Introduction: The brain can change its structure and functionality as a result ofexternal factors. The working memory (WM) of the brain is where informationcan be held and manipulated during a short period of time, with the purpose ofachieving higher cognitive functions such as reasoning and learning. The WMimproves in capacity during the development from childhood into adulthood,and variation of improvement is possible as an effect of situational factors andstimuli.Goal: The main goal of this project was to examine the effects of a WMtraining program on power distribution, connectivity and synchronicity withinbrain networks, using an intra-individual analysis approach.Method: A series of magnetoencephalography (MEG) measurements wasacquired for four subjects while they were performing WM and control tasks,during a WM training program, along with an MRI image of the brain for eachof the participants. The data was preprocessed for noise and artifact removaland a source reconstruction was performed. Time-frequency representationsof the data were created and the frequencies were categories into alpha,beta and gamma bands. The power difference between the WM and controltask was calculated as a function of cognitive load of each frequency band,and its variation over load was calculated as a constructed metric called’area under power difference curve’ (AUPDC), and visualised using colourscale representation upon the brain MRI of each subject. Brain parcels thatsignificantly deviated from a random distribution of AUPDC values wereidentified using a Gaussian distribution fit.Results and discussion: All subjects showed a clear improvement inperformance accuracy of the tasks, but as the effect on the power distributionsvaried considerably for each subject and frequency band, other aspects besidepower need to be investigated in order to understand the mechanisms behindthe improvement. However, the overall results indicate that many significantAUPDC values seem to have decreased during the WM training, both forthe positive and negative significant AUPDC values, suggesting a strongerdecreasing trend in power difference over cognitive load and a weaker increasingtrend. This could suggest an improved brain activation efficiency as an effectof the WM training.

Current neurobiological models of adolescent decision-making suggest that heightened risk taking during adolescence is a result of the asynchronous development of neural regions underlying cognitive control and reward processing, particularly during periods of heightened social and affective arousal (e.g., Casey, Getz, & Galván, 2008; Steinberg, 2008). Despite the emphasis on the interplay of cognitive and emotional processes during adolescence, the developmental literature has largely overlooked the potential importance of maturational changes in the anterior insular cortex (AIC), a region known for its role as a cognitive-emotional hub. In a recent review we proposed a theory of adolescent risk-taking in which development of the AIC, and its connectivity to other regions, biases adolescents towards engagement in risky behaviors (Smith, Steinberg, & Chein, 2014b). The current studies provide a test of the proposed model through an examination of specific aspects of AIC development and functioning, including the trajectory of structural development within the AIC, the role of AIC engagement in adolescents' risky decision-making, and the impacts of affective arousal on AIC recruitment. Results from Study 1 suggest that the AIC exhibits continued developmental changes during adolescence that likely affect its involvement in cognitive processes. Using a risk-taking task, Study 2 demonstrates the flexible role of the AIC during adolescent decision-making and explores how affective arousal biases the AIC towards engagement in risky behaviors. Implications for both the proposed model and the developmental literature are discussed. / Psychology

Neurosurgery is a demanding medical discipline that requires a complex interplay of several neuroimaging techniques. This allows structural as well as functional information to be recovered and then visualized to the surgeon. In the case of tumor resections this approach allows more fine-grained differentiation of healthy and pathological tissue which positively influences the postoperative outcome as well as the patient's quality of life. In this work, we will discuss several approaches to establish thermal imaging as a novel neuroimaging technique to primarily visualize neural activity and perfusion state in case of ischaemic stroke. Both applications require novel methods for data-preprocessing, visualization, pattern recognition as well as regression analysis of intraoperative thermal imaging. Online multimodal integration of preoperative and intraoperative data is accomplished by a 2D-3D image registration and image fusion framework with an average accuracy of 2.46 mm. In navigated surgeries, the proposed framework generally provides all necessary tools to project intraoperative 2D imaging data onto preoperative 3D volumetric datasets like 3D MR or CT imaging. Additionally, a fast machine learning framework for the recognition of cortical NaCl rinsings will be discussed throughout this thesis. Hereby, the standardized quantification of tissue perfusion by means of an approximated heating model can be achieved. Classifying the parameters of these models yields a map of connected areas, for which we have shown that these areas correlate with the demarcation caused by an ischaemic stroke segmented in postoperative CT datasets. Finally, a semiparametric regression model has been developed for intraoperative neural activity monitoring of the somatosensory cortex by somatosensory evoked potentials. These results were correlated with neural activity of optical imaging. We found that thermal imaging yields comparable results, yet doesn't share the limitations of optical imaging. In this thesis we would like to emphasize that thermal imaging depicts a novel and valid tool for both intraoperative functional and structural neuroimaging.

Neurosurgery is a demanding medical discipline that requires a complex interplay of several neuroimaging techniques. This allows structural as well as functional information to be recovered and then visualized to the surgeon. In the case of tumor resections this approach allows more fine-grained differentiation of healthy and pathological tissue which positively influences the postoperative outcome as well as the patient's quality of life. In this work, we will discuss several approaches to establish thermal imaging as a novel neuroimaging technique to primarily visualize neural activity and perfusion state in case of ischaemic stroke. Both applications require novel methods for data-preprocessing, visualization, pattern recognition as well as regression analysis of intraoperative thermal imaging. Online multimodal integration of preoperative and intraoperative data is accomplished by a 2D-3D image registration and image fusion framework with an average accuracy of 2.46 mm. In navigated surgeries, the proposed framework generally provides all necessary tools to project intraoperative 2D imaging data onto preoperative 3D volumetric datasets like 3D MR or CT imaging. Additionally, a fast machine learning framework for the recognition of cortical NaCl rinsings will be discussed throughout this thesis. Hereby, the standardized quantification of tissue perfusion by means of an approximated heating model can be achieved. Classifying the parameters of these models yields a map of connected areas, for which we have shown that these areas correlate with the demarcation caused by an ischaemic stroke segmented in postoperative CT datasets. Finally, a semiparametric regression model has been developed for intraoperative neural activity monitoring of the somatosensory cortex by somatosensory evoked potentials. These results were correlated with neural activity of optical imaging. We found that thermal imaging yields comparable results, yet doesn't share the limitations of optical imaging. In this thesis we would like to emphasize that thermal imaging depicts a novel and valid tool for both intraoperative functional and structural neuroimaging.

L’objectif de cette thèse a été de comprendre les mécanismes cérébraux associés aux symptômes du trouble de stress post-traumatique (TSPT), ainsi que les mécanismes cérébraux modulés par la disparition des symptômes, en utilisant la thérapie de désensibilisation et de retraitement de l’information par les mouvements oculaires (Thérapie EMDR). Cette thérapie associe rappel du traumatisme et stimulations bilatérales alternées (SBA). Premièrement, en utilisant l’IRM fonctionnelle (IRMf), nous avons mis en évidence une altération de l’activité fonctionnelle du système de récompense dans le TSPT, correspondant à une mobilisation déséquilibrée des processus motivationnels cognitifs et hédoniques (étude 1). Deuxièmement, par l’intermédiaire d’une étude en IRMf au repos, nous avons montré que les patients présentent des altérations de connectivité fonctionnelle entre un réseau neuronal impliqué dans les processus mnésiques et émotionnels, et un réseau neuronal impliqué dans les processus attentionnels (étude 2). Troisièmement, nous avons montré que les structures initialement altérées par la pathologie évoluent après rémission symptomatique, suggérant un rétablissement des altérations neuronales induites par le stress chronique (étude 3). Enfin, nous avons montré que les SBA employées dans la thérapie EMDR facilitent l’extinction de la peur ainsi que la récupération de cette extinction au sein d’un groupe de volontaires sains (étude 4). Ainsi, ces travaux offrent de nouvelles perspectives en termes de modélisation de la pathologie, et offre de nouvelles pistes de réflexion quant à la prise en charge thérapeutique de ce trouble. / Posttraumatic Stress Disorder (PTSD) is a debilitating psychiatric disorder that arises in the aftermath of a traumatic event. To date, the Eye Movement Desensitization and Reprocessing therapy (EMDR) therapy has shown to be the most efficient therapy for the treatment of PTSD. The aim of this thesis was therefore to understand neural mechanisms underlying PTSD and its recovery. To do so, we conducted four studies. In a first study, we showed alterations in the reward circuit activity in PTSD patients, which may underlie an imbalance mobilization of cognitive and hedonic motivational processes, possibly contributing to emotional numbing in PTSD (study 1). Following this, an altered resting state functional connectivity between a network associated with attentional processes and another associated with emotional and memory processes was also found, suggesting an atypical emotional regulation and attention processing (study 2). A third study showed changes of grey matter density in regions involved in emotional regulation after symptoms remission by EMDR therapy. Finally, we were also able to replicate, in PTSD patients, the fear extinction and fear extinction recall facilitation by bilateral alternating stimulations (BAS) a major component of EMDR therapy, previously demonstrated in animal studies. Taken together, the present findings of these studies contribute to enlarge our knowledge, opening new ways of thinking the actual model of explaining the PTSD. More importantly, we believe that our findings may contribute to improve therapeutic strategies to significantly ameliorate the life of these patients.

The temporal specificity of functional magnetic resonance imaging (fMRI) is limited by a sluggish and locally variable hemodynamic response trailing the neural activity by seconds. Here, we demonstrate for an attention capture paradigm that it is, never the less, possible to extract information about the relative timing of regional brain activity during cognitive processes on the scale of 100 ms by comparing alternative signal models representing early versus late activation. We demonstrate that model selection is not driven by confounding regional differences in hemodynamic delay. We show, including replication, that the activity in the dorsal anterior insula is an early signal predictive of behavioral performance, while amygdala and ventral anterior insula signals are not. This specific finding provides new insights into how the brain assigns salience to stimuli and emphasizes the role of the dorsal anterior insula in this context. The general analytic approach, named “Cognitive Timing through Model Comparison” (CTMC), offers an exciting and novel method to identify functional brain subunits and their causal interactions.

Chronic neuropathic pain affects up to 8% of the United Kingdom population and is a difficult condition to manage. It is established and maintained through many mechanisms, including central sensitisation (CS) in the spinal cord and brainstem. Neuropathic pain manifests as spontaneous pain, sensory loss and evoked hypersensitivity. The development of novel treatments for neuropathic pain is challenging, in part due to inadequate experimental models of clinically relevant pain. The use of functional magnetic resonance imaging (fMRI) techniques for imaging acute and increasingly tonic states enables the assessment of the neural correlates of evoked hypersensitivity and persistent pain, with the goal of developing appropriate biomarkers to test new therapies. This thesis develops novel techniques for the assessment of ongoing pain states and their modulation by therapies. We first identified a suitable human experimental model of CS using topical capsaicin, and an fMRI pipeline for the investigation of supraspinal involvement in pain hypersensitivity. In a placebo-controlled study, we then demonstrated the improved sensitivity of fMRI above subjective reports in detecting the efficacy of a known analgesic as compared to an ineffective active compound in a small cohort. To translate this to the more clinically relevant symptom of spontaneous pain, we developed and validated the use of a multi-inversion time pseudo-continuous arterial spin labelling (ASL) imaging and analysis pipeline for the neural assessment of tonic states and the absolute quantification of cerebral blood flow (CBF). Current evidence from structural and functional studies suggests a direct role for the posterior insula cortex in the encoding of nociception and pain. Using the ASL pipeline, we found that only a CBF change in the posterior insula region was correlated with the changing perception of persistent capsaicin-induced pain, and in a separate experiment showed that suppression of CBF in this region by gabapentin was related to the drug's suppression of subjective pain perception. We also demonstrated in a cohort of phantom limb patients that pain relief resulting from transcranial direct current stimulation of the deprived sensorimotor cortex is neurally represented by a decrease in posterior insula CBF. In a separate study, we showed that baseline CBF in the periaqueductal grey can predict individuals who are most vulnerable to pain and hypersensitivity following the induction of capsaicin-related CS. Taken together, these findings suggest that fMRI can be used as a tool to assess the efficacy of established and novel analgesics, with the midbrain reticular formation and posterior insula cortex being prime candidates as biomarkers of CS mechanisms and persistent pain respectively. Relatedly, ASL-fMRI may also be an effective technique for evaluating individuals' susceptibility to pain following inflammation or injury.

Associative plasticity, which involves modification of synaptic strength by coactivation of two synaptic inputs, has been demonstrated in many species. Here I explore whether it is possible to induce associative plasticity within a corticocortical pathway in the human brain using a novel protocol that activates two brain areas repeatedly with double-site transcranial magnetic stimulation (TMS). The pathway between ventral premotor cortex (PMv) and primary motor cortex (M1) which computes hand movements for precision grasp was manipulated. First, I selectively potentiated physiological connectivity between the stimulated brain areas. The effects as assessed with paired-pulse TMS were in accordance with principles of spike timing-dependent plasticity (STDP), pathwayspecific and showed a different pattern of expression during rest and during performance of a naturalistic prehension task. Furthermore, I demonstrated that effects evolved rapidly, lasted for up to three hours and were reversible. In a follow-up study, the protocol‘s effects on network interactions were investigated using functional magnetic resonance imaging (fMRI), specifically focussing on functional connectivity of network nodes within the wider parietofrontal circuit controlling reaching-and-grasping. The study demonstrated that functional connectivity was causally modified between stimulated nodes and that those changes in coupling also affected parallel, functionally-related pathways. Comparison of neurophysiological (paired-pulse TMS) and functional (fMRI) connectivity between individuals revealed a linear relationship of these connectivity indices; the first can assess the physiological nature of the interaction, whereas the latter can elucidate global network effects, making the techniques complementary. Neurophysiological interactions of ipsilesional and contralesional PMv-M1 were tested in chronic subcortical stroke patients during grasping. Patients showed a diminished facilitatory influence of ipsilesional PMv on M1 compared to healthy controls which might contribute to their motor disability. Application of paired-associative TMS “normalised“ the reduced effective influence of ipsilesional PMv on M1 and this effect correlated with the patient‘s potential to improve their dexterity.

<p>Patients suffering from different forms of neurodegenerative diseases, such as: Creutzfeldt Jacob Disease (CJD), Alzheimer disease (AD), mild cognitive impairment (MCI), frontotemporal dementia and Parkinson’s disease (PD) were examined with Positron Emission Tomography (PET) and the combination of different radiotracers: ¹⁵O-water, N-[¹¹C-methyl]-L-deuterodeprenyl (DED), [¹⁸F] 2-fluorodeoxyglucose: (FDG), N-methyl-[¹¹C]2-(4-methylaminophenyl)-6-hydroxybenzothiazole (PIB) and L-[¹¹C]-3,4-dihydroxiphenyl-alanine (DOPA). The radiotracers and the combinations of different radiotracers were selected with the intention to detect, in the brain, patterns of neuronal dysfunction, astrocytosis, axon degeneration or protein aggregation (amyloid), in the brain which are pathognomonic for specific diseases and may contribute to improve clinical differential diagnoses. Examinations in healthy volunteers were performed to allow comparisons with patients. In addition, animal studies were conducted to complement the information. In some cases, the PET findings could be compared with the results of autopsies.</p><p>In contrast to the micropathology, in which only a limited part of a tissue (obtained post-mortem or by biopsy) is inspected, one PET acquisition provides an image of the whole system (e.g.: the brain and the cerebellum). This form of imaging pathology is “<i>in vivo</i>”, where the examination is innocuous for the patient. </p><p>This thesis is an attempt to stimulate the development of new tracers, new tracer combinations and methods that directly or indirectly describe the anatomo-physiopathological changes produced in the brain in neurodegenerative diseases. A better description of different diseases can be obtained, confirming or questioning the clinical diagnoses and widening our understanding of the mechanisms underlying neurodegeneration. Different pathologies can produce similar symptoms and thus causing confusion regarding clinical diagnosis. The used PET combinations improved the accuracy of the diagnoses. The incipient knowledge emerging from a new neuroimaging pathology in combination with other disciplines may open the way to new classifications of dementias and neurodegenerative diseases based on an “<i>in vivo</i>” pathology. </p>

L’âge, le génotype et les traumatismes crâniens (TCC) sont trois facteurs de risque majeurs du développement de la maladie d’Alzheimer (MA). Avec une accumulation d’évidences démontrant la persistance d’anomalies cérébrales suite aux plus légers des TCC, qui affichent d’ailleurs la plus haute incidence, il devient impératif de tester l’hypothèse selon laquelle même les commotions cérébrales puissent interagir avec l’âge et les gènes afin de précipiter la neurodégénération. Trente ex-athlètes de haut niveau (âge M = 60 ans), dont la moitié a subi des commotions cérébrales il y a plus de 30 ans, ont été évalués en neuropsychologie, en neuroimagerie multimodale ainsi qu’en génétique. De nombreuses mesures neuroanatomiques, dont l’expansion du volume des ventricules latéraux, se trouvent à corréler avec divers déficits cognitifs (mémoire différée et de reconnaissance) détectés chez les participants commotionnés. D’un intérêt particulier, certains de ces résultats sont modulés par le polymorphisme nucléotidique simple du gène Apolipoprotéine E. Ces résultats appuient l’hypothèse selon laquelle la commotion cérébrale chez de jeunes athlètes serait un facteur de risque de neurodégénération dans le vieillissement normal. / Age, genotype and traumatic brain injury (TBI) are three of the most important risk factors of Alzheimer’s Disease. With a growing body of evidence showing the persistent deleterious effects of the mildest form of TBI, it becomes imperative to test the hypothesis that sports concussion could interact with aging to precipitate neurodegeneration. Thirty former high-level athletes (mean age = 60 yrs), half of them having sustained sports concussion during their young adulthood, underwent neuropsychological, neuroanatomical and APOE genotype examination. Data analysis revealed numerous neurobiological anomalies, such as ventricular enlargement, correlating with cognitive deficits (delayed and recognition memory) in concussed participants. Of particular interest, some neuroanatomical measures were found to be modulated by APOE single-nucleotide polymorphisms. These findings support the idea that sports concussions sustained in early adulthood are a risk factor of neurodegeneration in late adulthood.