Association Between Kynurenine Pathway and Cerebellar Microstructure in Bipolar Disorder With Childhood Trauma

Childhood trauma (CT) has been recognized as a risk factor contributing to clinical heterogeneity and adverse outcomes in bipolar disorder (BD). The neurobiological mechanisms linking CT and BD, particularly those involving the kynurenine pathway (KP) and cerebellar neuroplasticity, remain unclear.

A total of 51 BD patients with CT (BD+CT), 47 BD patients without CT (BD+NCT), and 50 healthy controls (HCs) were recruited. Peripheral KP metabolites were measured, and a biophysical neurite orientation dispersion and density imaging (NODDI) model was performed to evaluate microstructural alterations in cerebellar gray matter. Mediation analysis was conducted to examine whether these biomarkers mediate the association between CT and clinical phenotypes in BD.

In the BD+CT group, picolinic acid (PIC) levels were significantly lower, and the gray matter orientation dispersion index (ODI) in left cerebellar lobule VIIB was significantly higher, compared to other groups. PIC levels positively correlated with age of onset but negatively with emotional neglect and sexual abuse, anxiety and somatization, and left lobule VIIB ODI. Additionally, left lobule VIIB ODI showed a positive correlation with anxiety and somatization. Exploratory path modeling indicated that sexual abuse was indirectly associated with greater anxiety/somatization severity via reduced PIC levels and increased left lobule VIIB ODI.

In BD, CT exposure was associated with reduced PIC levels, altered gray matter microstructure in left cerebellar lobule VIIB, and more severe anxiety/somatization. These findings offer insights into mechanisms for BD with CT, though the exploratory path model could not adjust for medication and requires replication in medication-naïve samples.