Reduced prefrontal total choline MRS levels characterize the neurodevelopmental phenotype of bipolar disorder

Bipolar disorder (BD) is characterized by marked clinical heterogeneity, motivating efforts to identify biologically grounded subtypes such as the recently defined neurodevelopmental phenotype (NDP). Proton magnetic resonance spectroscopy (MRS) offers a non-invasive approach to detect neurochemical signatures potentially associated with these developmental deviations. In one of the largest MRS studies on BD to date, this cross-sectional study included 103 patients with BD who underwent single-voxel MRS of the bilateral prefrontal cortex (PFC). NDP load was computed according to validated clinical criteria, and associations between metabolite concentrations and NDP load were tested using linear regression models adjusted for age, sex, Montgomery-Asberg Depression Rating Scale (MADRS) score, and antipsychotic use. Higher NDP load was associated with reduced total choline (tCho) in both hemispheres (right PFC: β = -0.087, pFDR = 0.038; left PFC: β = -0.098, pFDR = 0.008), as well as with higher glutamate (Glu), Glx (Glu + glutamine (Gln)), and total N-acetylaspartate (tNAA) in the right PFC. These associations were not accounted by traditional diagnostic subtypes (BD-I vs BD-II). Moreover, sensitivity analyses performed using an independent quantification pipeline (Osprey) confirmed the association between higher NDP load and lower tCho concentrations in the left PFC, whereas associations involving glutamatergic metabolites and tNAA were not replicated after adjustment for covariates. These findings provide the first neurochemical evidence linking NDP load to prefrontal metabolites and highlight choline pathways as a biologically coherent marker of the developmental dimension of BD.