A picture of staff at Dr. Baron's lab holding a sign that reads

Pictured above is Dr. Mark Baron (far left) and his team of lab resarchers.

Bench Research

Dystonia

Dystonia is the third most common movement disorder. It is a devastating condition characterized by ineffective, twisting movements and contorted postures. Dystonia prevents normal movements, causing instead twisted, distorted attempts to move. In the most severe cases, the afflicted is chair, and even bed, bound. Dystonia is characterized in two forms. Primary dystonia manifests typically by adolescence, is more widely understood, and often responds well to therapeutics and surgical intervention. Secondary dystonia results from such causes as traumatic brain injury (TBI) or head trauma, stroke or cerebral palsy. In distinction from primary dystonia, the underlying abnormalities in the brain related to secondary dystonia are not thoroughly understood and, as a result, no therapies have been designed specifically to treat secondary dystonia to date. Consequently, secondary dystonia and its mechanisms are an important target for potentially life-changing research.

Secondary Dystonia Research

Dr. Mark Baron’s laboratory at the Hunter Holmes McGuire VAMC has been devoted to understanding the underlying abnormal brain cell signaling responsible for dystonia and other movement disorders in animal models. His investigations in rodent models of dystonia have led to remarkable insights into how specifically abnormal signals originating in the dystonic brain’s basal ganglia cause the thalamus to send pathological signals onto the motor cortex at the surface of the brain. These abnormal brain signals, in turn, ultimately lead to erroneous signals being sent to the muscles, leading to the devastating motor features of this condition.

Baron and his team discovered that the neuronal (brain cell) activity in a specific part of the basal ganglia, the globus pallidus (GP) in rodents (referred to in humans as the GPe) was consistently silent in advance of dystonic movements from the animals being jaundiced in their brain. This led the team to pursue small destructive chemical lesions in GP in other rodents, which confirmed that silencing signaling from a specific region of GP indeed leads to dystonia. The researchers also found that silencing of another nearby separate region caused signs of Parkinson’s disease. This then led the team to discover that these same anatomical relations hold in humans undergoing deep brain stimulation; thereby, guiding improved targeting of deep brain stimulation for these two conditions. This work was recently published in Neuroscience (Kumbhare et al., 2017). Additional work is ongoing to revise longstanding modeling of basal ganglia-thalamocortical brain signaling based on discoveries in the lab that the basal ganglia output signals serve critically to switch the thalamus from a regular firing to a preferred movement related burst firing (signaling) mode.

Building on the team’s success in understanding the signaling mechanisms underlying dystonia, Dr. Baron’s current studies focus is now on testing novel therapeutic approaches. Baron’s team is now aiming to reverse experimental dystonia by modulating the previously defined brain signaling abnormalities determined to be the origin of dystonia. Specifically, the team will place opsins (proteins found in microorganisms that are important for affecting action) directly into brain cells and then subject these opsins to highly specific light waves to program the brain cells to approach more natural activity. Additional methods will involve introducing a pharmacological agent into the thalamus to control the discovered abnormal burst activity, with the hope of reversing the dystonia in the rodents. Dr. Baron’s studies provide realistic hope to patients suffering from secondary and other forms of dystonia.