The effects of alterations in conditioning stimulus intensity on short interval intracortical inhibition

Abstract

Short interval intracortical inhibition [SICI] is mediated by cortical inhibitory interneurons, with two physiologically distinct phases at interstimulus interval [ISI] < 1 ms and 2.5–3 ms. The second phase of SICI is mediated by synaptic mechanisms, while the first phase has been attributed to axonal refractoriness, synaptic mechanisms or both. In the present study, threshold-tracking transcranial magnetic stimulation was used to explore mechanisms underlying SICI. SICI was studied in 10 normal subjects at three different conditioning stimulus [CS] intensities [40%, 70% and 90% of resting motor threshold, RMT, defined as the threshold for a MEP of ∼ 0.2 mV]. Motor responses were recorded from abductor pollicis brevis. Maximal SICI developed with CS set to 70% RMT [SICI_70%], with two phases evident, at ISI 1 ms [12.7 ± 3.4%] and ISI 2.5 ms [19.3 ± 2.9%]. With CS set to 40% RMT, SICI occurred between 1 ms and 5 ms, peaking at 2.5 ms and was reduced [1.9 ± 1.4%, P < 0.0001] compared to peak SICI_70%. The small SICI peak at 1 ms was absent. With CS at 90% RMT, SICI developed between 2 and 5 ms, peaking at 4 ms [11.2 ± 7.8%]. Facilitation was evident at 1 ms. The findings from the present study suggest that inhibitory circuits with different thresholds underlie the phases of SICI, with synaptic mechanisms also critical to the development of SICI at 1 ms.

Introduction

Cortical excitability can be assessed using a paired-pulse transcranial magnetic stimulation [TMS] paradigm. In the conventional constant stimulus paradigm, a subthreshold conditioning stimulus [CS] exerts an effect on a subsequent test stimulus [TS], such that when the interstimulus interval [ISI] is between 1 and 5 ms the motor evoked potential [MEP] amplitude produced by the test response is inhibited, a process referred to as short interval intracortical inhibition [SICI] (Di Lazzaro et al., 1998, Hanajima et al., 1998a, Kujirai et al., 1993, Nakamura et al., 1997).

Recently, a paired-pulse threshold-tracking TMS technique was developed to overcome the potential limitations of the constant stimulus method (Awiszus et al., 1999, Fisher et al., 2002, Vucic et al., 2006). Specifically, the utility of the constant stimulus technique may be limited by variability in the motor evoked potential [MEP] amplitude with consecutive stimuli (Kiers et al., 1993). This variability results from spontaneous fluctuations in the resting threshold of cortical neurons. The threshold-tracking technique attempts to control for variability in cortical excitability by assessing RMT every stimulus sequence (see Experimental procedures), but even so, resting threshold has to be reasonably stable for a reliable assessment of SICI. Using the threshold-tracking technique, two phases of SICI at ISIs of 1 and 2.5–3 ms were identified (Fisher et al., 2002, Vucic et al., 2006), and the presence of two phases of SICI has been confirmed using the constant stimulus method (Roshan et al., 2003). While there is supportive evidence to suggest that the later SICI peak at 2.5 ms is mediated by synaptic mechanisms, the physiological basis underlying the first peak [at 1 ms] is less clear. Fisher et al. (2002) proposed that refractoriness of axons of cortical interneurons subliminally activated by a subthreshold CS underlies the first phase of SICI, a suggestion also argued by Chen (2004). In contrast, Roshan et al. (2003) argued that axonal refractoriness could not entirely account for the first phase of SICI and suggested a role for synaptic processes. It has been argued that SICI is a complex neurophysiological measure, mediated in part by the interaction of multiple cortical circuits, reflecting a balance between inhibition and facilitation (Ni and Chen, 2008, Peurala et al., 2008). The present study used novel threshold-tracking TMS techniques to shed further light on the mechanisms underlying SICI by investigating the effects of variable CS intensity, in addition to correlating SICI at different CS intensities and interstimulus intervals.