Neuromodulation modifies α-synuclein spreading dynamics in vivo and the pattern is predicted by changes in whole-brain function

• Published in: Brain stimulation 2024-07, Vol.17 (4), p.938-946
• Main Authors: Dadgar-Kiani, Ehsan, Bieri, Gregor, Melki, Ronald, Hossain, Aronee, Gitler, Aaron D., Lee, Jin Hyung
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - metabolism; Animals; Brain - diagnostic imaging; Brain - physiology; Circuit function; Deep Brain Stimulation - methods; Disease Models, Animal; Life Sciences; Magnetic Resonance Imaging; Male; Mice; Neuromodulation; Neurons and Cognition; Optogenetics; Optogenetics - methods; Parkinson Disease - physiopathology; Parkinson Disease - therapy; Parkinson's disease; α-Synuclein
• ISSN: 1935-861X; 1876-4754; 1876-4754
• DOI: 10.1016/j.brs.2024.07.021

Many neurodegenerative disease treatments, such as deep brain stimulation for Parkinson's Disease, can alleviate symptoms by primarily compensating for circuit dysfunctions. However, the stimulation's effect on the underlying disease progression remains relatively unknown. Here, we report that neuromodulation can not only modulate circuit function but also modulate the in vivo spreading dynamics of α-synuclein pathology, the primary pathological hallmark observed in Parkinson's Disease. In a mouse model, pre-formed fibrils were injected into the striatum to induce widespread α-synuclein pathology. Two days after fibril injection, mice were treated for two weeks with daily optogenetic stimulation of the Secondary Motor Area, Layer V. Whole brains were then extracted, immunolabeled, cleared, and imaged with light-sheet fluorescent microscopy. Repeated optogenetic stimulation led to a decrease in pathology at the site of stimulation and at various cortical and subcortical regions, while the contralateral cortex saw a consistent increase. Aligning the pathology changes with optogenetic-fMRI measured brain activity, we found that the changes in pathology and brain function had similar spatial locations but opposite polarity. These results demonstrate the ability to modulate and predict whole brain pathology changes using neuromodulation, opening a new horizon for investigating optimized neuromodulation therapies. •We report that neuromodulation can alter in vivo dynamics of α-synuclein pathology.•In a mouse model, optogenetic stimulation modified pathology at the stimulation site and cortical and subcortical regions.•Changes in pathology had similar spatial locations but opposite polarity compared to brain function measured through ofMRI.•Neuromodulation alters brain pathology and ofMRI predicts the changes, opening a new horizon for brain disorder treatments.