Spreading Depolarizations in the Network Dysfunction Leading to Post-Traumatic Headache
Abstract
Traumatic brain injury (TBI) affects all Americans: high school athletes, drivers and passengers in motor vehicle accidents, and victims of domestic violence, to name a few. But its most striking effects are being seen in our Soldiers and Veterans. Though more and more of our Service personnel are surviving their initial injuries, long-term consequences of TBI can leave them completely incapacitated. Post-traumatic headache (PTH) is arguably the most common of these consequences, and it causes immense suffering. PTH is not “just” a headache; it is a multisensory disturbance where, in addition to head and neck pain, light hurts (photophobia), sound hurts (phonophobia), smells are uncomfortably amplified (osmophobia), and normal touch becomes painful (allodynia). We conceptualize PTH as a widespread disorder of sensory volume control (gain) and dysfunctional sensory learning (plasticity). The TBI that leads to PTH has multiple consequences – which ones could lead to a change in sensory volume control? We suspect that spreading depolarizations (SD; also known as cortical spreading depression; CSD) are the likely culprit, and that they occur during a “window of increased brain excitability” after TBI. Our lab focuses on SD, and we have shown that a single SD wave can cause long-term changes in the sensory response that are consistent with the sensory amplifications of PTH. We also know that SD are extremely common in humans with TBI. Our past work in PR130373 shows that every TBI we induced was followed by an SD, and new data shows that even mild TBI is associated with SD on impact. Importantly, in our PR130373 work we identified a period of increased excitability after TBI that favors the development of SD. Our first aim examines why this increase in excitability occurs, which will help develop new drug treatments. To understand the origins of PTH, we need to understand the changes that occur in sensory and pain circuits. Ultimately, we need to observe the individual cells involved, and see how they respond to the stimuli that generate PTH. Thus, we directly record individual brain cells in mice as they respond to light and touch after TBI. These studies can only be done in mice, but we can make them very relevant to our Soldiers by recording in awake animals as they respond to the same stimuli encountered in PTH, including SD. In our second and third aims, we directly address the question of whether and how SD contributes to the PTH state. Among other experiments, we will compare mice carrying a gene that increases susceptibility to SD to mice carrying a gene that reduces SD susceptibility, using novel miniscopes that record brain activity 24 hours a day. We will also test memantine, a drug that suppresses SD and shows promise for PTH. We predict that suppression of SD will reduce the PTH-relevant sensory amplifications that follow TBI. Finally, we will directly examine the development of head pain in PTH, with a new model that allows us to examine every element in the pain circuit, from nerves in the skin to the brain, using mice engineered to express fluorescent proteins exclusively in pain neurons. This will allow us to compare the effects of TBI and PTH-relevant sensory stimuli, directly on pain circuits. Here again we will compare SD-susceptible to SD-resistant mice, and use memantine to suppress SD, with the hypothesis that SD suppression will reduce pain circuit activity after TBI. The goal of this proposal is to understand the changes that lead to PTH after TBI. Our ultimate mission is to learn how we can prevent or reduce these changes, so that we can deploy new treatments for our Soldiers and Veterans. Our use of memantine, a drug that is already in clinical practice, means that if our testing is favorable it could be put to immediate use in the service of our military personnel. On a longer-term basis, if we can demonstrate that PTH is a dysfunctional plasticity state, we open up a whole category
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110807
Entities
People
- Kevin Brennan
Organizations
- United States Army
- University of Utah