邁向雙極性疾患的病理生理學之機械論模式

The proposed project aims to build a mechanistic model of the pathophysiology of bipolar disorder (BD). Various biological alterations at different levels, including inflammatory/immune dysregulation, neurotransmitter changes, and structural/functional brain alterations, have been detected in BD. However, these alterations appear to be unspecific and unrelated, preventing the understanding of its pathophysiology. Consequently, despite the huge accumulation of results from neuroscience research, to date very few, if any, of them have been translate into diagnostic and therapeutic applications, and current therapies are merely empirical and symptomatic. Based on the novel hypotheses generated by our recently proposed theoretical model, we will investigate the correlational and causal relationship between chronic low-grade inflammation, immune autoreactivity against white matter antigens, white matter damage of the limbic network, and changes in neurotransmitter signaling at clinical and preclinical levels in two parallel and complementary studies, by using a multimodal and integrated approach. The results from this project may provide novel and invaluable insights in the pathophysiology of BD. This pioneering project, by employing multiple units of analysis and combining clinical and animal studies, will be the very first to investigate the mechanistic relationships between core pathophysiological factors at the inflammatory, immune, white matter, and neurotransmitter level in BD. Moreover, the results from this project may provide the first animal model of BD linking the core immune and brain alterations. Our findings will be described in written papers and published in international journals of neuroscience and psychiatry, as well as disseminated at conferences. Finally, these scientific findings could provide us with rich information to serve as a basis to translate into diagnostic and therapeutic applications. A mechanistic model of the pathophysiology of BD is fundamental to detect specific biomarkers that can be used as diagnostic tools at the individual level in the clinical setting. More importantly, immune and white matter biomarkers could represent core targets for developing novel and more effective therapies, such as immune therapies, that have a neuroscientific basis and, rather than managing only the symptoms, can treat the disease itself.