Central Mechanisms and Treatment of Blast-Induced Auditory and Vestibular Injuries
Abstract
With increased use of improvised explosive devices (IEDs) and increased survivability due to advances in body armor, blast-induced traumatic brain injury (bTBI) has emerged as a key military medical issue. Of the 220,430 Service members worldwide who have been identified by the DoD as suffering traumatic brain injury since 2000 (to third quarter 2011), the vast majority (93+%) were closed head injuries classified as mild to moderate TBI. Clinical assessments indicated that nearly 60% of bTBI victims exhibit hearing loss, tinnitus, dizziness, and balance disorders. The symptoms of blast-induced auditory damage often overlap with those of concussion and mild TBI. Many casualties have symptoms persisting long after release from Service as evidenced by diagnoses of conductive or sensorineural hearing loss or mixed auditory deficits with vestibular injuries. However, there are no Food and Drug Administration-approved drugs for treatments. A comprehensive understanding of the structural and molecular components of injury is essential for the development of the most appropriate therapies for auditory and vestibular deficits resulting from blast exposure. The key sensory structures for both the auditory and vestibular systems are located not only in the inner ear, but also in central nervous system (CNS). Existing data indicate that the CNS is at high risk of injury with blast exposures, and blast-induced damage to particular brain structures can lead to central auditory processing and vestibular processing disorders. In particular, death or disruptive alteration of specific cell types underlying auditory processing and balance regulation, such as pyramidal cells and GABAergic neurons in primary auditory cortex or Purkinje neurons and granule neurons in cerebellum, will lead to permanent deficits. Defects in auditory and/or vestibular function can arise from multiple types of insults with significantly different potential recovery outcomes. Development of effective medical solutions for blast-induced auditory and vestibular impairments requires identification of key biochemical mechanisms in relevant neuroanatomical structures, which in addition to establishing potential biomarkers for accurate diagnosis and distinction from related symptoms of neurobehavioral deficits also identifies relevant neurobiological targets for pharmacotherapeutic intervention. We propose to utilize a well-defined shock tube simulation of blast in mice in combination with multiple histological assays to fully identify the neurobiological underpinnings of central auditory and vestibular injuries. Mice will be exposed to repeated blasts and undergo functional hearing tests and balance assessments. Cerebrospinal fluid, plasma, and brain tissue will be examined to verify the morphological and biochemical changes at varied times following blast exposures. We will also validate the efficacy of anti-TDP-43 signaling drugs as early interventions for mitigation of auditory and vestibular dysfunctions. This project will characterize the etiology of blast-induced primary and secondary effects on biochemical, molecular, cellular, and neural network changes in central auditory/vestibular systems. This research will drive development of non-invasive diagnostic tests and explore therapeutic strategies to counter the acute and chronic degeneration responsible for persistent neurosensory deficits after blast. In addition to establishing mechanisms and mediators, this project will provide insights into the acute neurobehavioral deterioration after blast TBI that can be confronted in the clinical care of blast-injured Service members.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1620002
Entities
People
- Joseph Long
Organizations
- United States Army
- Walter Reed Army Institute of Research