TMS-EEG signatures of glutamatergic neurotransmission in human cortex

Abstract

Physiological neuronal activity in the brain requires a balance between excitation and inhibition. Glutamate is the most important neurotransmitter of the excitatory system. Therefore, this thesis takes a closer look at the role of the glutamatergic system in brain activity. The combination of transcranial magnetic stimulation and electroencephalography (TMS-EEG) is a unique method for non-invasive measurements of brain physiological processes. TMS generates an EEG- response with specific positive and negative deflections called TMS evoked potentials (TEPs). TEPs can be used to quantify pharmacological effects on neuronal activity in the human cortex. In this work we tested the influence of two glutamatergic drugs on TEPs. First, perampanel, an AMPA receptor antagonist and second, dextromethorphan, a NMDA receptor antagonist. Additionally, the effect of nimodipine, a voltage-gated L-type calcium channel blocker, on TEPs. The study was conducted in a pseudorandomized, double-blind, placebo- controlled crossover design. A Total of 16 healthy subjects were included in the study after undergoing a screening protocol. All subjects participated in four measurements, in which we stimulated the hand area of the left motor cortex (M1) with single-pulse TMS and recorded TEPs before and after drug intake. Significant changes of the TEPs were observed after the intake of glutamatergic drugs. Dextromethorphan elevated the amplitude of N45, a negative potential about 45 ms after stimulation. Perampanel reduced the P70 amplitude, a positive potential about 70 ms after stimulation, in the non-stimulated hemisphere. Nimodipine and placebo had no influence on TEPs. These data complement previous pharmaco-TMS-EEG studies with important insights into the role of the glutamate receptor in the development of TEPs. More precisely, the new evidence indicates that the evolution of N45 is based on a balance of EPSPs and IPSPs generated by NMDARs and GABA-A-Rs. Whereas fast EPSP generation and interhemispheric propagation via AMPARs is responsible for P70 evolution. These new data deepen the understanding of the underlying processes of TEPs. This acts as a very important step towards TEPs as non-invasive biomarkers for excitability and propagation of neuronal activity in the human cortex in disease and health.