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Transcranial magnetic stimulation can be used to non-invasively study inhibitory processes in the human motor cortex. Interhemispheric inhibition can be measured by applying a conditioning stimulus to the motor cortex resulting in inhibition of the contralateral motor cortex. Transcranial magnetic stimulation can also be used to demonstrate ipsilateral cortico-cortical inhibition in the motor cortex. At least two different ipsilateral cortico-cortical inhibitory processes have been identified: short interval intracortical inhibition and long interval intracortical inhibition. However, the relationship between interhemispheric inhibition and ipsilateral cortico-cortical inhibition remains unclear. This study examined the relationship between interhemispheric inhibition, short interval intracortical inhibition and long interval intracortical inhibition. First, the effect of test stimulus intensity on each inhibitory process was studied. Second, the effects of interhemispheric inhibition on short interval intracortical inhibition and long interval intracortical inhibition on interhemispheric inhibition were examined. Motor evoked potentials were recorded from the right first dorsal interosseous muscle in 11 right-handed healthy volunteers. For interhemispheric inhibition, conditioning stimuli were applied to the right motor cortex and test stimuli to the left motor cortex. For short interval intracortical inhibition and long interval intracortical inhibition, both conditioning stimuli and test stimuli were applied to the left motor cortex. With increasing test stimulus intensities, long interval intracortical inhibition and interhemispheric inhibition decreased, while short interval intracortical inhibition increased. Moreover, short interval intracortical inhibition was significantly reduced in the presence of interhemispheric inhibition. Interhemispheric inhibition was significantly reduced in the presence of long interval intracortical inhibition when matched for test motor evoked potential amplitude but the difference was not significant when matched for test pulse intensity. These findings suggest that both interhemispheric inhibition and long interval intracortical inhibition are predominately mediated by low threshold cortical neurons and may share common inhibitory mechanisms. In contrast, the mechanisms mediating short interval intracortical inhibition are probably different from those mediating long interval intracortical inhibition and interhemispheric inhibition although these systems appear to interact.
Transcranial magnetic stimulation (TMS) has been used to demonstrate at least three different cortico-cortical inhibitory processes: interhemispheric inhibition (IHI), short interval intracortical inhibition (SICI) and long interval intracortical inhibition (LICI). IHI can be demonstrated by applying a conditioning stimulus (CS) to the motor cortex, which inhibits the size of the motor evoked potential (MEP) produced by the test stimulus (TS) of the opposite motor cortex (Ferbert et al. 1992; Hanajima et al. 2001). This result is consistent with animal studies that show stimulation of the motor cortex inhibits the contralateral motor cortex several milliseconds later (Chang, 1953; Asanuma & Okuda, 1962; Matsunami & Hamada, 1984). IHI can be observed at interstimulus intervals (ISIs) between 6 and 50 ms (Ferbert et al. 1992; Gerloff et al. 1998). Conversely, SICI and LICI are cortico-cortical inhibitory processes observed within the ipsilateral motor cortex. In the SICI paradigm, pairing a subthreshold CS with a suprathreshold TS at short ISIs (1-5 ms) inhibits the MEP produced by the TS (Kujirai et al. 1993). LICI results in attenuation of the MEP when a suprathreshold CS is paired with a suprathreshold TS at long ISIs (50-200 ms) (Valls-Sole et al. 1992; Wassermann et al. 1996).
Several lines of evidence suggest that these forms of cortico-cortical inhibition are mediated by cortical inhibitory neuronal mechanisms. For example, IHI is related to the activity of inhibitory interneurons and largely mediated by transcallosal pathways. This contention is supported by several findings. First, test responses evoked by small anodal electrical shock are not significantly inhibited by contralateral magnetic conditioning stimuli (Ferbert et al. 1992; Hanajima et al. 2001). Low intensity electrical stimuli excite descending pyramidal axons within the white matter that are not sensitive to changes in cortical excitability (Rothwell, 1997). Second, H-reflexes in the relaxed forearm flexor muscles are unaffected by conditioning stimuli to the ipsilateral hemisphere, suggesting that ipsilateral motor cortex stimulation does not change spinal excitability (Ferbert et al. 1992; Gerloff et al. 1998). Finally, reduced excitability of the contralateral motor cortex has been demonstrated directly by recordings of descending corticospinal volleys (Di Lazzaro et al. 1999). Similarly, evidence that SICI and LICI are mediated by cortical inhibitory interneurons include: absence of any change in spinal excitability (Fuhr et al. 1991); failure to suppress the response to double transcranial electrical stimulation (TES; Ferbert et al. 1992; Inghilleri et al. 1993; Kujirai et al. 1993), and marked reduction in the corticospinal waves evoked by TMS (Valls-Sole et al. 1992; Nakamura et al. 1997; Chen et al. 1999).
Although these findings establish that IHI, SICI and LICI are all mediated by cortical inhibitory interneurons, other lines of evidence suggest that they are related to different subtypes of GABAergic receptors. For example, Sanger et al. (2001) found that SICI and LICI respond differentially to increasing TS intensities and that LICI inhibits SICI. Another important difference between SICI and LICI is that SICI is associated with a low intensity CS which produces shorter periods of cortical inhibition; whereas LICI is associated with a high intensity CS which produces longer periods of cortical inhibition. It is also known that GABAA receptor-mediated responses have lower activation thresholds and their inhibitory influence is brief (Davies et al. 1990; Sanger et al. 2001). Further, GABAB receptor-mediated responses have higher activation thresholds and their inhibitory influence is longer lasting (Deisz, 1999; Sanger et al. 2001). These findings have led researchers to suggest that SICI may be mediated by GABAA receptors while LICI may be mediated by GABAB receptors (Roick et al. 1993; Siebner et al. 1998; Werhahn et al. 1999).
Neurons mediating IHI must arise from contralateral sites and travel to the opposite hemisphere to exert their inhibitory effects. Since inhibitory GABAergic neurons mainly serve local circuits (Somogyi et al. 1998), IHI is probably mediated through excitatory axons that cross the corpus callosum to act on local inhibitory neurons in the contralateral motor cortex (Berlucci, 1990). However, it is currently unknown whether IHI is related to SICI and LICI and therefore mediated by similar or different GABAergic mechanisms.
One way to investigate whether experimental phenomena (i.e. SICI, LICI and IHI) share common mechanisms of action is to assess whether their profiles of response are similar or dissimilar under conditions of controlled perturbations. In these experiments, this is achieved in two ways; first, by a controlled manipulation of TS intensities on SICI, LICI and IHI and second by examining the impact of one inhibitory phenomenon on the other. This was accomplished by examining the interactions between SICI, LICI and IHI and intracortical facilitation (ICF) using a triple stimulation protocol. ICF was included because it may interact with these different inhibitory measures. Such methods have been used by Sanger et al. (2001) to examine the relationship between LICI and SICI. In the present experiments we use a similar approach to examine how IHI interacts with SICI and LICI. The findings will help us to understand how local inhibitory mechanisms are influenced by interhemispheric projections.