Transcranial Magnetic Stimulation

Transcranial magnetic stimulation (TMS) is an indirect, non-invasive method of stimulating the human brain. It involves placing an electromagnetic coil against the subject's head to generate a powerful magnetic field. This magnetic field passes through the scalp and targets specific regions of the brain, triggering action potentials.

TMS serves as a valuable technique for studying cognitive processes by interfering with brain function and drawing causal inferences about the involvement of different brain areas. It can also be used to induce changes in plasticity by applying specific frequencies or burst intervals. These changes affect the excitability of the cortex, similar to long-term potentiation and long-term depression, which respectively increase or decrease the likelihood of action potentials occurring.

The initial application of TMS by Anthony Barker and his team in 1985 focused on stimulating the motor cortex (M1) non-invasively while monitoring muscle activity using electromyography (EMG) techniques. Since then, TMS has emerged as a primary method for investigating brain functionality in human subjects. Neuronavigation and neuroimaging advancements now enable researchers to use imaging techniques to determine precise coordinates or targets for TMS, ensuring accurate and reliable placement of TMS coils. This helps confirm the causal or correlational involvement of specific brain regions.

Today, TMS, is extensively utilised in research on various neurological conditions and diseases such as depression, Alzheimer's disease, Parkinson's disease, migraines, and more. TMS is generally considered a safe and painless method of non-invasive brain stimulation, and the technique has been used extensively in research and clinical applications since the 1980s.

TMS is often combined with electroencephalography (EEG) techniques in TMS-EEG experiments. This combination allows researchers to examine the effects of TMS on the brain by measuring TMS-evoked potentials and cortical oscillations, providing valuable insights into its impact (Tremblay et al., 2019).

Applications of TMS

What is TMS?

Transcranial magnetic stimulation (TMS) serves as an umbrella term encompassing various types of stimulation techniques, including repetitive TMS (rTMS), paired pulse TMS (ppTMS), theta-burst stimulation (TBS), quadripulse stimulation (QPS), and more.

What kinds of TMS are there?

Transcranial magnetic stimulation (TMS) can be administered through a range of techniques, ranging from single-pulse TMS to intricate quadripulse paradigms. Each method has its own unique advantages and limitations, which researchers should consider when designing their studies.

Single Pulse TMS

Single-pulse transcranial magnetic stimulation (TMS) is a technique that involves delivering a single, brief magnetic pulse to a specific region of the brain. This pulse induces electrical currents in the underlying neural tissue, temporarily stimulating or modulating brain activity in that area. Single-pulse TMS is commonly used to probe the chronometry of basic brain processes or assess the excitability of cortical circuits.

By utilising single-pulse TMS, researchers can investigate the timing of fundamental brain processes. In a seminal study, Amassian et al., (1989) applied single TMS pulses to the early visual cortex at specific intervals following the presentation of a visual target to subjects. These pioneering TMS experiments unveiled the critical role of the early visual cortex in identifying target identity within the 80ms-120ms timeframe after its appearance. This approach not only associates brain areas with specific tasks but also offers insights into the temporal engagement of brain regions in specific processes.

Furthermore, TMS pulses can be employed to examine changes in excitability resulting from pharmaceutical interventions or repetitive TMS. By targeting the motor cortex with TMS, researchers can assess whether these interventions alter cortico-spinal excitability, measured by the motor evoked potential (MEP). For example, in a study by Darmani et al., (2016), GABA-AR antagonists were administered, and subsequent TMS application revealed a decrease in the motor threshold. This indicates that the drug enhanced cortical excitability, as it became easier to evoke a specific amplitude of MEP through TMS.

Paired-Pulse TMS (ppTMS)

Paired pulse transcranial magnetic stimulation (ppTMS) allows for the exploration of both intra-cortical connections within a specific brain region and inter-cortical connections between different brain regions.

To illustrate, ppTMS involves delivering a low-intensity TMS pulse followed by a higher-intensity TMS pulse using the same coil. This technique modifies the activation of inhibitory neurons within the motor cortex (M1), leading to a reduction in the motor evoked potential (MEP) amplitude (Kujirai et al., 1993). The MEP elicited in a muscle by TMS over the primary motor cortex (M1) is a key measure used to assess alterations in corticospinal excitability (Spampinato et al., 2023).

Furthermore, the use of two TMS coils facilitates the investigation of inter-cortical connections, enabling the examination of interactions between the motor cortex in the left and right hemisphere (Chen et al., 2003). This approach is particularly useful for studying hierarchical connections within the visual system, such as V5 and V1, V2 and V3 (Pascual-Leone and Walsh 2001).

Short interval intracortical inhibition (SICI) and intracortical facilitation (ICF) are neurophysiological phenomena observed during ppTMS. SICI refers to the suppression of cortical excitability, while ICF enhances cortical excitability compared to a single pulse. These phenomena can be assessed using ppTMS with specific interstimulus intervals (ISIs). Du et al., (2014) found that SICI and ICF profiles are personalised and relatively stable, with moderate-to-good reliability for certain ISIs. These profiles reflect unique patterns of inhibition and facilitation, potentially indicating underlying neural traits.

Repetitive Transcranial Magnetic Stimulation (rTMS)

Repetitive transcranial magnetic stimulation (rTMS) has gained popularity as a technique that involves the application of magnetic brain stimulation at a repetitive and rhythmic frequency over an extended period.

For instance, Chen et al., (1997) conducted a study where rTMS was applied to the left motor cortex at a frequency of 0.9 Hz for 15 minutes. This approach resulted in a notable decrease in the amplitude of motor evoked potentials (MEPs) that persisted for at least 15 minutes.

Researchers have also employed rTMS in the form of "bursts" or "trains", which consist of sequences of TMS pulses separated by fixed intervals known as inter-burst or inter-train intervals.

The potential therapeutic applications of repetitive TMS have been extensively investigated, and it has gained approval from the US Food and Drug Administration (FDA) as a treatment for depression, anxiety, and migraines (Lefaucheur et al., 2020). 

Theta-Burst Stimulation (TBS)

Perhaps the most widely-known rTMS protocol amongst non-invasive brain stimulation researchers is ‘theta-burst stimulation’ (Huang et al., 2005), which requires administering three TMS pulses at 50 Hz every 200 ms (5 Hz). Theta-burst stimulation can be applied continuously (in the case of cTBS), or with eight-second intervals where no TMS is administered between the ‘trains’ (in the case of iTBS) (Huang et al., 2005).

DuoMAG XT rTMS System

Quadripulse Stimulation (QPS)

Quadripulse Stimulation (QPS) is a relatively new rTMS protocol that involves delivering a burst of four TMS pulses with either 5ms or 50ms between each pulse. Each of these bursts is then punctuated with a five-second interval, irrespective of whether a 5ms or 50ms delay was used (Hamada et al., 2008).

While the response to rTMS in general can be very variable (Hamada et al., 2013), research with quadripulse stimulation does seem to indicate that it may be less variable than other rTMS protocols. Research from Hamada et al. (2013) suggests that this could be a result of the monophasic pulse shape employed by quadripulse stimulation, which may be superior to the commonly-employed biphasic pulse shape in other types of rTMS.

Quadripulse Waveforms

A comprehensive list of TMS example studies and publications can be found in the 'references' section below.

Combination with Electroencephalography (TMS-EEG)

The combination of transcranial magnetic stimulation (TMS) and electroencephalography (EEG) offers a distinctive approach that allows for both the manipulation of ongoing brain processes using TMS and the observation of the resulting effects on electrophysiology or participant behaviour.

Read a full overview of TMS-EEG techniques, the ongoing research carried out with TMS-EEG, and how to set up your own TMS-EEG experiment on this page.

How is TMS applied to the correct brain region?

In transcranial magnetic stimulation (TMS) techniques, precise targeting of a specific brain region is crucial. Manual targeting by using a direct reference on the subject's scalp can be challenging, as the weight of the TMS coil can cause the operator to unintentionally deviate from the intended stimulation site over time.

To alleviate this, some researchers make use of digital neuronavigation systems - such as Brainsight TMS Neuronavigation - which allow the TMS coil's position relative to the patient's head to be tracked in real-time. Visual feedback delivered by the software can indicate immediately to the operator if they have moved away from their intended site of stimulation and provides an easily-interpreted frame of reference to help them correct the positioning of the coil.

Brainsight TMS Neuronavigation

Additionally, advances in robotic technology have opened up new avenues for ensuring the accuracy of delivering transcranial magnetic stimulation. Robotic navigation systems work in tandem with neuronavigation software to help the TMS operator automatically navigate to the desired state of stimulation and to actively monitor and adjust the position of the TMS coil throughout the experiment to ensure that stimulation is always delivered to the correct site. These systems also offer built-in safety measures, such as pressure detectors, to ensure the maximum comfort and safety of the participant during all studies.

TMS Side Effects

While TMS is generally considered to be a safe and painless method of non-invasive brain stimulation, some individuals may experience some common mild side effects, including:

- Headache
- Mild scalp discomfort at the stimulation site
- Twitching or tingling of facial muscles
- A feeling of lightheadedness

In rare occasions, more serious side effects may occur, including:

- Seizures
- Hearing loss, where recommended protection has not been worn.

A full review of TMS safety can be found in this journal reference.

Contraindications for TMS

Although TMS is well tolerated by the vast majority of subjects, there are a number of important contraindications that should be considered. Transcranial magnetic stimulation should not be used in populations with:

- Increased risk of, or susceptibility to, seizures
- Implanted/internal metal hardware (surgical plates, screws, etc.)
- Implanted medical electrical devices (cardiac pacemakers, medication pumps etc.)
- Other unstable medical conditions/disorders.

  1. Suppression of visual perception by magnetic coil stimulation of human occipital cortex. Amassian, V.E., Cracco, R.Q. and Maccabee, P.J., et al. EEG and Clinical Neurophysiology/Evoked Potentials Section 74(6): 458-462. (1989)
  2. Plasticity of the human motor system following muscle reconstruction: a magnetic stimulation and functional magnetic resonance imaging study. Chen, R., Anastakis, D.K. and Haywood, C.T., et al. Clinical Neurophysiology 114(12): 2434-2446. (2003)
  3. Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation. Chen, R., Classen, J. and Gerloff, C., et al. Neurology 48(5). (1997)
  4. Effects of the selective α5-GABAAR antagonist S44819 on excitability in the human brain: a TMS-EMG and TMS-EEG phase I study. Darmani, G., Zipser, C.M. and Böhmer, G.M., et al. Journal of Neuroscience 36(49): 12312-12320. (2016)
  5. Individualised brain inhibition and excitation profile in response to paired pulse TMS. Du, X., et al. Journal of Motor Behaviour 46(1): 39-48. (2014)
  6. Bidirectional long-term motor cortical plasticity and metaplasticity induced by quadripulse transcranial magnetic stimulation. Hamada, M. et al. J Physiol 586: 3927-3947. (2008)
  7. The role of interneuron networks in driving human motor cortical plasticity. Hamada, M., Murase, N. and Hasan, A., et al. Cerebral Cortex 23(7): 1593-1605. (2013)
  8. The brain electrophysiological recording and stimulation (BEST) toolbox. Hassan, U., Pillen, S. and Zrenner, C. et al. Brain Stimulation 15(1): 109-115. (2022)
  9. Evidence for immediate enhancement of hippocampal memory encoding by network-targeted theta-burst stimulation during concurrent fMRI. Hermiller, M.S., Chen, Y.F., Parrish, T.B. and Voss, J.L. Journal of Neuroscience 40(37): 7155-7168. (2020)
  10. Theta burst stimulation of the human motor cortex. Huang, Y., Edwards, M.J. and Rounis, E., et al. Neuron 45(2): 201-206. (2005)
  11. Corticocortical inhibition in human motor cortex. Kujiirai, T., Caramia, M.D. and Rothwell, J.C., et al. Journal of Physiology 471: 501-519. (1993)
  12. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): An update (2014-2018). Lefaucher, J., et al. Clinical Neurophysiology 131(2): 474-528. (2020)
  13. Quadripulse stimulation (QPS). Matsumoto, H. and Ugawa, Y. Experimental Brain Research 238: 1619-1625. (2020)
  14. Fast backprojections from the motion to the primary visual area necessary for visual awareness. Pascual-Leone, A. and Walsh, V. Science 292(5516): 510-512. (2001)
  15. Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: expert guidelines. Rossi, S. et al. Clinical Neurophysiology 132(1): 269-306. (2021)
  16. Motor potentials evoked by transcranial magnetic stimulation: interpreting a simple measure of a complex system. Spampinato, D.A., Ibanez, J., Rocchi, L. and Rothwell, J. The Journal of Physiology. (2023)
  17. Clinical utility and prospective of TMS-EEG. Tremblay, S., et al. Clinical Neurophysiology 130(5): 802-844. (2019)

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