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7Tel: +45 3862 6541; Email: hartwig.siebner@drcmr.dk; http://www.drcmr.dk/siebner 2 8All rights reserved. No reuse allowed without permission.was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/337782 doi: bioRxiv preprint first posted online Jun. 4, 2018; 2 Abstract (246 words) 2 9Transcranial Magnetic Stimulation (TMS) excites populations of neurons in the stimulated cortex, and the 3 0 resulting activation may spread to connected brain regions. The distributed cortical response can be 3 1 recorded with electroencephalography (EEG). Since TMS also stimulates peripheral sensory and motor 3 2 axons and generates a loud "click" sound, the TMS-evoked EEG potential (TEP) not only reflects neural 3 3 activity induced by transcranial neuronal excitation but also neural activity reflecting somatosensory and 3 4 auditory processing. In 17 healthy young individuals, we systematically assessed the contribution of 3 5 multisensory peripheral stimulation to TEPs using a TMS-compatible EEG system. Real TMS was 3 6 delivered with a figure-of-eight coil over the left para-median posterior parietal cortex or superior frontal 3 7 gyrus with the coil being oriented perpendicularly or in parallel to the target gyrus. We also recorded the 3 8 EEG responses evoked by sham stimulation over the posterior parietal and superior frontal cortex, 3 9 mimicking the auditory and somatosensory sensations evoked by real TMS. We applied state-of-the-art 4 0 procedures to attenuate somatosensory and auditory confounds during real TMS, including the placement 4 1 of a foam layer underneath the coil and auditory noise masking. Despite these precautions, the temporal 4 2 and spatial features of the cortical potentials evoked by real TMS at the prefrontal and parietal site closely 4 3 resembled the cortical potentials evoked by realistic sham TMS, both for early and late TEP components. 4Our findings stress the need to include a peripheral multisensory control stimulation in the study design to 4 5 enable a dissociation between truly transcranial and non-transcranial components of TEPs. 4 6 4 7All rights reserved. No reuse allowed without permission.was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

IntroductionTraumatic brain injury (TBI) is considered one of the most pervasive causes of disability in people under the age of 45. TBI often results in disorders of consciousness, and clinical assessment of the state of consciousness in these patients is challenging due to the lack of behavioural responsiveness. Functional neuroimaging offers a means to assess these patients without the need for behavioural signs, indicating that brain connectivity plays a major role in consciousness emergence and maintenance. However, little is known regarding how changes in connectivity during recovery from TBI accompany changes in the level of consciousness. Here, we aim to combine cutting-edge neuroimaging techniques to follow changes in brain connectivity in patients recovering from severe TBI.Methods and analysisA multimodal, longitudinal assessment of 30 patients in the subacute stage after severe TBI will be made comprising an MRI session combined with electroencephalography (EEG), a positron emission tomography session and a transcranial magnetic stimulation (TMS) combined with EEG (TMS/EEG) session. A group of 20 healthy participants will be included for comparison. Four sessions for patients and two sessions for healthy participants will be planned. Data analysis techniques will focus on whole-brain, both data-driven and hypothesis-driven, connectivity measures that will be specific to the imaging modality.Ethics and disseminationThe project has received ethical approval by the local ethics committee of the Capital Region of Denmark and by the Danish Data Protection. Results will be published as original research articles in peer-reviewed journals and disseminated in international conferences. None of the measurements will have any direct clinical impact on the patients included in the study but may benefit future patients through a better understanding of the mechanisms underlying the recovery process after TBI.Trial registration number: NCT02424656; Pre-results.