Distinct functional cerebral hypersensitivity networks during incisional and inflammatory pain in rats

Although the pathophysiology of pain has been investigated tremendously, there are still many open questions with regard to specific pain entities and their pain-related symptoms. To increase the translational impact of (preclinical) animal neuroimaging pain studies, the use of disease-specific pain models, as well as relevant stimulus modalities, are critical. We developed a comprehensive framework for brain network analysis combining functional magnetic resonance imaging (MRI) with graph-theory (GT) and data classification by linear discriminant analysis. This enabled us to expand our knowledge of stimulus modalities processing under incisional (INC) and pathogen-induced inflammatory (CFA) pain entities compared to acute pain conditions. GT-analysis has uncovered specific features in pain modality processing that align well with those previously identified in humans. These include areas such as S1, M1, CPu, HC, piriform, and cingulate cortex. Additionally, we have identified unique Network Signatures of Pain Hypersensitivity (NSPH) for INC and CFA. This leads to a diminished ability to differentiate between stimulus modalities in both pain models compared to control conditions, while also enhancing aversion processing and descending pain modulation. Our findings further show that different pain entities modulate sensory input through distinct NSPHs. These neuroimaging signatures are an important step toward identifying novel cerebral pain biomarkers for certain diseases and relevant outcomes to evaluate target engagement of novel therapeutic and diagnostic options, which ultimately can be translated to the clinic.