Testing a Subcortical Circuit Theory for the Pathophysiology of Blepharospasm
Abstract
Topic Area: Dystonia The Long-Term Challenge: Treatments targeting the causes not the symptoms. Blepharospasm (BSP) is one of the most common forms of dystonia. Patients suffer from involuntary contractions of the muscles around the eyes that cause increased blinking and very visible “squinching.” It can impair vision needed for activities like reading, watching TV, and driving. It is also misunderstood by others in the public leading to significant social disability and decreased quality of life. Some patients benefit from injections of botulinum toxin (sometimes referred to as “botox”) into the muscles. But the injections have to be repeated every 3-4 months and target only the symptoms. If we could determine what abnormal brain activity causes BSP symptoms, we could develop better treatments targeting the causes. An Innovative Approach: Detecting and preventing abnormal brain activity. A variety of evidence points to several regions deep inside the brain that could be causing BSP symptoms. Among these brain regions are structures called the basal ganglia, cerebellum, and thalamus. And among the many brain networks connecting these and other structures, there are two critical links stemming from the basal ganglia that are the focus of this project. The activity in these specific network connections can be easily measured and even modified thanks to advances in mouse genetics and neuroscience. Fortunately, we have a starting point for research in mice because past research has generated a simulation of BSP in rats. The animals exhibit several features that mimic symptoms in BSP patients, including increased blinking and abnormal activity in the muscles around the eyes. We will record brain network activity in the BSP mice to find a signature of brain activity that immediately precedes symptoms. We will also modify – through activation and/or silencing – the same brain network to see if we can not only detect impending symptoms but also prevent them immediately before they occur. Ultimate Applicability and Impact: To our knowledge, this will be the first research to directly measure and modify this circuitry in dystonia. It is also the first to examine the relationship between that neural activity and symptoms on a moment-by-moment basis. The results will provide unprecedented insight into the timing and causal relationships between activity in these deep brain circuits and BSP symptoms. By using mice, the research will open the door to several lines of future research. Genetic abnormalities associated with dystonia can be easily tested with our model, allowing us to begin to understand how genetic factors influence the brain circuit activity. Our project will also provide preliminary proof-of-concept data on how to make dramatic advances in deep brain stimulation (DBS) systems. Collectively, the work will lay the foundation for development of new drugs and better DBS systems to target the abnormal brain circuits causing dystonia and ultimately provide better treatments to patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910146
Entities
People
- David J. Peterson
Organizations
- United States Army
- University of California, San Diego