Novel insights into vascular dysfunction in cuprizone-induced demyelination through functional ultrasound imaging

Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), affecting 2.8 million people worldwide, that presents multiple features, one of which is demyelination. Although treatments exist to manage the condition, no cure has been found to stop the progression of neurodegeneration. To develop new treatments and investigate the multiple systems impacted by MS, new imaging technologies are needed at the preclinical stage. Functional ultrasound imaging (fUS) has recently emerged as a robust method to measure brain cerebral blood volume (CBV) dynamics as an indirect indicator of neural activity. This study aimed to quantify the amplitude of alteration of evoked hemodynamic response in the somatosensory cortex, and its potential link with demyelination in a mouse model of CNS demyelination induced by cuprizone. We demonstrate that extended demyelination leads to an increased hemodynamic response in the primary sensory cortex, both spatially and temporally, aligning with fMRI findings in MS patients. Second, using descriptors of the evoked cortical hemodynamic response, we demonstrate that certain parameters (the number of active pixels and the rise time) correlate with the level of Myelin Basic Protein in the primary sensory cortex and the thalamus, when taken together. Interestingly, the increased CBV is not associated with demyelination but instead reflects the well-documented vascular alteration described in MS. Moreover, these changes were absent in the thalamus, and in focalized demyelinated lesions induced by lysolecithin injection, suggesting the involvement of specific cortical mechanisms driven by oligodendrocyte depletion. In conclusion, our study introduces a novel, non-invasive functional approach for investigating vascular dysfunction in the context of MS, addressing an important yet understudied aspect in both pre-clinical and clinical research.