Dottorato in NEUROSCIENZE DEL COMPORTAMENTO

Titolo della tesi: Neurobiological mechanisms underpinning the maintenance of intrusive thinking: toward a precision psychiatry approach

For many psychiatric patients, the presence of intrusive, repetitive, and distressing thoughts significantly contributes to their overall burden and impairs daily functioning. Despite the growth of a precision psychiatry approach in the last decades, investigating the neurobiological correlates of intrusive thinking has been hindered by several factors, including the reliance on categorical-based approaches to research, the variability in defining intrusive thinking based on thought content and specific disorders, and the conflation of trait and state aspects of intrusive thoughts. In light of these challenges, the present work proposes novel and “precise” approaches for the comprehension of the neurobiological mechanisms underpinning the persistence of intrusive thinking. In the Study 1, experimentally engendering intrusive thinking resulted in a state- dependent increase of GABAergic neurometabolism within the anterior cingulate cortex in individuals with pathological anxiety. Such increase was accompanied by a dampened autonomic and resting state functional connectivity within downstream nodes of the Central Autonomic Network. This study informed on a putative negative reinforcement mechanism of pathological intrusive thinking in fostering the avoidance of a transition from a relaxed state to a sudden spike of autonomic activation. In Section 2, we investigated mechanisms at the intersection of intrusive thinking, physiological stress response, and reward processing abnormalities. In Study 2, we meta- analytically reviewed preclinical and clinical studies that manipulated physiological acute stress response in laboratory contexts to study the basic mechanisms of stress effects on reward-related behaviors. Results from Study 2 informed the methodology of Study 3. Findings indicated that in individuals with higher levels of depression severity, engendering a state of intrusive thinking facilitated the emergence of anhedonic-like behavior with a concomitant increase of electrophysiological markers of negative prediction error. This study informed on the possibility that the mesocorticolimbic system has a role in reinforcing intrusive thinking by amplifying negative prediction error and anhedonia. In Study 4, a novel data-driven machine learning model was adopted within an ecological perspective to question the clinical utility of large-scale network functionality to predict the emergence of daily-life intrusive thinking. The clinical utility of brain network functionality was established against a null model with only clinical and demographic information in relation to both severity and fluctuations of intrusive thinking. Overall, findings indicate that the daily emergence of specific intrusive thinking features was distinctively predicted by network features spanning default mode, frontoparietal, and limbic network functionality. This study provides an initial roadmap toward an ecological, multifaceted brain-based approach to intrusive thinking. Overall, present findings support the role of both negative and positive reinforcement mechanisms implicated in the maintainance of intrusive thinking and highlight the added value of investigating the underlying neurobiological pathways to fully understand this clinically-relevant and invalidating transdiagnostic contructs.