GABAergic modulation of MI activity in vitro compared to MEG

In vitro and in silico studies generally report a decrease in peak frequency in the motor

cortex after increasing the GABAergic drive and synchronisation, with the characteristic oscillatory power increase (Jensen et al., 2005; Yamawaki et al., 2008; Prokic et al., 2012). In neuroimaging reports, effects on oscillatory frequency from benzodiazepine, and alike, substances, have been reported with more inconsistency (Baker & Baker 2003; Jensen et al., 2005). This is most likely due to differences in the undertaken analysis approaches. We found a significant decrease in the mean peak frequency of the ongoing oscillatory activity in MI LV, but not in any other areas of recording, nor in the human MI. We speculate that this is due to the narrow natural frequency preference that appear characteristic of MI LV oscillatory activity, which this and other studies have reported on (Yamawaki et al., 2008; Prokic et al., under review). Previous research in this project has suggested that the oscillatory activity seen in MI LIII and SI LIV, as well as human MI, arise from more than one oscillator in the underlying neuronal substrate, as determined by the use of distribution and variability analysis. In contrast, the oscillatory network activity distribution in MI LV is centred round the mean peak frequency, instead suggesting that this activity arise from one oscillator. The effects on oscillatory peak frequency from GABAergic modulation on a neuronal network would be less clear if there was modulation of several oscillators of varying frequencies as these amalgamate into one averaged population signal. In MI LV the ongoing oscillatory peak is sharp with a symmetrical and unimodal distribution, thus any GABAergic modulation of the ongoing peak frequency is likely to be seen as a clear shift in peak frequency. Furthermore, the previous chapters have emphasised the difference between MEG and LFP oscillatory signals with regards to number of neuronal networks and source size and frequency. The theories discussed

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above, with regards to participating neuronal networks and oscillatory frequencies in the different laminae can be anecdotally scaled up to suit the aggregate MEG signal. We have been unable to locate any other research along these lines, so supporting or refuting these theories is currently difficult. More research on this, as well as the underlying mechanisms of the ongoing activity beta and mu seen in MI LIII and SI LIV, is required to elucidate and substantiate these claims.

In the MEG recordings of oscillatory activity in MI, administration of sub-sedative doses of zolpidem in healthy subjects significantly increased the overall mean beta peak power and oscillatory state power of the recorded oscillatory activity. This is in agreement with previous studies of the effects of benzodiazepine administration in healthy subjects, showing an increase of mean beta power (Domino et al. 1989; Glaze, 1990; Baker & Baker 2003; Jensen et al., 2005; Hall et al., 2009; 2010; 2011). The link with increased GABAergic modulation and increased mean beta power in MI recorded with MEG was reported by Gaetz et al. (2011). Our findings also agree with previous in vitro reports on the increase of beta power after zolpidem and benzodiazepine administration in MI LV (Yamawaki et al., 2008, Prokic et al., under review). In addition, we found that zolpidem significantly increased the mean peak power of the ongoing activity in MI LIII previously not reported. However, there was a non-significant increase in oscillatory state power in in

vitro; where the non-significance was suspected to be due to low n-numbers. The

modulation of the oscillatory mean peak power by zolpidem application suggests similar mechanisms to the oscillatory activity previously reported in MI LV, although the exact mechanisms cannot be determined from these recordings as this would require further pharmacological manipulation in vitro. Oscillatory activity has been found to depend on GABAergic interneurons, predominantly FS interneurons (Cobb et al., 1995, Hasenstaub

et al., 2005). Effects of benzodiazepines and substances acting on the benzodiazepine

site in the GABAA-receptor increase the chloride channel opening time and frequency

respectively. These substances affected the features of beta oscillation through increasing the IPSCs in interneurons (Jensen et al., 2005), and in effect by modulating phasic GABAA-R specific inhibition (Yamawaki et al., 2008). It is likely that the GABAergic

modulator zolpidem would modulate the overall beta oscillatory activity in all areas we have recorded from. We speculate that it is down to the neuronal network or natural resonance frequency to determine the level of reinforcement and thereby the oscillatory peak power, as the mu amplitude is not significantly changed by zolpidem (data not shown). Previous experiments in this project, discussed in chapter 4, have suggested that oscillatory power is higher in more local networks, although we have not been able to find any other research to substantiate this.

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Administration of sub-sedative doses zolpidem to patients with stroke with a sensorimotor lesion reduces the power of the abnormal pathological beta oscillations (Hall et al., 2010). In addition, the ‘beta-buzz’ in healthy subjects is well-established in the EEG literature as an increase in oscillatory beta power following administration with GABAergic drugs, such as benzodiazepines. In vitro experiments have found that the oscillatory beta power in layer V of MI increases after zolpidem application (100nM). Recent research has argued that the effects of zolpidem are dose-dependent and that a lower dose (10 nM) decreases the oscillatory power; this dose was suggested to be more similar to the sub-sedative dose administered to human participants and patients (Prokic et al., 2012). However, the results from this chapter indicate that the oscillatory beta power significantly increases in

healthy subjects after administration of sub-sedative doses of zolpidem, similar to

application of 30 and 100 nM zolpidem in the in vitro preparations.

5.4.3. GABAergic modulation of MI activity compared to SI activity in vitro