Multimodal TMS: Finding biomarkers for epilepsy

Epilepsy is characterized by the occurrence of epileptic seizures, resulting from an imbalance between excitatory and inhibitory brain activity. The tendency to generate seizures is reflected in the electroencephalogram (EEG) by the presence of epileptiform discharges. However, the limited sensitivity of the EEG motivated our search for biomarkers to improve the diagnostic process. We explored the potential of transcranial magnetic stimulation (TMS) as a novel biomarker for the diagnosis of epilepsy. We applied single and paired pulse TMS, while the stimulation effect was assessed using the muscle response (motor evoked potential: MEP), the brain response (TMS evoked potential: TEP), and MEP and TEP inhibition for intervals > 50 ms between paired pulses (long intracortical inhibition: LICI). Chapters 2-4 focusses on the clinical feasibility of multimodal TMS. Repeatability of the TEP and LICI after one week was good on a group level, whereas individual subjects showed a large variation in LICI repeatability. Additionally, we found no significant effect of a change in coil positioning on the MEP, TEP or LICI on a group level, while on the subject level significant effects were found for a 5 mm change in coil location and a 10° change in coil orientation. Chapter 5 focusses on finding biological modulators of cortical excitability. Very slow fluctuations may cause TMS responses to vary over time. Our findings indicate that infraslow EEG activity contributes to the variability, although other mechanisms are likely involved as well. By targeting TMS to a specific oscillatory phase, it might be possible to reduce the large response variation. Chapters 6-8 focusses on the diagnostic value of multimodal TMS in epilepsy. Previous findings in drug naïve epilepsy patients were most consistent for paired pulse TMS, showing a significant increase in cortical excitability. We were unable to confirm this finding in refractory epilepsy patients and first seizure patients. However, we could differentiate first seizure patients diagnosed with epilepsy from those without epilepsy and from healthy subjects, using LICI of the MEP and TEP. In conclusion, we showed the clinical feasibility and potential of multimodal TMS to improve the diagnostic process in epilepsy.