Altered Cerebral Tspo Availability and Functional Connectivity in Patients With Major Depressive Disorder: A Preliminary Multimodal Imaging Study Combining C-11 Pk11195 Pet and Rs-Fmri

Background Accumulating evidence indicates a high prevalence of major depressive disorder (MDD) in patients with chronic inflammatory diseases (1-6), suggesting a causal association between MDD and inflammatory processes. Moreover, functional changes at the protein level are associated with systems-level alterations in the neural circuits underlying specific pathological behaviors (7,8). However, direct in vivo evidence demonstrating a link between neuroinflammation and neural systems-level alterations in MDD is lacking. Aims & Objectives We aimed to investigate changes in cerebral translocator protein (TSPO) availability and the functional connectivity (FC) affected by these changes in treatment-naïve young adult patients with MDD using positron emission tomography (PET) imaging with the TSPO ligand [11C]PK11195 and resting-state functional magnetic resonance imaging (rs-fMRI). Method Twenty treatment-naïve young adult MDD patients without comorbidity and twenty-six healthy controls (HCs) underwent [11C]PK11195 PET and 3-Tesla MRI. For TSPO availability, we quantified [11C]PK11195 binding potential (BPND) using a reference tissue model (9) based on the supervised cluster analysis (SVCA4) algorithm (10). Voxel-based between-group comparisons of [11C]PK11195 BPND were performed using a two-tailed two-sample t-test. The relationships between [11C]PK11195 BPND and clinical variables were investigated using voxel-based regression analysis. Between-group differences in the [11C]PK11195 BPND seed-based FC were investigated using a two-tailed two-sample t-test. The correlations between [11C]PK11195 BPND seed-based FC and clinical variables were examined using voxel-based regression analysis. Results The MDD group had significantly higher [11C]PK11195 BPND in the left anterior cingulate cortex, left postcentral gyrus, bilateral superior temporal gyrus, and bilateral middle and inferior frontal gyri (IFG) compared to the HC group (uncorrected p < 0.001). In the MDD group, the total Beck Depression Inventory (BDI) score was positively correlated with [11C]PK11195 BPND in the pons, and the total 17-item Hamilton Rating Scale for Depression (HAMD-17) score was positively correlated with [11C]PK11195 BPND in the right pulvinar and midbrain (uncorrected p < 0.01). FC analysis showed that the FC from right IFG seed to the right precuneus was significantly increased in the MDD group compared to the HC group (uncorrected p < 0.0001). In the MDD group, the higher the BDI score, the greater the FC from the pons seed to the right supramarginal gyrus (SMG), and the higher HAMD-17 score, the greater FC from the midbrain seed to the left SMG and left IFG (uncorrected p < 0.001). Discussion & Conclusions Using a multimodal imaging, this study provides important information on the integrated molecular and neural systems-level changes associated with neuroinflammation in MDD. Notably, our results suggest the possibility of alterations in TSPO binding and associated FC perturbations in the pons and midbrain, key brain regions involved in the serotonergic system, in relation to depressive symptom severity in MDD. Further multimodal imaging studies with double-tracer PET imaging using [11C]PK11195 and serotonergic ligands are needed to clarify the link between neuroinflammation, serotonergic changes, and their significance relating to systems-level perturbations in MDD.