The effects of AMPA receptor blockade on resting magnetoencephalography recordings

Abstract

The ionotropic N-methyl-D-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors of the glutamatergic neurotransmitter system are of fundamental importance to healthy brain function. Neuroimaging studies in humans have previously been conducted using various drugs that interact with N-methyl-D-aspartate glutamate receptors, but no such studies have investigated AMPA receptor signalling. The recent approval of perampanel (Fycompa) for use in humans provides a means to specifically study the role of AMPA receptors in the pharmacological basis of neuroimaging signals. Twenty male subjects participated in this placebo-controlled crossover study that consisted of two study days separated by a minimum two-week washout period. On one occasion participants ingested a 6 mg dose of perampanel, and on the other a placebo. Ten minutes of wakeful rest was recorded before and after each dose using magnetoencephalography. Subjective ratings of intoxication were significantly higher following drug than placebo. Cluster-based randomisation testing of sensor-level magnetoencephalography data showed significant drug-induced increases in low frequency power (1-4 Hz, 4-8 Hz, 8-13 Hz, 13-30 Hz), along with a significant decrease in the high gamma range (50-90 Hz). We also observed selective increases in functional connectivity in the alpha and beta bands. The findings are consistent with preclinical work and are similar to the spectral profile of other anti-epileptic drugs.

Keywords: Magnetoencephalography; glutamate; perampanel; α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid.

Figure 1.

Differences in mean scores on psychometric scales between ‘pre’ and ‘post’ time points for drug and placebo, (a) and (b) for the Biphasic Alcohol Effects Scale (BAES), (c) Subjective High Assessment Scale (SHAS) and (d) State Hostility Scale (SHS). *Indicates significant interaction terms (p<0.01).

Figure 2.

Contrast performed on drug-placebo difference spectra, in the frequency bands: δ, θ, α, β, low γ, high γ. Red indicates a relative increase in power following drug and blue indicates relative decrease. Units are t statistics and * indicates significant sensor clusters (p<0.01, corrected for multiple comparisons).

Figure 3.

(a) Power-frequency plots for post-dose conditions at single sensors in the occipital, temporal, parietal and frontal regions. Frequency is plotted on the x-axis and power on the y-axis. Sensor locations are shown in the bottom-left schematic. Shaded bars are standard errors. Inset plots show 50–100 Hz on a log-scale. (b) Changes to peak frequency in the alpha (8–13 Hz) band, for pre-dose and post-dose drug and placebo conditions. Bars show standard error. *Indicates significant interaction. PMP: perampanel; PLA: placebo.

Figure 4.

Areas of significant drug-induced power increase (delta-alpha frequencies). Source localised power was compared at a single virtual sensor for each of the 90 automatic anatomical labeling (AAL) regions studied using randomisation testing, and only those regions that show significant (p<0.05) drug induced-changes following correction for multiple comparisons are displayed here.

Figure 5.

(a) Post-dose connectivity matrices for each of the frequency bands studied. Each point in the plot indicates the correlation of one automatic anatomical labeling (AAL) region with another (90×90). (b) For alpha (8–13 Hz; top) and beta (13–30 Hz; bottom), difference scores (post dose - pre dose) for z-corrected mean connection strength for all AAL regions. (c) Connectivity plots for AAL regions that exhibit significant drug-induced changes in connection strength, in the alpha band (left superior parietal lobule) and beta band (left postcentral gyrus, right inferior parietal gyrus and left caudate). Grey circles indicate AAL nodes. Increased coupling between nodes is plot on red-yellow scale and stronger connections have greater line thickness. PMP: perampanel; PLA: placebo.

Figure 6.

Scatter plots of the mean effects of drug administration connection strength and power in each frequency band (perampanel – placebo). Each point plotted represents the drug-induced change to power and connectivity for one automatic anatomical labeling (AAL) region, averaged across participants. Correlations between the mean effects were not statistically significant in any frequency band. Units are arbitrary due to the beamformer weights normalisation process that is needed to correct for biases introduced by non-uniform sensor-noise projection (Hillebrand et al., 2012).