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Related Experiment Video

Updated: Jun 18, 2025

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

Ehsan Dadgar-Kiani1, Gregor Bieri2, Ronald Melki3

  • 1Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, 94305, USA; Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA.

Brain Stimulation
|August 3, 2024
PubMed
Summary

Neuromodulation, a treatment for Parkinson's Disease, can alter the spread of alpha-synuclein pathology. This study shows optogenetic stimulation impacts pathology distribution, offering new therapeutic possibilities.

Keywords:
Circuit functionNeuromodulationOptogeneticsParkinson's diseaseα-Synuclein

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Area of Science:

  • Neuroscience
  • Neuromodulation
  • Neurodegenerative disease research

Background:

  • Current treatments for neurodegenerative diseases like Parkinson's Disease (PD) primarily manage symptoms by addressing circuit dysfunction.
  • The impact of these treatments on the underlying disease progression, particularly the spread of pathological hallmarks like alpha-synuclein, is not well understood.

Purpose of the Study:

  • To investigate whether neuromodulation can influence the in vivo spreading dynamics of alpha-synuclein pathology.
  • To explore the relationship between neuromodulation-induced changes in brain activity and pathology distribution.

Main Methods:

  • Induction of widespread alpha-synuclein pathology in a mouse model via striatal injection of pre-formed fibrils.
  • Application of daily optogenetic stimulation to the Secondary Motor Area (Layer V) for two weeks post-pathology induction.
  • Whole-brain imaging using light-sheet fluorescent microscopy after immunolabeling and clearing.

Main Results:

  • Optogenetic stimulation resulted in reduced alpha-synuclein pathology at the stimulation site and surrounding areas.
  • A notable increase in pathology was observed in the contralateral cortex.
  • Changes in pathology spatially correlated with, but were opposite in polarity to, optogenetic-fMRI measured brain activity.

Conclusions:

  • Neuromodulation can effectively modulate and predict the distribution of alpha-synuclein pathology across the brain.
  • These findings open new avenues for developing optimized neuromodulation therapies for Parkinson's Disease and related disorders.