Neuronal network pharmacodynamics of GABAergic modulation in the human cortex determined using pharmaco-magnetoencephalography

Abstract

Neuronal network oscillations are a unifying phenomenon in neuroscience research, with comparable measurements across scales and species. Cortical oscillations are of central importance in the characterization of neuronal network function in health and disease and are influential in effective drug development. Whilst animal in vitro and in vivo electrophysiology is able to characterize pharmacologically induced modulations in neuronal activity, present human counterparts have spatial and temporal limitations. Consequently, the potential applications for a human equivalent are extensive. Here, we demonstrate a novel implementation of contemporary neuroimaging methods called pharmaco-magnetoencephalography. This approach determines the spatial profile of neuronal network oscillatory power change across the cortex following drug administration and reconstructs the time course of these modulations at focal regions of interest. As a proof of concept, we characterize the nonspecific GABAergic modulator diazepam, which has a broad range of therapeutic applications. We demonstrate that diazepam variously modulates theta (4-7 Hz), alpha (7-14 Hz), beta (15-25 Hz), and gamma (30-80 Hz) frequency oscillations in specific regions of the cortex, with a pharmacodynamic profile consistent with that of drug uptake. We examine the relevance of these results with regard to the spatial and temporal observations from other modalities and the various therapeutic consequences of diazepam and discuss the potential applications of such an approach in terms of drug development and translational neuroscience.

Figure 1

Virtual electrode reconstruction of the neuronal activity at peak loci in a representative individual. Traces reflect band pass filtered oscillatory power at peak frequencies over 60 min at loci of maximal power change, as determined from individual SAM analysis in a representative individual.

Figure 2

Group SAM images of oscillatory power change in θ (4–7 Hz), α (7–14 Hz), β (15–30 Hz), and γ (30–80 Hz) frequency ranges in response to diazepam administration. Images displayed are a comparison of the initial baseline period (0–10 min) and the final drug active period (50–60 min). Hot colors reflect an increase and cool colors a decrease in synchronous power, with pseudo‐t values displayed for the peak loci of each image (green dot); images are thresholded at 50% of maximum. The panel shows: unilateral decrease in theta in left middle frontal cortex (A), a decrease in medial frontal theta (B), bilateral decrease in prefrontal theta (C), bilateral increase in occipital alpha (D), bilateral increase in alpha in middle temporal cortex (E), bilateral increase in beta power in the pre‐central gyrus (F), bilateral increase in β–γ in the postcentral gyrus (G), bilateral increase in occipital gamma (H), bilateral increase in inferior frontal gamma (I), increase in medial frontal gamma (J), and a bilateral increase in prefrontal gamma (K). For further details see Table I.

Figure 3

Pharmacodynamic envelopes of oscillatory power change at ROIs. RMS power in the θ, α, β, and γ frequency bands at peak loci. Data are displayed as 1 sample/minute for each individual, normalized to the maximal power (i), the group‐mean power displayed as 1 sample/minute (ii) and as the group‐mean power change over each 10 min period ±1.96 SEM, normalized to the baseline period (iii). Data are presented from loci that are consistent across participants and where bilateral or midline results are observed; all data shown are from the left hemisphere as an example. The data shown demonstrate the pharmacodynamic profiles of: medial frontal theta (A), prefrontal theta (B), occipital alpha (C), temporal alpha (D), precentral beta (E), postcentral β–γ (F), occipital gamma (G), and prefrontal gamma (H).

Figure 4

Time‐frequency representation of activity in the hand‐motor area in response to diazepam uptake. SAM analysis of beta power during isometric contraction of the right hand used to localize right primary motor cortex hand area (pseudo‐t = 2.9). The SAM peak (left) used to direct virtual electrode analysis using time frequency spectrograms (Morlett–Wavelet Mann–Whitney) to compare the activity in drug active phases with baseline in a representative individual (note a z‐value of 1.96 corresponds to P < 0.05).

Figure 5

Placebo‐control Data. Envelopes of RMS oscillatory power during the 60‐min postplacebo administration at functionally derived SAM peaks. Data show alpha power in the visual cortex determined from eye‐closure induced alpha SAM peak (A and D), gamma power in visual cortex determined from visually induced gamma SAM peak (B and E), and beta power in motor cortex determined from finger movement induced beta (C and F). The top panel shows data (1 sample/minute) for four subjects' placebo data, while the bottom panel shows group mean over each 10 min period ±1.96 SEM for placebo versus diazepam at the same loci.

Figure 6

Comparison of pharmaco‐MEG and PET. Comparative image of PET receptor density mapping of benzodiazepine receptors using [11C]‐flumazenil and MEG activity in the β–γ (15–80 Hz) frequency range following diazepam administration. This image is partially composed (left panel) of a modified image from the study by Fedi et al. [ 2006].