ASSESSMENT OF BEHAVIORAL AND FMRI DIFFERENCES IN A MINIPIG MODEL OF PEDIATRIC CONCUSSION

Traumatic brain injury (TBI) is a leading cause of death and disability among children and adolescents in the United States. An estimated 90% of head-injury-related emergency department visits result in a diagnosis of mild TBI (mTBI) also known as concussion. Historically ignored as a major public health concern, concussion can cause lasting neurocognitive changes that can persist for years or even decades; well beyond the typical 2-week clinical recovery period. Post-concussive syndrome (PCS) encompasses a constellation of cognitive and physiological symptoms that continue to occur weeks, months, or years after a concussion. In children and teenagers, these impairments can disrupt an individual’s developmental trajectory, leading to underperformance in academics, poor integration into the workforce, and diminished quality of life in adulthood. Preclinical neuroscience has greatly improved our understanding of the consequences of head injury, however vast architectural differences between rodent and human brains has resulted in dismal translation of therapeutic strategies from the bench to the bedside. In recent decades, the domestic pig (sus scrofa) has attracted substantial attention as a highly promising model animal for studying age-specific responses to mechanical trauma due to striking similarities between pig and human brain anatomy, development, and neuroinflammatory response. To add to the growing body of work utilizing pigs for the study of brain injury, we have developed a model of pediatric concussion in juvenile Yucatan miniature pigs. We conduct an extensive battery of cognitive and behavioral assessments designed to reveal post-concussive complication in pigs. We also conduct clinically relevant live imaging procedures to better understand the effects concussion can have on brain connectivity and function. Results from this work show that pigs with concussion are at greater risk of developing symptoms of depression and anxiety when compared to healthy counterparts. Additionally, pigs with brain injury are more active in the open field than healthy pigs, a potential maker of hyperactivity and ADHD-like symptoms. After injury, concussed pigs also exhibit deficits in memory and concentration reflective of the common learning deficiencies often reported in children with post-concussive complications. fMRI analysis revealed a trend towards abnormal response to visual stimulation 5 weeks post-injury in pigs with concussion. Preliminary work investigating the efficacy of non-invasive brain stimulation as a potential therapeutic option for PCS suggests that the delivery of repetitive transcranial magnetic stimulation (rTMS) may be beneficial for some symptoms, but not others. In pigs with brain injury, it was discovered that rTMS therapy minimizes symptoms of depression and improves memory and concentration. Imaging results in pigs who have received rTMS therapy show that rTMS potentially increases the sensitivity of pigs to tactile stimulation. The utilization of an animal model whose neuroanatomy closely resembles the human brain is critical to the development of therapeutic protocols that are effective and safe.