These results show that rTMS given at low frequency (1Hz) causes a persistent increase in the alpha coherence between the ipsilateral stimulated primary motor and more anterior motor areas (intrahemispheric) and in the coherence between the ipsilateral stimulated and contralateral unstimulated motor areas (interhemispheric). The effect of rTMS was relatively focal as there was no change in the coherence between primary motor cortex and more anterior motor areas over the cerebral hemisphere contralateral to stimulation.
The increase in alpha coherence is unlikely to be due to a general alteration in arousal of subjects for several reasons. The intrahemispheric changes only occurred ipsilateral to the rTMS and the interhemispheric changes were confined to periods of tonic contraction. An effect of general arousal would have been expected to involve both left and right hemispheres and both rest and active conditions. Additionally, in a simiiar experimental paradigm, high frequency (5Hz) rTMS over the motor cortex (100% active motor threshold; data analysed in an identical way) gives the opposite effect, causing ipsilateral cortico-cortical coherence to decrease post-stimulation (chapter 4). The lack of rTMS effects on regional power is also against any non-specific arousal changes during the paradigm. The effect must have been purely central in origin because the intensity of the individual rTMS pulses was less than active threshold. Therefore, no muscle twitches were evoked that could modify central processing through changed afferent input. Neither did differences in non-linear components of the signals account for differences in coherence. There was no change in EEG power with rTMS so that the increases in EEG-EEG coherence in the alpha band reflected a change in the absolute degree of coupling between areas.
Interestingly, although motor and premotor area alpha power changed according to whether the subjects were at rest or being recorded during voluntary muscle contraction, there was no variation in alpha coherence with rest versus contraction. This may be because sustained tonic contraction was examined, avoiding transients occurring during the first few seconds of contraction (Crone et al, 1998). Changes in coherence are, however, reported in phasic tasks (Gerloff et al., 1998; Manganotti et
al., 1998). As expected (Gerloff et al., 1998; Manganotti et al., 1998; Pfurtscheller et al., 2000), there was a significant reduction in power over the left and right motor and premotor areas in the alpha range during muscle contraction, as well as a reduction in power over the motor areas in the beta range. This reduction in power has been interpreted as a sign of regional activation (Pfurtscheller, 1988; Toro et al., 1994a, b; Stancak and Pfurtscheller, 1995; Gerloff et al., 1998).
One can only speculate on the possible mechanisms responsible for the change in the alpha band coherence after rTMS. The stimulus intensity used was below AMT, suggesting that it was insufficient to activate excitatory inputs to corticospinal neurones. On the other hand, such low intensities are used as conditioning pulses in paired-pulse testing of cortical inhibition and facilitation (Kujirai et al., 1993). Thus, the rTMS was probably capable of exciting cortical interneurones. Subthreshold 1 Hz rTMS has been shown to decrease local cerebral blood flow, consistent with TMS-induced activation of local inhibitory mechanisms, whereas subthreshold 20 Hz rTMS increased local cerebral blood flow (Speer et al., 2000).
Since inhibition is a critical factor in the development of cortical oscillations and coherence (Rubin and Terman, 2000; Contreras et al., 1997; Pauluis et al., 1999), it seems possible that long-lasting changes in the excitability of inhibitory mechanisms after rTMS could contribute to the present results. This suggestion is supported by the observation that 1Hz rTMS at 90% resting threshold could increase intracortical inhibition (ICI) in patients with writer's cramp (Siebner et al., 1999b). However, it is more difficult to reconcile with the lack of effect of 1Hz rTMS to motor cortex on ICI in healthy subjects at both 90% resting (Siebner et al., 1999b) and 80% active threshold (Munchau et al., 2002). One possibility is that the paired-pulse method of testing ICI in healthy subjects is prone to ‘floor’ effects because the baseline levels of inhibition are so strong (Fisher et al., 2002). Perhaps more sensitive measures of inhibition such as the threshold tracking design of Fisher et al. (2002) and Awiszus et al. (1999) would detect subtle effects that might mirror the changes in cortico-cortical coherence.
The pharmacological basis of the short-term plasticity in cortico-cortical coupling induced by rTMS is unclear. Gamma-aminobutyric acid (GABA) transmission is implicated in the effects of TMS on the cortex (Kujirai et al., 1993; ZIemann et al., 1996a,b; Werhahn et al., 1999) and modulation of GABA is felt to be the key mechanism of short-term plasticity in the adult mammalian central nervous system (Jones, 1993; Donoghue et al., 1996).
In summary, rTMS over the primary motor cortex seems to modulate the coupling of this area with distant sites. This modulation preferentially involves the alpha frequency band, which is believed to have mainly inhibitory activities. These results therefore suggest one means whereby low frequency rTMS may, in part, result in decreased excitability of the motor cortex, through an increase in the cortico-cortical and interhemispheric coupling in the alpha frequency band. Changes in cortico-cortical and interhemispheric coupling following rTMS over motor cortex occurred at intensities that were likely to be too low to change cortical excitability as measured by MEP size (Siebner et al., 1999b; Gerschlager et al., 2001), suggesting that cortico-cortical and interhemispheric coherence may provide a more sensitive measure of cortical function following rTMS. More speculatively, rTMS appears to be a non-invasive tool whereby certain connections within the brain may be strategically modulated.