Hand function depends on sensory feedback to direct an appropriate motor response. There is clear evidence that somatosensory cortices modulate motor behaviour and physiology within primary motor cortex. However, this information is mainly from research in animals and the bridge to human hand control is needed. Emerging evidence in humans supports the notion that somatosensory cortices modulate motor behaviour, physiology and sensory perception. Transcranial magnetic stimulation (TMS) allows for the investigation of primary and higher-order somatosensory cortices and their role in control of hand movement in humans. This review provides a summary of several TMS protocols in the investigation of hand control via the somatosensory cortices. TMS plasticity inducing protocols reviewed include paired associative stimulation, repetitive TMS, theta-burst stimulation as well as other techniques that aim to modulate cortical excitability in sensorimotor cortices. Although the discussed techniques may modulate cortical excitability, careful consideration of experimental design is needed to isolate factors that may interfere with desired results of the plasticity-inducing protocol, specifically events that may lead to metaplasticity within the targeted cortex.
There is emerging evidence that alterations in somatosensory processing may underlie challenges in hand control after neurological injury. Abnormalities in somatosensory physiology and perception are observed in clinical populations such as stroke and focal hand dystonia [
Somatosensory input is represented in multiple cortical areas, similar to other sensory areas. The significance of multiple cortical representations of the hand remains unclear, although one hypothesis is that each area contributes a particular attribute to the process of sensory-guided movement [
There is substantial evidence that alterations in SI activity can affect somatosensation, M1 physiology, and motor control. In monkeys, manipulation of peripheral input through nerve crush or digit amputation [
In humans, understanding somatosensory physiology and its influence on M1 activity and motor control of the hand is important to basic and clinical neuroscience. This review is focussed on the use of plasticity-inducing TMS protocols to further the understanding of somatosensory contributions to hand function. Identifying methods to increase or decrease neural activity within hand representations may advance the development of therapies intended to improve hand function in clinical populations. We focus primarily on evidence that three TMS protocols applied to SI modulate perception and neural activity within SI and M1 and include paired associative stimulation, repetitive TMS and theta-burst TMS. For each, we briefly describe the neural mechanisms that appear to underpin effects, the influence on somatosensory and motor physiology, tactile perception and motor behaviour when delivered over SI, and the potential limitations of the technique. We subsequently describe additional paradigms that have also provided evidence of modulating SI activity.
Investigations into the somatosensory influence on M1 activity in humans often employ TMS paradigms to examine corticospinal excitability and specific neural circuitry. We briefly review specific TMS paradigms to measure such circuitry and refer the reader to other reviews intended to cover these topics more thoroughly [
Single-pulse TMS delivered over a particular muscle representation within M1 at intensities above threshold can evoke a motor response in that contralateral muscle. The amplitude of the resultant motor-evoked potential (MEP) recorded from the target muscle reflects the excitability of corticospinal circuitry and spinal motoneurons [
Paired associative stimulation (PAS) involves peripheral nerve stimulation followed by a TMS pulse delivered over the cortex, typically M1. Pairs of nerve-cortex stimuli are applied repetitively and result in long-lasting changes in cortical excitability [
The PAS protocol was developed based on animal models of spike timing-dependent plasticity, particularly long-term potentiation (LTP)/depression (LTD) (for review, see [
Long-lasting changes in M1 excitability are induced for up to an hour following the use of the PAS technique which combines somatosensory afferent input and direct modulation of cortical activity using TMS. Though several studies have demonstrated the influence of PAS on corticospinal excitability as measured via MEPs [
PAS has also been used to demonstrate changes in SI excitability. PAS may be performed by pairing median nerve stimulation with TMS pulses delivered directly over SI. The interval between the nerve and SI stimulation may be determined by using the individual latencies of the N20 SEP potential. Using this technique, intervals that aim to closely time the arrival of the afferent volley with the TMS pulse applied to SI lead to a facilitation of the P25 SEP. In contrast, when the SI TMS pulse is delivered in advance of the arrival of the afferent volley by ~20 ms, the P25 is decreased [
The facilitatory and inhibitory effects of PAS 25 and 10 ms are altered by prior neural activity. This effect known as metaplasticity describes a change in the neuroplasticity effects as a result of the recent history [
The after effects of PAS seem to be more effective depending on the time of day, suggesting that circadian rhythms and hormonal fluctuations may influence the magnitude of PAS effects [
There is conflicting evidence of the effects of PAS on spinal circuit excitability. While authors report no changes in spinal excitability with the use of F-waves [
TMS, applied repetitively, can be used to induce short-term changes in cortical excitability. The effects of repetitive TMS (rTMS) are dependent on the stimulus parameters of the protocol, with the main determinants being the frequency of pulse delivery and the intensity [
The physiological basis of increases and decreases in cortical excitability with high- versus low-frequency rTMS has been attributed to LTP and LTD of cortical synapses [
In humans, Satow et al. (2003) investigated the influence of low-frequency rTMS (0.9 Hz) over the left-hemisphere motor hotspot for APB and at two alternate positions 3 cm anterior and 3 cm posterior to the hotspot. Effects were only induced at the APB site which the authors refer to as the “sensorimotor” site [
High-frequency rTMS applied to SI alters tactile acuity and physiology. Gains in tactile spatial acuity achieved using tactile coactivation paradigms were further improved by combining it with high-frequency rTMS (5 Hz) over SI [
In humans, rTMS has been applied to SI to investigate the after effects on motor behaviour and M1 physiology. Vidoni et al. (2010) studied the influence of low-frequency rTMS over SI on the ability to learn a motor tracking task. Real and sham 1 Hz rTMS was applied over SI, while participants learned to perform a visually cued wrist flexion/extension tracking task. Participants receiving real rTMS demonstrated greater errors in tracking during task acquisition and at a second testing session the following day when no rTMS was delivered [
One consideration in attempting to induce rTMS effects relates to monitoring muscle activity during stimulation. In one study, the effects of 5 Hz rTMS over M1 were modified by flexion or extension of the wrist during rTMS application [
Low-frequency rTMS over SI has been shown to have only slight, nonsignificant effects on SEPs recorded from ipsilateral SI [
Technical aspects of rTMS are an important consideration. In general, the coil orientation, stimulus intensity and frequency are factors that can be controlled by the experimenter. Tings et al. (2005) performed 5 Hz rTMS over M1 using both PA and AP orientations in separate sessions. Monophasic rTMS in the PA orientation induced facilitation of MEP amplitudes, whereas monophasic rTMS with AP orientation suppressed MEP amplitudes [
A novel form of repetitive TMS called theta-burst stimulation (TBS) is composed of bursts of three pulses delivered at 50 Hz and repeated at 5 Hz [
The neural mechanisms that mediate TBS effects in humans remain unclear, though information obtained from rat models is advancing our understanding. At the cellular level, TBS delivered over rat cortex alters the expression of glutamic acid isoforms GAD 65 and GAD 67 and GAT-1 [
In humans, evidence suggests that TBS paradigms may be related to LTP/LTD-like effects and GABAergic activity [
Several studies have examined TBS paradigms applied over M1. CTBS over M1 decreases MEPs for 20–60 minutes [
Investigating the effects of TBS over SI, Ishikawa et al. (2007) delivered cTBS to left SI (2 cm posterior to M1) and recorded SEPs elicited from right and left median nerve stimulation. Following cTBS over left SI, a reduction in the amplitude of SEP components P22-N30 and P25-N33, elicited from the right but not left median nerve, was observed for 13 minutes following stimulation as measured by two time blocks at 0–3 and 10–13 minutes [
Intermittent TBS applied over SI also provides the opportunity to modulate SI physiology and perception. Katayama and Rothwell (2007) applied iTBS over left SI (2 cm posterior to left M1) and measured SEPs elicited from the right median nerve. Following stimulation, SEP amplitudes (N200-N20p, N20p-P25, and P25-N33) were increased at 15 and 30 minutes following stimulation [
Continuous TBS has been used to investigate the influence of SI on the excitability within M1. Ishikawa et al., (2007) delivered cTBS over SI and observed that MEPs were unchanged. Our lab has recently furthered this investigation by probing the influence SI on corticospinal excitability, intracortical and interhemispheric motor circuitry for the representation of the first dorsal interosseous muscle (FDI) of the hand (paper in preparation). We observed that cTBS over left-hemisphere SI increases the corticospinal output of the contralateral hand (increased MEPs), leads to modest but insignificant increases in contralateral ICF and ipsilateral SIHI, and does not alter SICI. Importantly, the influence on corticospinal excitability is specific to the direction of induced current, a topic that will be discussed later within this paper, and relates to the discrepancy between previous findings [
In addition to the influence of SI, higher-order somatosensory loci may also influence M1 activity. One such area that has been a focus of interest in our lab is Brodmann’s area 5. Using dual coil TMS, we observed that area 5 facilitates M1 output to the FDI muscle of the hand when the thumb and index finger receive tactile stimulation [
Although cTBS and iTBS protocols have been in use since the original publication appeared in 2005 [
The effects of TBS are also dependent on stimulus intensity and the direction of induced current within the cortex. Some studies have demonstrated a lack of excitability change, or an effect in the opposite direction to the original observations by Huang et al. (2005), and this may relate to the intensity of TBS delivered. In contrast to the MEP suppression following cTBS delivered at 80% active motor threshold [
Metaplasticity is also a consideration for TBS protocols. Muscle activity preceding, during, or immediately following TBS may alter after effects. CTBS-induced suppression and iTBS-induced facilitation of MEPs were abolished when stimulation was applied during simultaneous 10% MVC of the target muscle [
In monkeys, the excitability of M1 pyramidal tract neurons is altered in response to stimulation of peripheral nerves [
Longer-lasting changes in M1 excitability can be observed following manipulation of somatosensory afferent input. Blocking the peripheral afferent volley from synapsing within SI may also induce changes within M1. In humans, ischemic nerve block (INB) has been used to reproduce deafferentation, and TMS protocols may be used to examine changes in motor excitability. Compared to pre-INB measures, muscles proximal to the INB in the upper [
Another promising TMS-plasticity approach is called quadripulse stimulation (QPS) and involves four monophasic pulses delivered at 0.2 Hz for 30 minutes with effects that persist for 75 minutes following stimulation [
This paper has illustrated the importance of understanding hand function through contributions of the somatosensory cortex using TMS plasticity-inducing protocols. Evidence clearly demonstrates that plasticity-inducing TMS protocols are a powerful tool to modulate SI physiology, tactile perception, and neural activity within M1. PAS, rTMS, and TBS are repetitive forms of TMS brain stimulation that may be used to alter the neurophysiology of cortical circuitry related to hand control. TMS paired with measures of physiology and/or perception further the understanding of the neural mechanisms that underpin somatosensory-guided hand control. This information is fundamental to creating new therapeutic applications of TMS plasticity protocols for clinical populations such as stroke and dystonia that present with impaired hand movement. An important consideration in all TMS techniques described in this paper is the state of neural activity within cortex prior to application of the plasticity-inducing stimulation since all protocols appear to be sensitive to metaplastic effects. Further, stimulus parameters such as intensity, orientation, and frequency influence the outcome of TMS protocols and are therefore important considerations in experimental design. Through further use of TMS plasticity-inducing protocols, we will continue to advance the understanding of sensorimotor hand control and further optimize protocols to evoke desired effects. This latter step will be a key element for future studies that aim to use plasticity-inducing TMS protocols as a potential therapeutic avenue to improve hand function.