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A single transcranial magnetic stimulation (TMS) pulse is thought to recruit a mixture of excitation and inhibition in human cortex. Therefore, both the assessment of cortical excitability and the response to repetitive TMS protocols depend on the relative recruitment of a range of neuronal populations, each with different physiological characteristics. Currently, the only method for modulating the balance of excitation/inhibition recruited is to manipulate pulse amplitude: some forms of inhibition in primary motor cortex have a lower threshold for recruitment than the excitation involved in generating a motor evoked potential (MEP) [
], and test the idea that pulse duration can be used to modulate the relative recruitment of excitation and inhibition.
We used the short-interval intracortical inhibition (SICI) paradigm, where a sub-motor threshold pulse (conditioning pulse) has the effect of suppressing the MEP generated by a subsequent supra-motor threshold pulse (test pulse) delivered a few milliseconds later [
]. Our aim was to examine the effects of different conditioning pulse durations on the level of MEP suppression, with the following rationale. First, we know that motor thresholds vary as a function of pulse duration: brief pulses require greater pulse amplitudes to produce an MEP [
]. Second, the amplitude of the conditioning pulse in the SICI paradigm is typically set as a percentage of the motor threshold. The question then is whether different conditioning pulse durations, delivered at the same relative intensity (% motor threshold), produce similar SICI. If they do, then the threshold for inhibition (SICI) and excitation (MEP) would seem to scale with one another across pulse durations, the implication being that the balance of excitation/inhibition recruited by a single pulse is preserved. Alternatively, if the inhibition differs across pulse durations, then excitation/inhibition thresholds do not scale with one another. In this case, different pulse durations presumably recruit a different balance of excitation/inhibition.
28 right-handed volunteers (13 females; age 25 ± 4 years), who reported no contraindications to TMS, participated in two experiments involving TMS over the representation of the right first dorsal interosseous (FDI) muscle. Conditioning pulses were delivered via a figure-of-eight coil (70mm; Magstim Company Ltd, UK) connected to a prototype controllable-pulse parameter TMS device (cTMS3, Rogue Research Inc., Canada; [
]) secured over the top of a flat, elliptical coil connected to a standard TMS device (Magstim 2002, Magstim Company Ltd., UK) (Fig. 1A), which delivered test pulses. MEPs were recorded via surface electromyography.
Two current directions were applied for the test and conditioning pulses (Fig. 1A), and two pulse durations were used for the conditioning pulses (Fig. 1B). In experiment 1 (n = 15), we assessed SICI at intervals corresponding to the peaks/troughs of each participant’s short-interval intracortical facilitation curve (SICF; [
], Fig. 1D), using standard posterior-anterior induced currents and with the FDI muscle at rest. These intervals were chosen to assess whether any differences in SICI between pulse widths could in fact be explained by a differential recruitment of overlapping facilitation [
]), and since we found no evidence of overlapping SICF in experiment 1 (see Fig. 1E), we used a pragmatic range of inter-stimulus intervals up to 20 ms (Fig. 1F).
Resting and active motor thresholds (RMT and AMT) and test pulse intensity, defined at that required to produce a ∼1mV MEP at rest in experiment 1 or during voluntary contraction in experiment 2, were determined at the start of each experiment. Following that, a SICI recruitment curve (2 ms inter-stimulus interval, 50–110% AMT conditioning pulse intensities) was generated using the standard TMS device. The relative intensity (%AMT) producing ∼50% inhibition (experiment 1) or the greatest inhibition (experiment 2, because SICI can sometimes appear weaker during contraction) was selected for use as the conditioning pulse in the main experiments. Conditioning pulse intensities for brief (30 μs) and long (120 μs) pulses were therefore equivalent in relative terms (%AMT), despite being different in absolute terms (i.e. % maximum stimulator output, %MSO; Fig. 1C). The SICF recruitment curve in experiment 2 was generated using 0.3 ms inter-stimulus intervals, 1mV test pulse and 90%RMT conditioning pulse.
Repeated-measures ANOVA were used to evaluate the influence of pulse width and inter-stimulus interval on SICI (expressed as MEP amplitudes normalised to the amplitude of unconditioned test MEPs). Paired-sample t-tests were used to compare stimulus intensities and to follow-up interactions in the repeated-measures ANOVA.
Data are shown mean ± SEM and MEP amplitudes are expressed relative to those obtained with the test pulse alone. Absolute test pulse MEP amplitudes were similar across different conditions within each experiment (both P > 0.19). As expected [
], AMT was greater for brief pulses compared to long pulses in each experiment (both P < 0.001). Thus, within each experiment, the intensity of the conditioning pulse was greater for brief compared to long pulses in absolute terms (%MSO; Fig. 1C), but identical in relative terms (%AMT; Fig. 1C).
In experiment 1, brief conditioning pulses were associated with less SICI compared to longer pulses (Fig. 1E; see legend for results of ANOVA). In experiment 2, brief conditioning pulses were again associated with less SICI compared to longer pulses (Fig. 1F; see legend for results of ANOVA). However, an interaction of conditioning pulse duration and inter-stimulus interval, also indicated that the reduction in SICI for brief pulses was particularly prominent at 2 ms.
We show for the first time that the extent and duration of SICI is influenced by the duration of the conditioning pulse: brief pulses recruit less pronounced SICI. The reason for this is probably because the neurones responsible for SICI are not the same as those that generate MEPs, and must differ in how they respond to pulses of different duration (i.e. their stimulus strength-duration behaviour [
]). Consequently, setting the conditioning pulse intensity as a proportion of the motor threshold results in differential recruitment of inhibition for different pulse durations. The main implication of these results is that even when using a single TMS pulse, one will recruit a different balance of inhibition and excitation depending on pulse duration. This could, in part, explain why the outcomes of rTMS differ according to the pulse duration [
SICI at ∼1 ms (including SICF peak 1 in experiment 1) appeared broadly similar across the different pulse widths. This confirms previous work suggesting that its mechanism is different from that at later intervals [
]. Furthermore, given that this early inhibition persists for both directions of current pulses (experiment 1 and 2), it is consistent with the possibility that it relates to the neuronal refractory period [
A curious finding was that SICI with brief anterior-posterior directed pulses produced very little inhibition at 2 ms by comparison with the longer-lasting pulse (Fig. 1F). This suggests that brief anterior-posterior conditioning pulses recruit a distinct form of inhibition with a later onset than typical posterior-anterior or even long-duration anterior-posterior pulses, though the issue requires more thorough investigation.
We conclude that pulse duration offers a potential method with which to bias the relative ratio of inhibition and excitation recruited by a TMS pulse, and that this has relevance to assessments of cortical circuitry as well as the outcomes of rTMS protocols.
Declaration of competing interest
There are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.
RH and JCR were supported by a Biotechnology and Biological Sciences Research Council grant (BB/N016793/1). ST was supported by a Canadian Institutes of Health Research fellowship award (#MFE-14096). EW was supported by the Wolfson Foundation.
Suppression of voluntary motor activity revealed using transcranial magnetic stimulation of the motor cortex in man.