Neuronal network pharmacodynamics of GABAergic modulation in the human cortex determined using pharmaco-magnetoencephalography.
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.
Hall
Stephen D
SD
Biomedical Sciences, School of Life and Health Sciences, Aston University, Birmingham. hallsd@aston.ac.uk
Barnes
Gareth R
GR
Furlong
Paul L
PL
Seri
Stefano
S
Hillebrand
Arjan
A
D000328:Adult; D001931:Brain Mapping; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D003975:Diazepam / Q000494:pharmacology*; D004569:Electroencephalography; D018757:GABA Modulators / Q000494:pharmacology*; D006801:Humans; D015225:Magnetoencephalography / Q000379:methods*; D008297:Male; D008875:Middle Aged; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D010507:Periodicity; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D018757:GABA Modulators; D005680:gamma-Aminobutyric Acid; D003975:Diazepam