Identifying potential therapeutic targets for abusive head trauma

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 DESCRIPTION (provided by applicant): My goal is to become a uniquely qualified, highly productive, independent biomedical investigator of abusive head trauma (AHT) in children. Specifically, I am interested in studying lesion evolution in children and modeling this type of injury in piglets to develop age- and injury-specific treatments that will translate to effective therapies for infants and children. Successful interventions to lessen the burden of morbidity and mortality after injury require understanding the pathophysiological cascades that lead to the extensive injury patterns observed. Currently, the pathophysiology of AHT in children is poorly understood, though clues exist from clinical, radiologic, biomechanical, and pathologic observations. I will initially focus on investigating the age-dependent pathophysiology after injuries and insults characteristic of AHT in our unique immature large- animal model. Though I have considerable basic neuroscience experience and have studied accidental pediatric head trauma in Dr. Duhaime's translational lab, it has only been through recent increasing clinical exposure that I have become aware of this pervasive and understudied public health problem that garners more controversy than data and answers. In order to accurately model AHT in my future independent career, I request additional multidisciplinary training in clinical abusive head trauma through coursework at Harvard Medical School, national and international meetings, a forensic pathology observership, and training by Drs. Duhaime, Newton, and McGuone who are clinicians treating and studying children with AHT. Focused training in what is known about this injury (clinical presentation, injury evolution, and outcome metrics via MRI or autopsy) will allow me to more accurately model, characterize, and interpret this complex injury in our piglets and to translate this to the pathophysiology in children. As one important component, subclinical and clinical seizures are common after AHT and are highly likely to contribute to the pathophysiological cascades due to unique features of the developing brain. In order to study the potential role of seizures in exacerbating damage after AHT, I request training from Dr. Staley who is a world leader in electrographic seizure detection, ion transport, and basic pathophysiology of cytotoxic cerebral edema in the immature brain. I will gain additional in- depth knowledge of developmental differences in the immature brain through coursework at Harvard University. In vivo imaging is a powerful tool to study injured children and observe the parallel injury in our model. Therefore, I seek training through coursework at MIT and the Martinos Center for Bioimaging and with Dr. Hunter who is a world authority in the use of MRI to study head injury in children. With my previous experience in the field of accidental pediatric brain trauma, my team of mentors and collaborators, and the educational opportunities at MGH/ Harvard/ MIT/ The Martinos Center, I believe this training will help me optimize my career goal of shedding light on these mysterious and unfortunately common injuries. Traumatic brain injury is THE leading cause of death and disability in children. In children under the age 2, the majority of severe TBI is due to AHT. Though the injury event is usually occult, there is often evidence of an impact and a subdural hematoma (SDH), the most common intracranial abnormality resulting from inflicted injury. Children with severe injuries typically present with seizures and apneic episodes. Tissue damage is not restricted to the zone immediately underlying the SDH, but patches of damaged parenchyma develop remotely. In severe cases, the injury can evolve into profound damage of the entire hemisphere associated with the subdural hematoma, termed "hemispheric hypodensity" for its appearance on acute computed tomography. Hemispheric delineated damage underlying the SDH with striking sparing of the other hemisphere is an injury pattern unique to immaturity. Infants often exhibit injury in both hemispheres, while toddlers more commonly exhibit relative sparing of the hemisphere contralateral to the SDH. Infants have immature chloride gradients that can result in subclinical seizures that may play a role in exacerbating the extent of tissue damage. No medical treatments currently exist that can halt the progressive evolution of this injury. A significant barrier to understanding the pathophysiology in AHT is a lack of an animal model that replicates these injuries. Here we propose to test the effect of subject age in our unique model of AHT which combines cortical impact, unilateral subdural hematoma, midline shift, apnea, and seizures in order to illuminate the pathophysiology. We have a long history of studying age-dependent differences in response to TBI using piglets developmentally comparable to human infants (PND 7) and toddlers (PND 30). Here we propose to determine the effect of age on 1.) the pattern of tissue injury after AHT injuries determined by MRI and pathology and 2.) the development of seizures after injuries typical of AHT. Our central hypothesis is that combined insults act synergistically to overwhelm the inherent compensatory abilities of the immature brain, leading to more widespread damage in patterns that are age-dependent. Determination of age-dependent patterns in pathology after injury and identification of key components that lead to tissue damage, such as seizures and edema, will produce targets for directed therapies. Therapeutics that abort the cascades set in motion after AHT may reduce the severity of neural injuries and reduce the number of children that die or are permanently disabled from inflicted injuries.