Pharmaco-TMS-EEG: Establishing a novel tool for measuring excitability in human cerebral cortex

• Applicant: Professor Dr. Ulf Ziemann
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2016 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 318343452

Pharmaco-TMS-EMG, i.e. the combination of neuropharmacology with transcranial magnetic stimulation (TMS) of motor cortex and recording of motor evoked potentials with electromyography (EMG) from a hand muscle has provided important insight to use TMS-EMG for differentiated non-invasive assessment of excitation and inhibition in motor cortex [Ziemann et al. 2015, Clin Neurophysiol 126:1847-68]. On this basis, TMS-EMG is being employed worldwide to detect abnormal excitability in neurological and psychiatric diseases. However, applications and gain of knowledge of TMS-EMG are significantly limited because recordings are made from a muscle (rather than from the brain) and assessment is restricted to motor cortex (no quantifiable responses with stimulation elsewhere). Recent advances in electroencephalography (EEG) amplifier technology allow now recordings of TMS-evoked responses directly from the brain. Therefore, TMS-EEG has a significant potential to overcome these limitations of currently practiced TMS-EMG technology. Focal TMS of primary motor cortex results reliably in TMS-evoked EEG potentials with reproducible latency and topology (e.g., P25, N45, P70, N100, and P180). However, the physiological mechanisms of these potentials are largely unknown. Therefore, observations of alterations of these potentials by experimental manipulation or in disease conditions remain, at present, at the descriptive level. We have started recently, to characterize these TMS-evoked EEG potentials by CNS active drugs. We could show for the first time that GABAAergic inhibition contributes to the N45 and GABABergic inhibition to the N100 [Premoli et al. 2014, J Neurosci 34:5603-12; Premoli et al. 2014, NeuroImage 103C:152-62]. To extend these data, and in analogy to a large body of previous work on pharmaco-TMS-EMG, we propose here a systematic pharmacological characterization of TMS-evoked EEG potentials. We will focus on CNS active drugs with specific modes of action in the glutamatergic and GABAergic system, and on blockers of voltage-gated ion channels. We expect from this research a novel, direct and therefore highly informative tool to assess excitability of the human cerebral cortex. This tool could, as soon as pharmaco-physiologically characterized, play an important role in the diagnostic assessment of abnormal brain excitability in neurological and psychiatric diseases.

• DFG Programme: Research Grants