Paired-pulse transcranial magnetic stimulation (ppTMS) has gained popularity as a valuable technique for investigating both intra-cortical connections within a specific brain region and inter-cortical connections between different brain regions. Although ppTMS is commonly utilised to study motor cortex and motor cortical pathways, recent research has demonstrated its effectiveness in exploring other brain regions, including the visual cortex, as well as interhemispheric and interregional stimulation.
Moliadze et al. (2005) examined the effects of paired-pulse transcranial magnetic stimulation (ppTMS) on cat visual cortex. They found that the strength of the conditioning stimulus (CS) had a significant impact on ppTMS, while the timing between stimuli (ISI) had minimal effect. It is possible that differences in physiological states and synaptic interactions may explain variations between cat visual cortex and human motor cortex.
In paired-pulse paradigms, two TMS pulses are required, which can be delivered using either a single coil or two separate coils. When using a single coil, a low-intensity conditioning pulse precedes a higher-intensity test pulse. By altering the activation of inhibitory neurons within the motor cortex (M1), ppTMS can effectively reduce the amplitude of the motor evoked potential (MEP), reflecting the influence of the conditioning pulse on the intracortical neural circuit.
In the case of ppTMS with two coils, researchers can examine inter-cortical connections between, for example, the motor cortex in the left and right hemispheres.
Paired-pulse TMS is extensively employed in research investigating the impact of TMS on neurological conditions and diseases such as stroke and epilepsy. It serves as a valuable tool for understanding and treating these conditions.
SICI, LICI, and ICF
For researchers using ppTMS, it is important to consider the various protocols associated with the technique and the differences in effect that each of these entails. In this section, we will explore the differences between Short Intracortical Inhibition (SICI), Long Intracortical Inhibition (LICI), and Intracortical Facilitation (ICF).
Short Intracortical Inhibition (SICI)
In short intracortical inhibition (SICI) protocols, there is a short interval (1-5ms) between the conditioning pulse and the test pulse. To observe SICI, this interval needs to be paired with appropriate intensity levels for both pulses. The conditioning pulse should be subthreshold, typically set between 60-80% of resting motor threshold (RMT) or 70-90% of active motor threshold (AMT). On the other hand, the test pulse needs to be suprathreshold, with a motor evoked potential (MEP) amplitude of approximately 1.5mV.
SICI is thought to occur when the conditioning pulse activates inhibitory neurons in the motor cortex that have a lower threshold compared to the neurons activated by the second suprathreshold test pulse. This population of inhibitory neurons is believed to involve GABAA receptors, as the administration of GABAA agonists has been found to enhance the magnitude of SICI.
Kujirai et al., (1993) observed that increases in MEP amplitude also occurred with 10-15ms intervals between the test pulse and the conditioning pulse. This suggests that paired pulse transcranial magnetic stimulation (ppTMS) paradigms can lead to increased MEP amplitude, depending on the interval between TMS pulses. Interestingly, this phenomenon of increased MEP amplitude can be observed when a subthreshold conditioning pulse is used, indicating that ppTMS can also probe excitatory circuits.
Du et al., (2014) used ppTMS to investigate inhibitory and facilitatory circuits in the brain related to motor control. They found that certain time intervals between the pulses produced consistent results in evaluating these circuits, while other intervals did not. Interestingly, individuals showed unique patterns of inhibition and facilitation that remained stable over time, with high repeatability within the same person. These individualised profiles may reflect underlying traits associated with neural inhibition and excitation.
Intracortical Facilitation (ICF)
The increase in motor evoked potential (MEP) amplitude following the presentation of a sub-threshold conditioning pulse, with a 10-15ms interval between pulses, produces a phenomena known as intracortical facilitation (ICF). ICF is thought to rely on an NMDA-dependent mechanism, as administration of NMDA antagonists (i.e. dextromethorphan) decreases the magnitude of ICF (Reis et al., 2008)
Long Intracortical Inhibition (LICI)
Long intracortical inhibition (LICI) is the suppression of excitatory neural activity in the motor cortex through the activation of inhibitory interneurons, leading to decreased motor evoked potential (MEP) amplitude. It is induced by paired pulse transcranial magnetic stimulation (TMS) protocols and involves GABAB receptors. LICI provides insights into motor control and dysfunction.
Valls-Solé et al., (1992) investigated the effects of varying the interval between pulses and the intensity of a suprathreshold conditioning pulse during voluntary contraction. They found that when the intensity of the conditioning pulse exceeded 110% of the resting motor threshold, the motor evoked potential (MEP) evoked by the test pulse was suppressed within an interval range of 60-150ms. This suppression occurred at a different timeframe compared to short interval intracortical inhibition (SICI), indicating a different site of action for these two paradigms. Confirming this, an experiment administering Baclofen, a GABAB agonist, increased long intracortical inhibition (LICI) 90 minutes after drug administration.
For some further information please consult the video below, where Professor Charlotte Stagg (University of Oxford) and Dr Roisin McMackin (Trinity College Dublin) discuss what we do and do not know about the physiology underpinning SICI and how we can fill in the blanks for unanswered questions
- Segregating two inhibitory circuits in human motor cortex at the level of GABAA receptor subtypes: A TMS study. Di Lazzaro, V., et al. Clinical Neurophysiology 118(10): 2207-2214. (2007)
- Individualised brain inhibition and excitation profile in response to paired pulse TMS. Du, X., Summerfelt, A.M and Chiappelli, J., et al. Journal of Motor Behaviour 46(1): 39-48. (2014)
- TMS investigations into the task-dependent functional interplay between human posterior parietal and motor cortex. Koch, G. and Rothwell, J.C. Behavioural Brain Research 202(2): 147-152. (2009)
- Corticortical inhibition in human motor cortex. Kujirai, T., et al.. The Journal of Physiology 471(1): 501-519. (1993)
- Paired-pulse transcranial magnetic stimulation protocol applied to visual cortex of anaesthetised cat: effects on visually evoked single-unit activity. Moliadze, V., Giannikopoulos, D., Eysel, U.T. and Funke, K. The Journal of Physiology 556(3): 955-965. (2005)
- Contribution of transcranial magnetic stimulation to the understanding of cortical mechanisms involved in motor control. Reis, J., et al. Journal of Physiology 586(Pt 2): 325-251. (2008)
- Human motor evoked responses to paired transcranial magnetic stimuli. Valls-Solé, J., Pascual-Leone, A., Wassermann, E.M. and Hallett, M. Electroencephalography and Clinical Neurophysiology/Evoked Potentials Section 85(6): 355-364. (1992)
- Effects of antiepileptic drugs on motor cortex excitability in humans: A transcranial magnetic stimulation study. Ziemann, U., Lönnecker, S., Steinhoff, B.J. and Paulus, W. Annals of Neurology 40(3): 367-378. (1996)
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