Pharmaco-fUS in cognitive impairment: Lessons from a preclinical model

Abstract

Background: There is an urgent need to understand and reverse cognitive impairment. The lack of appropriate animal models combined with the limited knowledge of pathophysiological mechanisms makes the development of new cognition-enhancing drugs complex. Scopolamine is a pharmacologic agent which impairs cognition and functional imaging in a wide range of animal species, similarly to what is seen in cognitive impairment in humans. Methods: In this study, using a functional ultrasound (fUS) neuroimaging technique, we monitored the impact of donepezil (DPZ), a potent acetylcholinesterase inhibitor and first-line treatment in patients with mild to moderate Alzheimer's disease, in a scopolamine-induced mouse model. Results: We demonstrated that despite its low impact on the cerebral blood volume (CBV) signal, scopolamine injection produced an overall decrease in functional connectivity between various brain areas. In addition, we revealed that DPZ induced a strong decrease in CBV signal without causing a difference in functional connectivity. Conclusion: Finally, our work highlighted that DPZ counteracted the impact of scopolamine on functional connectivity changes and confirmed the interest of using pharmaco-fUS imaging on cognitive disorders, both in frequent and rare neurological disorders.

Functional ultrasound detects frequency-specific acute and delayed S-ketamine effects in the healthy mouse brain

“…The current gold standard BOLD-fMRI suffers from the convoluted nature of its signal and can be prone to artifacts, especially when filtered at high frequencies, as discussed above. With its higher sensitivity and spatiotemporal resolution, fUS is ideally placed to investigate drug effects, although pharmaco-fUS studies are still sparse up to date ( Rabut et al, 2020 ; Vidal et al, 2020 , 2022 ).…”

“…Both methods can therefore be used to infer measures of functional connectivity (FC) ( Biswal et al, 1995 ; Osmanski et al, 2014 ; Ferrier et al, 2020 ; Rabut et al, 2020 ; Vidal et al, 2020 ; De Paz and Macé, 2021 ; Vidal et al, 2022 ), derived from the temporal correlation between the timecourses of distinct brain areas. Since its emergence ( Biswal et al, 1995 ), FC has been used to delineate the functional organizations of both human and animal brains, as well as changes occurring under different conditions such as diseases or pharmacological interventions, therefore emerging as an important in vivo biomarker for neuroscience ( Khalili-Mahani et al, 2017 ; Spinosa et al, 2022 ).…”