Abstracts

Rationale:
Robust biomarkers for anti-epileptic drugs (AEDs) activity in the human brain are essential to increase probability of successful drug development. Transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) produces TMS-evoked potentials which can provide cortical readouts for AEDs. TMS-EEG responses can also be interrogated in the time-frequency domain as TMS-induced oscillations capturing a more complex cortical response. The spectral profile of single-pulse TMS of the motor cortex is characterized by an early increase of theta, alpha and beta band power, followed by a beta suppression or de-synchronization with a final beta power increase. A systematic evaluation of AEDs activity on cortical oscillations either induced by TMS stimulation or in the absence of a stimuli (resting-state EEG) has not been yet provided and results will enlarge knowledge about additional biomarkers to be used in future trials.
Method:
We studied the role of AEDs on theta (4-7Hz), alpha (8-12Hz) and beta (13-30Hz) bands power of cortical oscillations in healthy subjects. In Experiment 1, we tested the effects of a single oral dose of lamotrigine and levetiracetam and in Experiment 2, a novel potassium channel opener (XEN1101) under clinical development on TMS-induced oscillations and resting state EEG.
Results:
Compared to baseline, levetiracetam suppresses theta (p=0.001), alpha (p=0.01) and beta power (two clusters, p=0.01, p=0.03) from 30 to 670ms, whereas lamotrigine significantly increases alpha (p=0.01) close to the stimulated area at 400ms post TMS (p=0.01). XEN1101 decreases theta power (p=0.02) from 30 to 370ms and increased beta desynchronization (p=0.04) at around 300ms. Resting state showed a significant widespread decreases of spontaneous theta band (p = 0.03) after lamotrigine intake. Levetiracetam significantly increases beta (p< 0.001) over central and frontal electrodes and theta power at left temporal site (p=0.03) while XEN1101, at high plasma level, produces a widespread increase of delta (p=< 0.001) and theta power (p=0.01) and an increase of beta in cento-frontal sites (p=0.005).
Conclusion:
Cortical oscillations induced by M1 stimulation and at rest can characterize unique profile for AED activity in the healthy human brain. Spectral fingerprints should be further investigated to provide robust and objective biomarkers of target engagement in human clinical trials.  
Funding:
:This study represents an independent research supported by the National Institute for Health Research (NIHR)-Well come King’s Clinical Research Facility and the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. The research has been also partially funded by Xenon Pharmaceuticals Inc.