Nettekoven, Charlotte Maria (2015). Imaging cortical plasticity in the human motor system. PhD thesis, Universität zu Köln.


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Intermittent theta-burst stimulation (iTBS) is a novel form of repetitive transcranial magnetic stimulation (rTMS) inducing increases in cortical excitability that last beyond stimulation. Compared to conventional rTMS protocols iTBS induces strong and long-lasting aftereffects with shorter stimulation time and less stimulation intensity. However, mechanisms underlying iTBS-induced aftereffects as well as factors contributing to a high inter-individual variability between subjects are still poorly understood. The aim of the present study was to gain some new insights into these mechanisms by combining non-invasive brain stimulation with neuroimaging and connectivity analyses of the human motor system. Previous studies suggested a link between rTMS aftereffects and activity as well as connectivity of the stimulated region. However, the mechanisms underlying iTBS-induced plasticity on the systems level are still incompletely understood. Hence, the aim of the first study of the present thesis was to investigate how neural activity and connectivity of the motor system are related to aftereffects of iTBS. Therefore, 12 healthy, right-handed volunteers underwent functional magnetic resonance imaging (fMRI) during rest (resting-state fMRI, rs-fMRI) and while performing a simple hand motor task. Based on this data, resting-state functional connectivity (rsFC) and task-induced activation as well as task-related effective connectivity were assessed. In separate sessions, aftereffects of iTBS applied over the left, primary motor cortex (M1) and the parieto-occipital vertex (sham) were tested for up to 25 min by measuring motor-evoked potentials (MEPs). High MEP increases post stimulation correlated with low movement-induced blood oxygenation level dependent (BOLD) activity in the stimulated M1. MEP changes also correlated positively with the effective connectivity between M1 and different premotor regions. However, no correlation could be found for rsFC. Therefore, our data suggest that changes in cortical plasticity induced by iTBS not only depend on local properties of the stimulated region, but also on activity-dependent properties of the cortical motor system. Furthermore, different studies recently aimed at enhancing iTBS aftereffects by increasing the dose. However, no additive aftereffects could be observed. This may result from the incomplete understanding of the mechanisms underlying the dose-dependent induction of cortical plasticity in humans. The second study, therefore, aimed at investigating the dose-dependency of iTBS aftereffects by applying multiple stimulation blocks within a short time-interval. Possible mechanisms underlying cortical plasticity should be revealed by combining iTBS with connectivity analyses of the motor system. 16 healthy, right-handed subjects received three serially applied blocks of iTBS with an interstimulus-interval of 15 min. Each subject underwent M1- and sham-iTBS in two separate sessions. Aftereffects were tested on both MEP amplitudes as well as rsFC leading to a total of four sessions: M1-iTBS_MEPs, sham-iTBS_MEPs, M1_rs-fMRI, sham_rs-fMRI. For the first time, a dose-dependent buildup of aftereffects after the third block could be found both on the local level (MEPs) as well as on the systems level (rsFC). These increases in MEP amplitudes and rsFC were not linearly correlated, thus, possibly representing two parallel mechanisms underlying iTBS-induced plasticity. Of note, similar dose-dependent alterations of cortical protein expression of distinct subgroups of GABAergic inhibitory interneurons were observed following multiple iTBS blocks in an animal model. Hence, possibly suggesting a similar mechanism to be involved in iTBS aftereffects in humans. Recently, a considerable number of studies addressing the variability of TBS aftereffects reported strong variations across subjects often resulting in no overall effects on the group level. The reasons for this variability remain poorly understood. Moreover, the question arises whether non-responders to iTBS can be turned into responders by increasing the dose. Therefore, in the third study, the data of the second study were re-analyzed with respect to the individual susceptibility to iTBS. Subjects were grouped into responders (n=7) and non-responders (n=9) according to their increase in MEP amplitudes after one iTBS block. When taking the individual responsiveness to iTBS into account a higher rsFC between M1 and premotor areas before stimulation could be found for non-responders compared to responders. Interestingly, non-responders to iTBS after one block could not be turned into responders by increasing the dose, i.e., applying a second or third block of iTBS. In contrast, responders after one block of iTBS featured a dose-dependent increase in MEP amplitudes as well as rsFC after all three iTBS blocks. Hence, our data suggest that responsiveness to iTBS at the local level (i.e., M1 excitability) is related to the capability of modulating network connectivity of the stimulated region (i.e., motor network). A ceiling effect at the systems level might underlie non-responsiveness to iTBS since higher levels of pre-interventional connectivity precluded a further increase upon iTBS. Taken together, the findings of the present thesis add to the understanding of the mechanisms underlying iTBS aftereffects as well as the factors contributing to the high inter-individual variability. Furthermore, our data might help to improve the usefulness of iTBS in both basic research and as a therapeutic intervention.

Item Type: Thesis (PhD thesis)
CreatorsEmailORCIDORCID Put Code
Nettekoven, Charlotte Mariacharlottenettekoven@gmail.comUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-62609
Date: 2015
Language: English
Faculty: Faculty of Mathematics and Natural Sciences
Divisions: Ehemalige Fakultäten, Institute, Seminare > Faculty of Mathematics and Natural Sciences > no entry
Subjects: Life sciences
Medical sciences Medicine
Uncontrolled Keywords:
TMS, fMRI, dose, plasticity, motor systemEnglish
Date of oral exam: 23 June 2015
NameAcademic Title
Grefkes, ChristianProf. Dr.
Büschges, AnsgarProf. Dr.
Refereed: Yes


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