Cheeran, B.J.; (2011) Stimulation genomics: probing the effects of genetic variation on human cortical plasticity and its clinical implications. Doctoral thesis , UCL (University College London).

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Abstract

The studies presented in this thesis employ neurophysiological outcome measures and the application of artificially induced cortical stimulation plasticity paradigms to study the effects of human genetic variation on human cortical neuroplasticity. The introductory chapter includes a review of illustrative models of neuroplasticity. I also cover the principles, physiology and pharmacology of TMS and rTMS. With this background, I set out the scope and principles of such an approach applied to the study of human genetic variation, and define the field of Stimulation Genomics. I set out the case for such an approach, highlighting previous studies that have employed neurophysiological outcome measures and the application of artificially induced cortical stimulation plasticity paradigms to study the effects of disease-causing human genetic mutations. In the subsequent introductory chapters I have focused on the rationale of selecting the Brain Derived Neurotrophic Factor polymorphism Rs6265 (BDNF Val66 Met) as the candidate polymorphism for our studies, covering the molecular biology and physiological roles of this highly conserved protein, and with a particular focus on its diverse roles in neuroplasticity. The 1st experiment presented here used established rTMS and TDCS paradigms to probe the effects of the BDNF Val66Met SNP on cortical plasticity and metaplasticity. The results generated from this study, and particularly the results suggesting an effect on metaplasticity, formed the basis for the studies in patients. We investigated the influence of this SNP on the rate of onset of Levodopa-Induced Dyskinesia (LID) in patients with Parkinson's disease and on the penetrance of DYT1 Dystonia. The final experiment presented here was designed to confirm the effects of the BDNF Val66Met polymorphism on the iTBS paradigm, and quantify its effects alongside other variables thought to influence the response to rTMS paradigms. This study also provides some crucial insights into the iTBS paradigm itself.

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