Background Aneurysmal subarachnoid hemorrhage can lead to multi-organ disturbances as a result of central and autonomic nervous system injuries. Alterations in the brain-body interface associated with this cerebrovascular disorder have significant impact on patient morbidity and mortality. Knowledge of the most pertinent brain-body associations, as well as demographic, systemic and neurological prognostic factors on hospital admission, along with their progression during hospitalization can assist the clinician and patient family in the process of treatment decision making. Objectives The goals of this dissertation are to: (1) synthesize and critically appraise the methodologic quality of existing studies that derive clinical predictor tools and clinical predictors used to determine outcome prognosis in patients with aneurysmal subarachnoid hemorrhage (SAH), (2) synthesize and critically appraise the methodologic quality of existing studies that derive pathophysiologic mechanisms of brain-body associations in aneurysmal SAH, (3) provide new insights into the significance of brain-body associations that are essential in influencing outcome in aneurysmal SAH, and (4) create a decision making algorithm for aneurysmal SAH patients that is useful in bedside prognostication and clinical treatment decision making. Methods Existing prospective and retrospective cohort studies and randomized controlled trials were included in the systematic review investigating prognostic factors and clinical prediction tools associated with determining the neurologic outcome in adults patients with aneurysmal SAH. Existing prospective and retrospective cohorts were included in the systematic review investigating the pathophysiologic mechanisms of brain-body associations in patients with ruptured brain aneurysms. The multicenter Tirilazad database (3551 patients) was used to create the aneurysmal SAH prognostic model, in order to elucidate significant brain-body associations. Traditional binary logistic regression models were used. The classification and regression tree analysis technique is applied to the multicenter Tirilazad database in order to create a decision making algorithm. Results Systematic review of the literature confirmed the most frequently retained clinical outcome predictors, namely, age, neurological grade, aneurysm size and blood clot thickness. Systematic review of the literature clarified currently known pathophysiologic mechanisms of brain-body associations in aneurysmal SAH, specifically, sympathetic activation of the cardiopulmonary system with subsequent delayed activation of neuro-cardio-endocrinological responses as part of the secondary injury cascade in response to the primary ictus of aneurysmal SAH. Logistic regression models found the significance of hepatic disease and hypertension in development of brain edema, and the negative consequences of seizures in those with history of myocardial infarction and post admission fever worsening neurological outcome. A clinically useful classification and regression tree revealed prognostic subgroups with important explanatory nodes including neurological grade, age, post admission fever and post-admission stroke. Discussion This dissertation clarified existing information on clinical predictors and pathophysiologic mechanisms of brain-body associations in aneurysmal SAH. It also provides novel information on brain-body associations that are essential in influencing outcome in aneurysmal SAH patients despite scarce existing literature on such important relationships. A clinically useful classification and regression tree was generated to guide both bedside prognostication and clinical treatment decision making in aneurysmal SAH patients. / Thesis / Doctor of Philosophy (PhD)

Les théories sur le soi ont postulé que celui-ci serait ancré dans le suivi des signaux viscéraux par le cerveau. Cependant, peu de preuves expérimentales soutiennent ce postulat. L’objectif de cette thèse était de tester si on peut trouver un lien entre couplage cœur-cerveau et soi. Nous avons opérationnalisé le concept de soi en définissant deux dimensions: le «Je», expérientiel, et le «Moi», introspectif.Nous avons d’abord montré, en magnétoencéphalographie, que le rapport au soi des pensées spontanées est encodé dans l’amplitude des réponses évoquées aux battements cardiaques (heartbeat-evoked responses, HERs), dans les régions médiales du réseau du mode par défaut. Les HERs dans le cortex cingulaire postérieur et precuneus ventral encodent le «Je», alors que la dimension «Moi» est associée à des HERs dans le cortex préfrontal ventromédian. De plus, ces résultats sont spécifiques de chacune des dimensions du soi.Nous avons ensuite étendu ces résultats à l’aide d’enregistrements intracérébraux. Nous avons montré une covariation entre l’amplitude des HERs et le rapport au soi des pensées, essai par essai. Une analyse de l’insula antérieure droite a démontré que les HERs dans cette région sont modulés par la dimension «Je».Dans une tâche d’imagination, nous avons trouvé que dans les régions motrices médiales et le cortex préfrontal ventromédian, l’amplitude des HERs varie en fonction de la personne imaginée, soi-même ou un ami.Les signaux cardiaques pourraient donc contribuer à l’établissement d’un référentiel centré sur le corps, utilisé par le cerveau pour attribuer un «label soi» aux pensées. Ceci pourrait constituer un mécanisme pour l’implémentation du soi. / The self has been hypothesized to be anchored in the neural monitoring of visceral signals; yet experimental evidence is scarce. The goal of this thesis was to address this question, by testing whether we could find a link between heart-brain coupling and the self. We operationalized the concept of self by defining two self-dimensions: the experiential “I” and the introspective “Me”. We showed in a first magnetoencephalography (MEG) experiment, that the self-relatedness of spontaneous thoughts was encoded in the amplitude of heartbeat-evoked responses (HERs), in midline regions of the default-network. HERs in the posterior cingulate cortex / ventral precuneus encoded the “I” dimension, whereas the “Me” dimension was associated with HERs in the ventromedial prefrontal cortex (vmPFC). In addition, these results were specific to each self-dimension.In a second study, we extended these results using intracranial recordings and new analyses of the MEG data. Here, HER amplitude co-varied with the self-relatedness of spontaneous thoughts, at the single trial level. Moreover, an analysis of the right anterior insula showed that HERs in this region were also associated with the “I”. A third study aimed at testing these results in the context of oriented thoughts, in an imagination task. We found that HER amplitude in medial motor regions (anterior precuneus, mid-cingulate and supplementary motor area), and vmPFC, varied depending on whether the self or a friend was being imagined. Cardiac signals could contribute to a body-centered reference frame, to which the brain would refer to in order to tag thoughts as being self-related. This could be a mechanism for implementing the self.