Abstract
Epilepsy is a chronic disorder characterized by recurring and unpredictable seizures that disrupt normal brain function. These seizures, stemming from abnormal neuronal activity, can severely impact the quality of life for individuals with epilepsy. A crucial factor in this disorder is cortical excitability, referring to the brain cells' ability to
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generate and transmit electrical signals. Altered cortical excitability is associated with seizure development. Quantifying this excitability can aid in developing effective treatments. Diagnostic biomarkers are indicators used to identify health conditions, while therapeutic biomarkers predict or monitor treatment responses. Both types are vital in medical practice, guiding treatment decisions and improving patient care. This thesis aims to identify such biomarkers for epilepsy diagnosis and treatment evaluation.
One diagnostic biomarker involves high-frequency oscillations (HFOs), brief intracranial EEG oscillations. While HFOs are used to guide epilepsy surgery, their causal relationship with seizures is unclear. In the first presented study we linked HFO occurrence to increased neuronal connectivity in the microscopic compartmental model, which resulted in an amplification of seizure susceptibility in the higher level neural mass model. However, HFOs' clinical relevance is still being determined.
In the second study we explored the use of Resting-state EEG as a diagnostic tool. Computational models revealed that the mean functional connectivity (MFC) reflected epileptogenicity when using the appropriate pre-preprocessing and correlation measure. Clinical EEG data validated this measure in a small dataset, showing changes in responders, non-responders, and negative responders to antiseizure medication. Further research is needed for broader validation.
Using a perturbation-based approach, we examined cortical excitability in different disorders in the following studies. Transcranial magnetic stimulation (TMS)-evoked EEG potentials (TEP) were assessed in juvenile myoclonic epilepsy (JME) and migraine patients compared to controls. Alterations in TEP patterns hinted at changes in cortical inhibition. Another approach, relative phase clustering index (rPCI), quantified responses to TMS and light stimulation. In JME, increased rPCI suggested elevated excitability, which correlated with medication dose. Migraine patients did not show significant differences. In another study, TEP stability was studied in refractory epilepsy patients undergoing perampanel treatment. TEPs remained constant across measurements, suggesting normalized excitability due to long-term medication use. Electromyography (EMG)-based measures demonstrated potential biomarkers for treatment response. Resting motor threshold (rMT) increased with perampanel dose in responders, suggesting reduced excitability.Further validation of TMS-EMG markers was conducted in the epilepsy monitoring unit. Dose-response effects were observed when tapering antiseizure medication, indicating rMT's potential as a biomarker. Postictal evaluations revealed distinct excitability changes after different seizure types.
These studies showcased various EEG, TMS-EMG, and TMS-EEG measures for quantifying cortical excitability and epileptogenicity. The diverse nature of epilepsy necessitates tailored biomarkers for different patients or epilepsy types. This research advances the understanding of epilepsy's underlying mechanisms and offers potential tools for diagnosis, treatment monitoring, and personalized care.
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