The application of paired-pulse transcranial magnetic stimulation (ppTMS) has become an increasingly popular method of using TMS techniques to probe both intra-cortical connections (i.e. within a targeted brain region) and inter-cortical connections (i.e. between two separate brain regions). While paired-pulse TMS is perhaps most commonly used to examine connections in the motor cortex and motor cortical pathways, some contemporary research has demonstrated the technique’s effects in other regions of the brain such as the visual cortex, as well as in interhemispheric and interregional stimulation.
While all paired-pulse paradigms require the delivery of two TMS pulses, these pulses may be applied through either one single or two separate TMS coils.
In paired-pulse paradigms using one coil, a low-intensity TMS pulse (a conditioning pulse) is administered prior to a higher-intensity TMS pulse (a test pulse). In this instance, ppTMS is able to reduce the resultant motor evoked potential (MEP) amplitude by altering the activating inhibitory neutrons within the motor cortex (M1) - reflecting the impact of the conditioning pulse on the intracortical neural circuit.
In the case of ppTMS using two TMS coils, researchers are able to examine inter-cortical connections between, for example, the motor cortex in the left and right hemispheres.
Paired pulse TMS is used extensively today in research exploring the effect of TMS on neurological conditions and diseases such as stroke and epilepsy. µ
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 SICI protocols, a short (1-5ms) interval exists between the conditioning pulse (the first, low-intensity pulse) and the test pulse.
For SICI to be present, the 1-5ms interval between pulses must be used along with an appropriate intensity of both the conditioning and test pulses: the conditioning pulse, for instance, must be subthreshold, with an intensity of between 60-80% of resting motor threshold (RMT), or 70-90% of active motor threshold (AMT). The conditioning pulse, conversely, must be suprathreshold with a motor evoked potential (MEP) amplitude of ~1.5mV.
SICI is believed to rely on the conditioning pulse activating a population of inhibitory neurons within the motor cortex that have a lower threshold than the neurons activated by the second, suprathreshold test pulse. This inhibitory population of neurons is thought to involve GABAA receptors, as the administration of GABAA agonists has been shown to increase the magnitude of the SICI.
Kujirai et al. (1993) also noted, however, that increases in MEP amplitude were also observed when 10-15ms intervals separated the test pulse from the conditioning pulse- suggesting that ppTMS paradigms can also produce increases in MEP amplitude, dependent on the interval between TMS pulses.
This phenomenon where increases in MEP amplitude are observed takes place when a subthreshold conditioning pulse is used, suggesting that excitatory circuits can also be probed with the use of ppTMS.
Intracortical Facilitation (ICF)
The increase in 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.
Long Intracortical Inhibition (LICI)
Valls-Solé et al. (1992) varied the interval between pulses in addition to varying the intensity of a suprathreshold conditioning pulse during voluntary contraction. When the intensity of the conditioning pulse was greater than 110% of the resting motor threshold, the MEP evoked by the test pulse was suppressed when the interval between these pulses ranged between 60-150ms5. Given that suppression occurs at a different timeframe to SICI, the site of action is likely to differ between these two paradigms. This was conﬁrmed by an experiment that administered Baclofen, a GABAB agonist, which increased LICI 90 minutes after drug administration6.
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.
- TMS investigations into the task-dependent functional interplay between human posterior parietal and motor cortex.. Koch G., Rothwell JC.. Behavioural Brain Research. (September 2009), pp. 147-152.
- Corticocortical inhibition in human motor cortex.. Kujirai T., Caramia M D., Rothwell J C., Day B L., Thompson P D., Ferbert A., Wroe S., Marsden C D.. The Journal of Physiology, 471.. (November 1993), pp. 501-519.
- Segregating two inhibitory circuits in the human motor cortex at the level of GABAA receptor subtypes: A TMS study.. Di Lazzaro V., Pilato F., Dileone M., Profice P., Ranieri F., Ricci V., Bria P., Tonali P A., Ziemann U.. Clinical Neurophysiology, 118.. (October 2007), pp. 2207-2214
- Effects of anti epileptic drugs on motor cortex excitability in humans: a transcranial magnetic stimulation study.. Ziemann U., Lönnecker S., Steinhoff B J., Paulus W.. Annals of Neurology, 40.. (September 1996), pp. 367-378.
- Human motor evoked responses to paired transcranial magnetic stimuli.. Valls-Solé J., Pascual-Leone A., Wasserman E M., Hallet M.. Electroencephalography and Clinical Neurophysiology/Evoked Potentials Section, 85.. (December 1992), pp. 355-364.
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