PhD Defence Esther ter Braack

tms-eeg: first steps towards a clinical application in epilepsy 

Esther ter Braack is a PhD student in the research group Clinical Neurophysiology. Her supervisor is prof.dr.ir. M.J.A.M. van Putten from the faculty of Science and Technology. 

Epilepsy, resulting from an imbalance in excitation and inhibition of brain activity, is characterized by the occurrence of seizures. A patient is diagnosed with epilepsy when there have been two or more seizures, when there is evidence for a specific epilepsy syndrome, or when there has been one seizure with an increased risk of more seizures. An increased risk exists when the electroencephalogram (EEG) shows epileptiform discharges, or when structural brain abnormalities are seen on a magnetic resonance imaging (MRI) scan. In patients presenting with a single seizure without evidence for an increased risk of more seizures, uncertainty remains. Currently the only option is waiting if a second seizure occurs. The first line of treatment in epilepsy is starting anti-epileptic drugs (AEDs) to prevent additional seizures. Treatment efficacy is determined by seizure recurrence. Searching for an effective dosage of a certain AED (or combination of AEDs), or concluding that a patient does not respond to medication, can take up many months.

Two major challenges in epilepsy management are to improve the diagnostic process in patients presenting with a single seizure, and to shorten the time needed to evaluate the success of AEDs in epilepsy patients. At present we mainly rely on seizure recurrence, but since seizures are disturbing events with possible damaging effects, there is a need for a new biomarker to assess the disease status.

With Transcranial Magnetic Stimulation (TMS) short magnetic pulses are applied to the cortex. The strength of the response of the activated neurons to this stimulus can be used as a measure for the balance in excitation and inhibition of brain activity. TMS may be a useful new tool to study (changes in) this balance, and is therefore of interest in the field of epilepsy. In this thesis we focus on the TMS evoked potential (TEP): the EEG response induced by TMS obtained after averaging over multiple single TMS pulses. As epilepsy is associated with a higher excitability, the TEP may be different in epilepsy patients. If so, the TEP could serve as a potential biomarker for epilepsy diagnostics, and as a monitoring tool for evaluating treatment efficacy.

Two large amplitude artifacts hinder the evaluation of the TEP. Principal Component Analysis (PCA) applied on single TMS-EEG trials results in a distribution of the large amplitude artifacts in the first principal components and the relatively small amplitude neuronal activity in later principal components. After consecutive removal of the principal components from the TMS-EEG data, the subsequent reduction in artifact amplitude as well as in TEP amplitude can be evaluated. Using PCA both artifacts are effectively reduced, thereby revealing the first TEP components and allowing further TEP analysis (chapter 2).

TMS pulses are accompanied by a clicking sound, inducing an auditory evoked potential (AEP) which is superimposed to the TEP. This AEP can be minimized by using a headphone playing noise and with a layer of foam between the coil and head (chapter 3). Applying TMS-EEG to a completely deaf person proves that the TEP is definitely not only evoked by sound alone. However, the contribution of the somatosensory evoked potential (SSEP) to the TEP still needs to be elucidated.

For a clinical application of TMS-EEG, the variation of the TEP is of great importance. It appears that the variation between subjects is large, which may make it difficult to differentiate healthy from disease. The within subject variation of the TEP seems to be smaller, possibly enabling follow-up measurements for therapy evaluation. The motor threshold and motor evoked potential do not vary significantly during the day, and the TEP is highly reproducible at different TMS-EEG sessions during daytime (chapter 4).

A study in a group of 14 epilepsy patients using anti-epileptic drugs showed a higher motor threshold and a larger amplitude of the TEP when compared to healthy controls (chapter 5). Part of these differences may possibly be explained by the use of AEDs. Therefore, future research to assess the diagnostic utility of the TEP should focus on performing TMS-EEG studies in first-seizure patients as well as in drug-naïve epilepsy patients. In addition, TMS-EEG should be applied before and after taking AEDs to evaluate the utility of the TEP in individual follow-up measurements.