Mechanism-driven neuroprosthetics to restore hemodynamic stability in parkinsonian syndromes

Objective

About 1 million people with Parkinson’s disease live in the EU, including those with atypical parkinsonian syndromes. Up to 50% of them suffer from severe hypotensive symptoms, which include debilitating episodes of fatigue, nausea, and syncope. These complications are a significant cause of morbidity as they decrease mobility, increase the incidence of falls, reduce quality of life, and increase the risk of stroke. We recently developed a neurosurgical approach that applies epidural electrical stimulation (EES) over the thoracic spinal cord to prevent hypotension in people with spinal cord injury, and also demonstrated proof of concept in one patient with multiple system atrophy. While these results encouraged us to implant a second patient with multiple system atrophy, we found that the effect of EES on orthostatic hypotension was considerably less effective. This observation suggested that improper patient selection could render the therapy ineffective, and that the mechanisms underlying pressor responses induced by EES in parkinsonian syndromes may differ from those in people with spinal cord injury. Here, we will conduct a series of mechanistic experiments in newly developed rodent models of parkinsonian syndromes to understand how EES accesses sympathetic circuits in neurodegenerative states, and how long-term EES impacts these circuits. To address these questions we will deploy a combination of single-cell RNA sequencing, optogenetics, and CRISPR-Cas9 knockouts. Finally, we will leverage the mechanistic insight gained from these experiments to carefully select two participants who will be implanted with EES to treat severe orthostatic hypotension. The proposed work will expose fundamental mechanisms by which neurodegeneration provokes circuit reorganisation, how neuromodulation therapies can leverage this reorganisation to gain access to the circuits required to restore neurological functions, and use this understanding to develop new therapies.