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Title: Exploring threshold-tracking transcranial magnetic stimulation for cortical inhibition as a novel biomarker for γ-aminobutyric acid A α2,3 receptor signalling in humans
Author: Samusyte, Gintaute
ISNI:       0000 0004 7964 9979
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2019
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Transcranial magnetic stimulation (TMS) is a non-invasive neurophysiological method used to investigate the human motor system. Variability of TMS measures remains one of the main concerns in the research field and a major limitation for their clinical application. Conventional TMS paradigms are largely based on the measurement of the motor evoked potential (MEP) size and are confounded by its large trial-to-trial variability. An alternative approach is to measure threshold, i.e. the stimulus intensity required to obtain a MEP of or above a certain size, and threshold-tracking TMS is emerging as a useful diagnostic test. However, little is known about its reliability and comparability with conventional methods. In this thesis, threshold-tracking was for the first time directly compared with conventional TMS approaches in healthy volunteers. Estimation of resting motor threshold by threshold-tracking was validated against common probabilistic methods. The extent of changes in corticospinal excitability observed in individual recordings during a standard TMS session suggested that threshold-tracking may improve the reliability of paired-pulse TMS paradigms as it allows continuous monitoring and adjustment for these fluctuations. This hypothesis was tested with one of the most widely-used paradigms - short-interval intracortical inhibition (SICI). Mean group SICI obtained at an interstimulus interval of 2.5 ms and a range of conditioning stimulus intensities by both conventional 'amplitude' method and threshold-tracking showed a close relationship suggesting that they reflect similar inhibitory mechanisms, while threshold-tracking had a potential for improved reproducibility and acquisition speed. Availability of a safe selective positive allosteric γ-aminobutyric acid A α2,3 receptor modulator AZD7325 allowed for the first time to test the hypothesis that SICI is mediated by this pathway and to directly compare the biomarker sensitivity of the two techniques in a randomised double-blind placebo-controlled cross-over study. This trial showed no modulatory effect of the drug on SICI at the exposure level used.
Supervisor: Koltzenburg, M. ; Rothwell, J. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available