Targeting TNF-Alpha for Treatment of Blast-Induced Tinnitus
Abstract
Tinnitus, often called "ringing in the ear" in layman s terms, is scientifically defined as sound perception without an external acoustic event. When blast-related high-pressure shock waves occur or improvised explosive devices are detonated, the sound level can exceed 140 dB SPL (sound press level). The intense noise combined with the instantaneous overpressure created by the detonation inflicts injuries both to the ears and the brain. In the ears, blasts perforate the tympanic membrane and damage hair cells, causing hearing loss. In the brain, blast shockwaves damage the nerve cells, causing traumatic brain injury. These problems often cause tinnitus that is often accompanied by a variety of psychological disorders. Clinical studies have demonstrated that blast injuries account for over 80% of combat-related injuries. Blast-induced neurotrauma and post-traumatic stress disorder are referred to as "signature injuries" of the Global War on Terrorism, with prevalence as high as 16% and 14%, respectively. Though rare in the civilian population, the socio-economic impacts of blast injuries have risen in public awareness. Blast-induced tinnitus is the most common sequalea of blast injuries, and is listed as the number one diagnosis for Service-connected disability claims. Of all military personnel who have sustained blast injuries, 70% reported tinnitus symptoms within 72 hours of the exposure, and 43% reported suffering persistent tinnitus one month afterwards. The annual cost to compensate Veterans for tinnitus in the United States is nearly $2 billion and rising. Tinnitus is often intensified by sounds that trigger "flashbacks," and Service members who have both tinnitus and post-traumatic stress disorder experience post-traumatic stress symptoms more frequently and with greater intensity than Veterans with just post-traumamatic stress disorder and no tinnitus. A potentially important player in blast-induced tinnitus and its associated anxiety and cognitive impairment, and traumatic brain injury, is a protein called tumor necrosis factor alpha (TNF-alpha). This protein is produced by nerve cells in the brain following blast trauma. Once produced, TNF-alpha causes secondary injury and worsens the damage to the brain. In addition, it can make nerve cells overexcited and fire erroneously, which could cause phantom tinnitus perception along with a number of other psychological symptoms. Scientifically, it remains to be determined as to whether blast-induced traumatic brain injury activates TNF-alpha, which, together with blast-induced hearing loss, synergistically increases the incidence of blast-induced tinnitus. In this project, we hypothesize that blast-induced traumatic brain injury activates TNF-alpha, which, together with blast-induced hearing loss, synergistically increases the incidence of blast-induced tinnitus, and that blast-induced activated TNF-alpha in limbic structures exacerbates the psychological aspects of blast-induced tinnitus. We will use a mouse model to pursue the following three aims: (1) Determine whether blast-induced traumatic brain injury and hearing loss synergistically contributes to tinnitus and its associated psychological disorders. (2) Investigate whether proinflammatory cytokines are involved in blast-induced tinnitus and its associated psychological disorders. (3) Elucidate the neural mechanisms underlying blast-induced traumatic brain injury, tinnitus, and its associated limbic dysfunctions. In the second and third aims, we will also test three TNF-alpha inhibitors to determine (1) whether they reverse blast-induced increases in TNF-alpha expression; (2) whether they abolish putative neural signals of tinnitus and its associated psychological disorders; and (3) whether they attenuate blast-induced traumatic brain injury and abolish blast-induced tinnitus and psychological disorders. Our immediate goal is to further understand the neural mechanisms underlying blast-
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510356
Entities
People
- Shaowen Bao
Organizations
- United States Army
- University of Arizona