rMT), increasing in increments of 5% rMT, TS intensity was set at an intensity that evoked a MEP of approximately 1mV, and ISIs were set to 100ms and 150ms. Results: Significant inhibition of the conditioned MEPs was evident at a lower CS intensity when the ISI was set to 100ms (LICI100) than 150ms (LICI150). Significant facilitation of the conditioned MEP was evident at a range of subthreshold CS intensities, from 75% to 90% rMT, when ISI was set to 100ms. Conclusions: The emergence of LICI100 at a lower CS intensity than LICI150 provides support for the suggestion that independent LICI processes with different time courses exist. It is plausible that LICI100 and LICI150are mediated by pre-and postsynaptic GABAB receptor activity respectively (1); this suggestion is supported by evidence from animal studies showing peak activation of presynaptic GABAB receptors at 100ms and postsynaptic GABAB receptors at 150ms Davies et al., 1990. The identification of independent LICI processes with different time courses might have important implications for studies examining the role of GABAB inhibition in motor function and plasticity. The current results also provide evidence for a long-lasting corticospinal facilitation or disinhibition, however, at present, the mechanism (s) underlying this process remains unknown. [Copyright &y& Elsevier]