The use of biomarkers in Alzheimer’s disease (AD) has been fundamental for early diagnosis. Currently, biomarkers in use for clinical purposes assess the presence or quantify molecular markers of the disease, i.e., ß-amyloid or Tau protein, or quantify the medial-temporal atrophy caused by the disease. Neuroimaging techniques such as structural, functional and diffusion magnetic resonance imaging and positron-emission tomography have been essential in showing how Alzheimer’s disease pathology spreads within resting-state networks, ultimately impairing their functioning. However, neuroimaging techniques provide indirect measures that do not capture the physiological status of the affected cerebral tissues. Neurophysiological techniques, such as transcranial magnetic stimulation (TMS) and electroencephalography (EEG), are established techniques that can be used in combination to capture both the status of a target cortex and its connections through the brain through TMS-evoked potentials (TEPs). Therefore, TEPs have gained momentum as a possible novel AD biomarker. In the last decade, a specific five-phase framework for the development of novel AD biomarkers has been developed, with the goal of standardizing the steps needed to bring a measure from research to clinical practice. Phase 1 for TEPs, concerning the rationale of using them as a biomarker in AD, could be considered completed, while most of the research is now focusing on phase 2. In this phase, the ability of a measure to distinguish between healthy elderly individuals and AD patients is assessed, together with the reliability and replicability of the measure. In this thesis, we address several aims of phase 2 by testing whether early TEP responses could be used to differentiate between healthy elderly, prodromal, late-onset, and early-onset AD. Then, we test the sensitivity of TEPs to different preprocessing pipelines to assess their robustness. Third, we review the current literature on TEP reliability and describe which tests are missing for this measure to enter clinical practice. Finally, we propose a tool to promote replicability in noninvasive brain stimulation paradigms, such as TMS–EEG. We conclude that despite a solid rationale for the employment of TEPs in clinical practice, several methodological issues need to be addressed before TEPs can gain clinical utility.

Ce travail précise le rôle du cervelet dans la physiopathologie de la dystonie. Nous étudions comment le cervelet contrôle le développement et l’étendue de la plasticité sensorimotrice, celle-ci étant anormale dans la dystonie. Nous démontrons l’implication du cervelet dans la dystonie en constatant des performances anormales à une tâche d’adaptation sensorimotrice dépendant du cervelet. (Hubsch et al., 2011) Puis chez des sujets sains, en utilisant des techniques d’induction de plasticité cérébrale nous démontrons que le cervelet module la plasticité corticale reposant sur des afférences sensorielles. Ainsi, une inhibition du cortex cérébelleux amplifie la réponse du cortex à un protocole d’induction de plasticité sensorimotrice, une excitation du cortex cérébelleux bloque la réponse du cortex à ce protocole. (Popa et al., 2013) Avec les mêmes méthodes, nous étudions le rôle du cervelet dans la modulation de la plasticité du cortex sensori-moteur chez des sujets atteints de dystonie focale. Dans la crampe de l’écrivain, le cervelet n’exerce plus ce rôle modulateur de la plasticité sensorimotrice: il n’y a ni inhibition ni renforcement du phénomène de plasticité induit par une modulation des sorties cérébelleuses. (Hubsch et al., 2013)Dans la dystonie cervicale, il persiste une modulation de la plasticité sensorimotrice par le cervelet mais cette modulation a une direction opposée par rapport aux sujets sains contrôles. Par des expériences complémentaires, nous démontrons que le contrôle cérébelleux sur la plasticité corticale sensorimotrice est adaptatif aux afférences proprioceptives de la nuque possiblement en rapport avec la construction de l’espace égocentré. / This study specifies the role of the cerebellum in the physiopathology of dystonia. We study how the cerebellum controls the development and the extent of sensorimotor plasticity, this one being abnormal in dystonia. We show the implication of the cerebellum in dystonia by noting abnormal performances with a task of sensorimotor adaptation depending on cerebellum. (Hubsch and al., 2011) Then with healthy subjects, by using techniques of cerebral plasticity’s induction we show that the cerebellum modulates cortical plasticity depending on sensory afferents. Thus, an inhibition of the cerebellar cortex amplifies the response of the cortex to a protocol of induction of sensorimotor plasticity, an excitation of the cerebellar cortex blocks the response of the cortex to this protocol. (Popa and al., 2013) With the same methods, we study the role of the cerebellum in the modulation of the plasticity of the sensorimotor cortex with dystonic subjects. In writer's cramp, the cerebellum does not exert any more this modulating role of sensorimotor plasticity: there is neither inhibition nor reinforcement of the phenomenon of plasticity induced by a modulation of the cerebellar outputs. (Hubsch and al., 2013) In the cervical dystonia, it persists a modulation of sensorimotor plasticity by the cerebellum but this modulation has a direction opposed compared to the healthy subjects. By complementary experiments, we show that cerebellar control on cortical sensorimotor plasticity is adaptive with the proprioceptive afferents of the neck possibly in keeping with the construction of egocentric space.

Simulation of the electromagnetic response of the human body relies heavily upon efficient computational CAD models or phantoms. The Visible Human Project (VHP)-Female v. 3.1 - a new platform-independent full-body electromagnetic computational model is revealed. This is a part of a significant international initiative to develop powerful computational models representing the human body. This model’s unique feature is full compatibility both with MATLAB and specialized FEM computational software packages such as ANSYS HFSS/Maxwell 3D and CST MWS. Various mesh processing algorithms such as automatic intersection resolver, Boolean operation on meshes, etc. used for the development of the Visible Human Project (VHP)-Female are presented. The VHP - Female CAD Model is applied to two specific low frequency applications: Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS). TMS and tDCS are increasingly used as diagnostic and therapeutic tools for numerous neuropsychiatric disorders. The development of a CAD model based on an existing voxel model of a Japanese pregnant woman is also presented. TMS for treatment of depression is an appealing alternative to drugs which are teratogenic for pregnant women. This CAD model was used to study fetal wellbeing during induced peak currents by TMS in two possible scenarios: (i) pregnant woman as a patient; and (ii) pregnant woman as an operator. An insight into future work and potential areas of research such as a deformable phantom, implants, and RF applications will be presented.

No description available.

Long-term motor skill learning has been consistently shown to result in functional as well as structural changes in the adult human brain. However, the effect of short learning periods on brain structure is not well understood. In the present study, subjects performed a sequential pinch force task (SPFT) for 20 min on 5 consecutive days. Changes in brain structure were evaluated with anatomical magnetic resonance imaging (MRI) scans acquired on the first and last day of motor skill learning. Behaviorally, the SPFT resulted in sequence-specific learning with the trained (right) hand. Structural gray matter (GM) alterations in left M1, right ventral premotor cortex (PMC) and right dorsolateral prefrontal cortex (DLPFC) correlated with performance improvements in the SPFT. More specifically we found that subjects with strong sequence-specific performance improvements in the SPFT also had larger increases in GM volume in the respective brain areas. On the other hand, subjects with small behavioral gains either showed no change or even a decrease in GM volume during the time course of learning. Furthermore, cerebellar GM volume before motor skill learning predicted (A) individual learning-related changes in the SPFT and (B) the amount of structural changes in left M1, right ventral PMC and DLPFC. In summary, we provide novel evidence that short-term motor skill learning is associated with learning-related structural brain alterations. Additionally, we showed that practicing a motor skill is not exclusively accompanied by increased GM volume. Instead, bidirectional structural alterations explained the variability of the individual learning success.

Blindsight is a phenomenon in which patients suffering damage to the primary visual cortex (V1) perceive themselves as blind, but nonetheless seem to have some residual capacity to distinguish between visual stimuli better than chance. Blindsight can be divided into two subtypes: blindsight type I and blindsight type II. Blindsight type I is defined as visual capacity in the absence of acknowledged awareness. Patients with blindsight type II have visual capacity with some feeling or sensation in the blind field. Visual pathways bypassing V1 are assumed to be responsible for the residual capacity in blindsight. To investigate whether these pathways are present in healthy individuals we examined if it is possible to induce blindsight in healthy individuals by reviewing studies that have tried to induce blindsight with transcranial magnetic stimulation (TMS). We found that TMS might be able to induce blindsight type I of side detection. We also found that TMS might be able to induce blindsight type II of colour, orientation, and trustworthiness. Further, we found that both conscious and unconscious perception of shapes are dependent on processing in early visual cortex (EVC) in healthy individuals. We conclude that the full capacity seen in blindsight is most probable caused by neural reorganisation post trauma. The visual pathways bypassing V1 are, if present in healthy individuals, too weak to influence behaviour with the possible exception of side detection. Additionally, we conclude that the use of a binary awareness scale in blindsight studies fails to capture vaguely seen stimuli.

Sensorimotor integration refers to the process of combining incoming sensory information with outgoing motor commands to control movement. Short-Latency Afferent Inhibition (SAI), Long-Latency Afferent Inhibition (LAI) and Afferent Facilitation (AF) are three neurophysiological measures collected using Transcranial Magnetic Stimulation (TMS) to assess sensorimotor integration in humans. No studies to date have investigated the influence of tactile discrimination training on these measures. This study aimed to determine whether SAI, LAI, and AF are modulated following training on a custom-designed sensorimotor task which required participants to use their sense of touch to successfully navigate 3D printed maze with interchangeable paths. The maze training was separated into “high difficulty” and “low difficult” conditions which reflected the tactile challenge embedded within the maze. On an additional visit, no maze training was performed to serve as a control condition. Despite evidence of performance improvements during training, there were no significant changes in SAI, LAI or AF following training in either condition. Further, there was no correlation between the % change in SAI/LAI and improvements in total dwell time on the maze. As the functional significance of these measures is still unclear, these findings suggest that changes in SAI, LAI or AF may not be a valid metric to measure meaningful or functional changes related to skills or performance improvements induced by training. / Thesis / Master of Science in Kinesiology / Sensorimotor integration refers to the combination of incoming sensory information with outgoing motor commands in the nervous system to control movement. Short- Latency Afferent Inhibition, Long-Latency Afferent Inhibition and Afferent Facilitation are three measures that probe sensorimotor integration in humans using Transcranial Magnetic Stimulation. Although these measures have been well studied in both healthy and clinical populations in a variety of contexts, the influence of sensorimotor training on these measures remains unclear. This thesis aimed to determine if SAI, LAI and AF change following training on a novel tactile discrimination maze task. Further, the relationship between changes in sensorimotor integration and improvements in maze performance was explored. SAI, LAI and AF were not shown to be influenced by training, and there was no association between the changes in these measures and improvements in maze performance.

Evidence indicates attention can alter afferent inhibition, a Transcranial Magnetic Stimulation (TMS) evoked measure of cortical inhibition following somatosensory input. This measure is emerging as a valuable tool for clinical assessment of sensorimotor function. However, the reliability of the measure remains relatively low. Further, attention is capable of modifying the magnitude of afferent inhibition. Therefore, for afferent inhibition to become an assessment with translation within and beyond the research lab, the reliability of the measure must be improved. Controlling the focus of attention may be one method to improve the reliability of afferent inhibition. In the present study, two experiments were conducted. One to assess the biological effects of attention on SAI and LAI, and the other to address whether the reliability of SAI and LAI are altered in the presence of varying attentional demands. The magnitude of short- and long-latency afferent inhibition (SAI and LAI, respectively) was assessed under four conditions with varying attentional demands focused on the somatosensory input that mediates SAI and LAI circuits. Further, the reliability of SAI and LAI was assessed with and without directed attention to the relevant somatosensory input to explore whether attention to the tactile stimulation can improve intrasession and intersession reliability of these measures. Thirty individuals participated in four conditions; three conditions were identical in their physical parameters and varied only in the focus of directed attention (visual attend, tactile attend, non- directed attend) and one condition consisted of no external physical parameters (no stimulation). Reliability was measured by repeating conditions at three time points to assess intrasession and intersession reliability. Results indicate the magnitude of SAI and LAI were not modulated by varied attention. Reliability assessments demonstrated that the attention manipulations increased intrasession and intersession reliability of SAI and LAI compared to the no stimulation condition. This research exposes the influence of attention, and its impact on the reliability of afferent inhibition. By quantifying these influences, this research has identified new information to inform the design of TMS research in sensorimotor integration. / Thesis / Master of Science in Kinesiology / Attention can alter transcranial magnetic stimulation (TMS) evoked afferent inhibition. Measures of afferent inhibition are emerging as valuable tools for clinical assessments of sensorimotor function. However, the reliability of afferent inhibition remains relatively low, limiting its value in the clinic. Afferent inhibition is increased when the one’s attention is focused on the peripheral nerve stimulation used to elicit afferent inhibition. However, it is unknown whether afferent inhibition, with attention directed to somatosensory input, will improve the reliability of these measures. This is important as it suggests that changes to the methodology used to acquire afferent inhibition can improve the reliability of this measure, thereby increasing the opportunity for translation to the clinic. The goal of this study was to assess the influence of attention on afferent inhibition circuits, short afferent inhibition (SAI) and long afferent inhibition (LAI) and determine whether attention modulation would increase the reliability of afferent inhibition.

Despite a rise in the use of “learning by doing” pedagogical methods in praxis, little is known as to how the brain benefits from these methods. Learning by doing strategies that utilize complementary information (“enrichment”) such as gestures have been shown to optimize learning outcomes in several domains including foreign language (L2) training. Here we tested the hypothesis that behavioral benefits of gesture-based enrichment are critically supported by integrity of the biological motion visual cortices (bmSTS). Prior functional neuroimaging work has implicated the visual motion cortices in L2 translation following sensorimotor-enriched training; the current study is the first to investigate the causal relevance of these structures in learning by doing contexts. Using neuronavigated transcranial magnetic stimulation and a gesture-enriched L2 vocabulary learning paradigm, we found that the bmSTS causally contributed to behavioral benefits of gesture-enriched learning. Visual motion cortex integrity benefitted both short- and long-term learning outcomes, as well as the learning of concrete and abstract words. These results adjudicate between opposing predictions of two neuroscientific learning theories: While reactivation-based theories predict no functional role of specialized sensory cortices in vocabulary learning outcomes, the current study supports the predictive coding theory view that these cortices precipitate sensorimotor-based learning benefits.:I. Abkürzungsverzeichnis II. Abbildungsverzeichnis III. Einleitung 1. Fremdsprachenlernen 1.1 Sensorische Modalitätsvergleiche 1.2 Sensomotorisches Lernen 2. Lerntheorien 2.1 Theorie des prädiktiven Kodierens 2.2 Theorie des prädiktiven Kodierens für multisensorisches Lernen 3. Sulcus temporalis superior für biologische Bewegung 4. Transkranielle Magnetstimulation 4.1 Passagere Funktionsinhibition mittels transkranieller Magnetstimulation IV. Ableitung der Rationale V. Publikationsmanuskript VI. Zusammenfassung VII. Literaturverzeichnis VIII. Appendix A. Abbildungen B. Ergänzendes Material der Publikation C. Darstellung des eigenen Beitrags D. Erklärung über die eigenständige Abfassung der Arbeit E. Lebenslauf F. Publikationen G. Danksagung

Resting-state functional MRI(rs-fMRI) represents a powerful means to assess brain functional connectivity in healthy subjects and in neuropsychiatric patients. Aberrant functional connectivity has been observed in subjects affected by Alcohol Use Disorders (AUD) and other forms of substance dependence, a major health issue worldwide with limited treatment options. Despite intense investigation, the specific neuronal substrates involved and the functional implications of aberrant connectivity in these patients remain unknown. Moreover, it is unclear whether treatment can reverse these alterations, and normalize functional connectivity. Several methodological and conceptual questions in the analysis of functional connectivity are still open, and contribute to this uncertainty. Functional connectivity is defined in terms of correlated MR-signal fluctuations, and in-scanner patient motion and other nuisance signals can introduce spurious correlations, thus representing substantial confounding factors. At a more general level, understanding the effects of complex conditions, like AUD, on brain connectivity and their functional implications requires a deep comprehension of the brain organizational principles at multiple scales, a tremendous challenge that is at the heart of modern neuroscience. In this PhD dissertation I address some of the outstanding questions in the analysis and interpretation of aberrant functional connectivity in AUD. To this end, I have embraced the formalism of graph-theory, a powerful framework to assess the effects of alcohol abuse on the local and global topological organization of resting state connectivity. On the methodological side, I have investigated the effects of subject’s motion on the structure of resting state networks, and compared efficacy of different approaches to remove motion-related confounds. Moreover, I demonstrate the importance of network sparsification to remove spurious connections from the graph while maximizing the structural information that can be extracted from the system. Leveraging these methodological developments, I have evaluated functional alterations in different samples of AUD patients. In two independent studies, I demonstrated specific alterations in the topological organization of the insular cortex and subcortical basal structures in recently detoxified alcoholics. Interestingly, protracted abstinence appears to partially normalize functional connectivity, thus suggesting that alcohol-induced alterations in connectivity may be amenable to treatment. Based on these findings, I have studied the effects on brain functional networks of a putative novel treatment based on deep Transcranial Magnetic Stimulation (TMS). Specifically, I analyzed resting state connectivity in AUD patients subjected to repetitive TMS of the bilateral insula and of the anterior cingulate cortex (ACC), and demonstrated treatment-induced changes that may underlie the efficacy of this potential treatment in surrogate clinical read-outs.