Transcranial Magnetic Stimulation - a brief overview

TMS Principles
Studies involving electrical stimulation over muscles and nerves date back since Galvani and Volta. There were different attempts incorporating invasive stimulation on the cortex during 60's-80's in humans, e.g. Penfield, Graziano, etc. During the 80s, Merton and Morton showed that directly stimulation is able to activate the muscle. This technique, known as transcranial electrical stimulation or TES, then was applied to motor cortex through the intact scalp and able to elicit motor evoked potential (MEP). For TES, current flows from anode (+) to cathode (–) placed on the scalp. However, the technique obviously is painful. In 1985, Barker et al. from Sheffield showed that it was possible to apply Faraday's Law to excite neurons using electromagnetic coils. This is undoubtedly the start of TMS in the field of neurophysiology.

How does TMS work? A brief, high-amplitude pulse of current, lasting for approximately 100 to 200 msec, is discharged into a TMS coil. The current induces a magnetic field perpendicular to the current flow following the "right-hand rule". In tissue, this magnetic field, in turn, induces an electric field perpendicular to itself. The strength of the induced electric field mainly depends on the rate of change of the magnetic field, which, in turn, depends on the rate of change of the electrical current in the coil. In a homogeneous medium, spatial change of the electric field will cause current to flow in loops parallel to the plane of the coil, which will be predominantly tangential in the brain.

The loops with the strongest current will be near the circumference of the coil itself, anywhere on it. Conversely, the current loops become weak near the center of the coil, and there is no current at the center itself. A more focal stimulation can be achieved by a more modern figure-8-shaped coil, producing a maximal current at the intersection of the two round components. Refer to Fig-1.

Fig-1: Illustration of magnetic & electrical field generated by a TMS coil and the difference between 2 most common coils.

Neuronal elements are activated by the induced electric field by two mechanisms. If the field is parallel to the neuronal element, then the field will be most effective where the intensity changes as a function of distance. If the field is not completely parallel, activation will occur at bends in the neural element. Axons, terminals, and branches have the lowest threshold (stimulated easily), while the cell body has the highest. Also, it's important to note that the more superficial the brain tissue, the stronger the stimulation effect.

As mentioned, the sinusoidal electric current is delivered to the TMS stimulator but the way it is designed has two main types. The first, monophasic: active only during the first peak of the sine wave. It is easier to characterize. On the other hand, biphasic: functional during both positive/negative peaks and neuronal effects are thought to be quicker, more spread out. Monophasic TMS has a stronger short-term effect during repetitive stimulation than biphasic TMS, because monophasic pulses preferentially activate one population of neurons oriented in the same direction so that their effects readily summate. Biphasic pulses, in contrast, may activate several different populations of neurons (both facilitatory and inhibitory) so that summation of the effects is not so clear as with monophasic pulses. When single stimuli are applied, however, biphasic TMS is thought to be more powerful than monophasic TMS because the peak-to-peak amplitude of stimulus pulse is higher and its duration is longer when the same intensity of stimulation (the same amount of current is stored by the stimulator) is used.

Motor Evoked Potential (MEP)
The non-invasive brain stimulation by either electrical or magnetic source is able to generate observable behavior responses such as muscle twitches (for M1 stimulation) and phosphenes (for V1 stimulation). Originally, however, such stimulations were done to evoke observable movements. The electrical signal resulting from a TMS stimulation on the motor cortex is called motor evoked potential and is typically observed by two different methods. The first one is through observing the descending volley using microelectrodes, i.e. the activity of motoneurones in the corticospinal tract. This method shows us two components:
     a)  D-waves (direct), if you hit pyramidal cells residing in the motor cortex directly.
     b)  I-waves (indirect), which originate from the indirect corticospinal neurons and interneurons.
There is usually one D-wave resulting from a single stimulation but multiple I-waves that appear later than the D-waves, depending on how many possible synapses exist. D-wave measurement can be used in a clinical setting for intraoperative monitoring.

Another way, perhaps the easiest, is through electromyography (EMG) measurement from target muscles, the muscle we want to twitch or contract. EMG measures myogenic or muscle activity, or compound muscle action potential (CMAP). In many TMS experiments, EMG is usually the preferred observation method of the motor evoked potential. Refer to Figure 2 showing typical MEP curves for biceps and FDI respectively. Note that a curve consists of negative and positive peaks. The delivery of the TMS pulse is aligned with t = 0. Note that the latency of FDI activity is slower than the biceps MEP.

Fig-2: Motor evoked potential of biceps and FDI muscle respectively after delivering a single strong TMS pulse to the arm area of the primary motor cortex (M1). The plots are produced by the BrainSight navigation system.


Sometimes, such activity is also called M-waves, "M" for muscles, that have usually a larger peak-to-peak. The excitatory postsynaptic potentials in the spinal anterior horn cells summate to bring them to a threshold and fire them. M-waves are also used in the context of reflex. E.g. M1 is the earliest or short-latency onset following a sudden muscle stretch, followed by a transcortical reflex and a voluntary component. TES predominantly generates D-waves under the stimulating anode, and therefore predominantly generates M-waves in muscles contralateral to the stimulating anode

On Finding a Hotspot
Traditionally, the easiest way to induce movements is by stimulating the "hand" area of the motor cortex and observe the hand twitching. There are two most popular target muscles used in TMS studies.
     a)  FDI, first dorsal interossei, a muscle to flex the index finger.
     b)  APB, abductor pollicis brevis, a muscle to abduct the thumb.
EMG electrodes are placed in these target muscles and a TMS pulse is delivered to the "hand" area of M1. The most crucial job comes: localizing the correct area or the hotspot. One has to patiently shift and adjust the orientation of the coil from one area to the next. Higher intensity is usually used until one is able to see a good response. Once twitching occurs, it is said that we have found the hotspot.

There are two terms associated with the TMS stimulator intensity to evoke twitching.

1. Resting Motor Threshold (RMT) is defined as the minimum stimulus intensity that evokes a minimum motor evoked response when the muscle is at rest. As a rule of thumb, the observed MEP should be 50 µV in at least 5 of 10 trials at rest. 
2. Active Motor Threshold: the minimum stimulus intensity that produces a minimum motor evoked response (in at least 5 of 10 trials) during an isometric contraction of the tested muscle at about 10% of the maximum force.

Coil orientation influences the amplitude of MEP (replicated by Pascual-Leone, 1992). See the figure below. The actual reason why this happens is unclear, but tDCS electrode placement has a similar characteristic.

Fig-3: Different coil orientation and MEPs of lateral-medial (LM) and posterior-anterior (PA) in different intensities.

Does TMS Cause Excitation or Inhibition?
When we talk about reversible plastic changes, TMS has been shown to excite or inhibit certain neural circuits. But in what circumstance does either occur? It seems that it depends on the pulse frequency parameter, not the intensity. A series of rapid pulses of TMS over a short period of time is known as repetitive TMS, rTMS. High-frequency rTMS with pulses at about 5–10 Hz, has been used as a more powerful stimulus to produce a brief period of excitation (Pascual-Leone et al., 1994). Conversely, slow varying pulses between ~0.2 - 1 Hz can be used to inhibit neural activity (Chen et al., 1997). Such plastic changes are thought to be mediated by LTP/LTD like mechanism, that is, a persistence change in synaptic strength (Huang et al., 2007).

However, it has been shown that the plastic effect is highly variable and lasts < 1 hr. A variant of rTMS is called theta burst stimulation (TBS), where pulses are applied in bursts of three, delivered 50 times per second (50 Hz) and an inter-burst interval of 200 ms (5 Hz) (Di Lazzaro et al., 2005, Huang et al., 2005). Based on recent animal studies, TBS is also shown to be based on LTP/LTD-like mechanisms. For example, NMDAR antagonists and Ca²⁺ channel blockers are shown to interfere with TBS. What is interesting is that one can induce either an excitatory or inhibitory mode using TBS depending on the timing protocol, see Figure 4.

An application of TBS twice separated by a break was found to have differential effects on MEP. For example, giving 2 x cTBS separated by a 10-minute break showed that the effect of continuous TBS can last for around 1 hour (Ridding et al.). Recent research has found the efficacy of TBS has a high variability that depends on genetic factors and muscle states; and that some people do not respond well to it (see: Suppa et al., 2016).



Fig-4: Different types of TBS (cTBS and iTBS) result in a differential effect on normalized MEPs (Suppa et al. 2016)

Heterosynaptic plasticity can be realized in humans with a peripheral stimulus paired with a TMS brain stimulus. A nice set of experimental paradigms has been developed by Classen and collaborators which is called paired associative stimulation (PAS) (Stefan et al., 2000; Wolters et al., 2003). If a median nerve stimulation at the wrist is paired with a single TMS pulse to the sensorimotor cortex at 25 ms, then the two stimuli arrive at about the same time, and the MEPs will be facilitated. If the interval is about 10 ms, however, the TMS comes about 15 ms before the median nerve volley arrives, and the MEP will be depressed. The former behaves like LTP and the latter like LTD (McDonnell et al., 2007). As a simple motor learning task and PAS interact with each other, it does appear that PAS is a highly relevant model for brain plasticity (Ziemann et al., 2004).

Some major contributions of TMS
TMS can be used to localize brain function or study the neural substrate of a particular behavior. It was originally employed to study motor behavior (being the easiest to observe), but has later been used for other sensory (e.g. visual system) and cognitive functions (e.g. working memory). For example, Wasserman et al used TMS to perform MEP mapping. The authors stimulate the scalp and systematically shifted the coil to see which body parts got impacted. Similar to studies in monkeys, they found some overlapping regions responsible for movements of different body parts. One example in the motor system is the study of the role of SMA in the production of sequential finger movements. Stimulation over the SMA induced accuracy errors in complex, but not simple, sequences. Patterns of muscle activity provoked by TMS have some physiological relevance, as these can be recognized as principal components of natural movement (Gentner and Classen, 2006).

Consolidation of a simple motor skill such as phasic pinch force was disrupted by stimulation selectively over M1, without disruption of other aspects of motor function (Muellbacher et al., 2002). Another study failed to find a similar disruption of learning of motor adaptation in a force field, suggesting that only some types of motor consolidation occur in M1 (Baraduc et al., 2004). On the other hand, rTMS of M1 prior to learning of force field dynamics did interfere with consolidation without interfering with the learning itself (Richardson et al., 2006). More research has to be done on this theme.

TMS is also beneficial to understand other sensory behavior. For example, studying the visual cortex with TMS helps to understand how inhibiting the region impacts object recognition, disrupts motion perception (on V5), or reading ability. Others use TMS to understand working memory. For example, stimulating left DLPFC impairs working memory of alphabets but not of faces. Low-frequency rTMS over either the right or left prefrontal cortex (but not the parieto-occipital cortex) impaired behavior on a task involving visuospatial planning. TMS has also been used in conjunction with functional MRI to see if such stimulation changes the time course of the BOLD activity. Lastly, rTMS has been a popular non-invasive method in a clinical setting to treat major depression and, more recently, in stroke rehabilitation.

[Main source = a primer article by M. Hallet, 2007, in Neuron journal].