The effects of elevated endogenous GABA levels on movement-related network oscillations
Highlights
āŗ Recorded MEG during a movement task before and after tiagabine or placebo āŗ Tiagabine elevates the activity of endogenous GABA. āŗ Results showed increased beta-ERD, decreased PMBR and no change in MRGS. āŗ It is suggested that beta-ERD depends on GABAA while PMBR depends on GABAB.
Introduction
During voluntary movements, the primate sensorimotor cortex exhibits a number of task-dependent oscillatory modulations, with time-locked, frequency-specific amplitude decreases and increases. Beta (15ā30Ā Hz) rhythm decreases, known as beta event-related desynchronisation (beta-ERD), occur both before movement initiation, and during transient movements in both ipsilateral and contralateral sensorimotor areas (Jurkiewicz et al., 2006, Pfurtscheller, 1992, Pfurtscheller et al., 2003). Upon movement termination, beta power rapidly exceeds pre-movement levels before returning to the resting state. This power increase, known as the post-movement beta rebound (PMBR) can last several seconds before returning to baseline levels, and is strongest in contralateral cortex (Jurkiewicz et al., 2006, Neuper and Pfurtscheller, 2001). Although they often appear co-localised in non-invasive (MEG/EEG) recordings, PMBR and ERD are most likely generated by anatomically separate cortical circuits, with PMBR typically localised to the contra-lateral precentral gyrus and beta-ERD localised to the postcentral gyrus, with greater bilateral involvement (Jurkiewicz et al., 2006). In addition to movement-related beta band changes, a contralateral movement related gamma synchronisation (MRGS) is also seen. This was first described in humans in epilepsy patients undergoing intracranial electrode recording over motor areas (Crone et al., 1998) and more recently observed with both EEG (Ball et al., 2008, Darvas et al., 2009) and MEG (Cheyne et al., 2008, Gaetz et al., 2011, Muthukumaraswamy, 2010). MRGS peaks just after electromyographic onset, is more topographically focused than beta band responses, and is seen in contralateral primary motor cortex (Crone et al., 1998, Miller et al., 2009, Muthukumaraswamy et al., 2010).
Evidence from both neuronal network models and in vitro animal experiments suggests that the most plausible substrate for the generation of temporally organised spontaneous oscillatory activity is in reciprocally connected neuronal networks containing interconnected glutamatergic pyramidal cells and GABAergic inhibitory interneurons (Bartos et al., 2007, Traub et al., 1996, Yamawaki et al., 2008). In a relatively simple model, the divergent synaptic contacts of interneurons onto multiple pyramidal cells, simultaneously decreases the probability of pyramidal cells firing together. This is followed by a subsequent escape from inhibition, with associated synchronised firing of spikes and local field potential oscillations (Gonzalez-Burgos and Lewis, 2008). Increased IPSC decay-times are thereby associated with decreased oscillatory frequency, which facilitates recruitment of pyramidal cells into the network, and hence oscillatory power is increased (Yamawaki et al., 2008). Consistent with this, increases in the amplitude and decreases in the frequency of resting beta oscillations have been observed after administration of diazepam, a non-selective GABAA agonist (Hall et al., 2010, Jensen et al., 2005).
The rich spectrum of responses seen in movement tasks provides a potential, non-invasive window into the functioning of these neuronal networks which could be applied to clinical populations. For example, in a recent study we demonstrated that patients with juvenile myclonic epilepsy (JME) exhibit selectively decreased beta-ERD (Hamandi et al., 2011). More generally, given the growing importance of altered GABA function in neuropsychiatric disorders, the development of quantitative biomarkers of GABA function could allow them to be explored in a range of neuropsychiatric disorders. However, as pointed out by Hall et al. (2011), it is unclear to what extent the described neuronal mechanisms for resting beta oscillations, also apply to the task-dependent neuronal oscillations in the sensorimotor cortex. In their experiment, 8 participants were administered with 5Ā mg of diazepam while they performed a simple cued response task. The results showed that in addition to the expected baseline increase in beta power there was enhancement of the beta-ERD suggesting that it is a GABAA mediated process. Somewhat surprisingly however, neither MRGS, nor PMBR showed any GABAA driven modulation. While most EEG/MEG studies of sensorimotor oscillations have used diazepam, a wide range of neuropharmacological agents are available in order to test the GABAergic influences on the oscillatory phenomena in question. These include, but are not limited to, other subunit selective drugs, re-uptake inhibitors and enzymatic modulators. Here, to investigate the influence of endogenous GABA itself rather than an exogenous modulator of the GABAA receptors such as the benzodiazepine, diazepam, on sensorimotor oscillations, we used the anti-convulsant drug tiagabine. Tiagabine binds with high affinity and selectivity to GAT-1 (Borden et al., 1994), the primary GABA reuptake transporter in the human cerebral cortex (Conti et al., 2004). GAT-1 transporters are located on both neurons and glia (Minelli et al., 1995) and their location at fast-inhibitory GABAA synapses terminates GABA activity and shapes IPSP activity. The effect of tiagabine, measurable by microdialysis, is to elevate the extracellular/synaptic concentration of GABA (Dalby, 2000, Fink-Jensen et al., 1992, Suzdak and Jansen, 1995). We used a blinded, placebo-controlled, crossover design to investigate the effects of elevated endogenous GABA levels on task-dependent sensorimotor oscillations.
Section snippets
Participants, design and stimuli
Eighteen right-handed volunteers (fourteen males and four females) participated in the experiment after giving informed consent, with all procedures approved by the UK National Research Ethics Service (South East Wales). The volunteers were screened and excluded for personal histories of neurological and psychiatric disease, current recreational or prescription drug use and impaired liver function (by standard liver function tests (LFTs)). Early in the data collection, three female volunteers
Results
Behavioural data from the movement task indicated no significant tiagabine effects in terms of peak movement displacement (F(1,14)Ā =Ā 0.44, F(3,42)Ā =Ā 1.57, F(3,42)Ā =Ā 1.15), the latency at which peak displacement was reached (F(1,14)Ā =Ā 0.05, F(3,42)Ā =Ā 1.14, F(3,42)Ā =Ā 1.00), or for time to movement onset from the tone (F(1,14)Ā =Ā 12.9, pĀ <Ā .002, F(3,42)Ā =Ā 0.31, F(3,42)Ā =Ā 1.93). Hence, we can conclude that the bio-feedback paradigm was effective in aiding the participants to perform the same movements in each
Discussion
In the current experiment, we elevated endogenous GABA in human participants by administering the GAT-1 blocker tiagabine, whilst measuring movement-related oscillatory responses with MEG. We found no difference in MRGS responses but did see elevated baseline beta power, enhanced beta-ERD and reduced PMBR.
The present data are largely consistent with the results of Hall et al. (2011). In their experiment they found increased baseline beta oscillations, no modulation of MRGS, enhancement of
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