Different patterns of white matter and immunological alterations in the various phases of bipolar disorder

Bipolar disorder (BD) is a prevalent recurrent and chronic mental disease, clinically characterized by the occurrence of active phases of illness, mania and depression, alternated to asymptomatic periods of euthymia. Considering the complex clinical presentation of BD, our work aimed to investigate the neurobiological underpinning of the various phases of BD separately in order to detect their specific abnormalities, thus helping clarifying the pathophysiology of this disorder. Firstly, we investigated potential abnormalities of brain white matter (WM) in BD by using the diffusion tensor imaging (DTI) technique. By using a tract-based spatial statistics (TBSS) voxel-wise approach, we found a widespread alteration in WM microstructure (as evidenced by a decrease in fractional anisotropy (FA) and increase in mean diffusivity (MD) and radial diffusivity (RD) parameters) in BD, showing distinct patterns of changes in the different phases of illness. In particular, such WM abnormalities were larger in the active phases of illness (i.e., depression and mania) with respect to euthymia. Then, by using a probabilistic tractography, we coherently detected a reduction in the structural connectivity of the cingulum in mania. Secondly, we explored potential factors associated with the observed pattern of WM alterations of BD, by conducting a combined immunological-DTI study on an independent BD sample. By using a TBSS approach, we found a widespread combined FA-RD alteration mainly in the manic phase, with relatively specific involvement of the body of corpus callosum (BCC) and superior corona radiata (SCR). Then, by using flow cytometry, we detected peripheral immunological alterations in the manic phase, mainly characterized by an increase in CD4+ T cells as well as a decrease in total CD8+ T cells and their subpopulations effector memory (CD8+CD28-CD45RA-), terminal effector memory (CD8+CD28-CD45RA+) and CD8+IFNγ+. Finally, an association between WM and immunological alterations was found in the whole cohort, and a correlation of FA-RD alterations in the BCC and SCR with reduced CD8+ terminal effector memory and CD8+IFNγ+ T cells was detected in mania. Finally, we conducted a longitudinal study, collecting both DTI and bio-humoral follow-up data of our sample and investigating WM and immunological alterations in BD patients across their different phases of illness. The results preliminarily confirmed our previous findings in a longitudinal perspective, by showing increased FA/decreased RD in midline structures complemented by an increase in the circulating activated CD8+ T cell subsets, in BD patients passing from active phases to euthymia. Collectively, these findings suggest a new pathophysiological model of mania. Accordingly, an acute immune response may occur in mania, sustained by early generated CD4+ T cell compartment (likely with T helper function), leading to activation of CD8+ effector T cell subpopulations that leave the circulation to migrate into the brain, where exert their cytotoxic action, finally leading to WM damage. Our model thus supports a relationship between BD and immune-inflammatory neurological diseases such as multiple sclerosis. Moreover, our results suggest a prominent role of mania in BD and, interestingly, seem to be in accordance with the “primacy of mania” hypothesis, where mania is described as the fire of BD and seen as the core of the pathophysiology of the illness. Finally, our data suggest a potential role for immunotherapy as an important future aid in the treatment of BD.