Studying Brain Injury…a Launching Point for Discovery
Molly Hubbard and Uzma Samadani
In Minnesota, as in the rest of the nation, traumatic brain injury (TBI) is the greatest cause of death and disability in people under the age of 35. Nationally, according to the CDC, TBI leads to almost 2.5 million hospitalizations, emergency department (ED) visits, and deaths. Concussion, also called “mild traumatic brain injury,” has an incidence rate of 600/100,000 patients, and represents 90 percent of head injured patients seen in the ED. Sports and other recreational activities account for almost 20 percent of concussions in those younger than age 19.
Despite the high prevalence of brain injury, it is poorly understood. There have been more than 30 consecutive failed clinical trials assessing treatments for brain injury, with zero successful
phase III trials. These failures may arise from an inability to objectively quantify radiographically silent injury and identify patients who are likely to have a poorer functional outcome after injury. A lack of sensitive outcome measures for recovery from brain injury also contributes to the successive failures.
Hennepin County Medical Center (HCMC) is attacking brain injury on all fronts by launching a comprehensive study to improve detection and classification; invoking cutting edge therapies such as electroceuticals, hyperbaric oxygen, novel rehabilitative strategies; as well as educating the community about brain injury prevention.
Classifying brain injury
This spring, we launched the Brain Injury Assessment Study, which is the largest single site TBI study in the country. The study is sponsored by the diagnostics business of Abbott, the global health care company; the Minnesota State Spinal Cord Injury and Traumatic Brain Injury Grant Program; and the Rockswold Kaplan endowed chair funding at HCMC. It represents
a collaboration among several groups including trauma surgery (Dr. Chad Richardson); emergency medicine (Drs. Jim Miner and Johanna Moore); radiology (Dr. Charles Truwit);
laboratory medicine (Dr. Fred Apple); brain injury rehabilitation (Dr. Sarah Rockswold); statistics (Dr. David Gilbertson); bioinformatics (graduate student Margaret Mahan); and neurosurgery (Drs. Thomas Bergman, Walter Galicich, Molly Hubbard, Gaylan Rockswold, and Uzma Samadani).
In this study, trauma patients are enrolled directly from the ED and undergo a multimodal assessment in an effort to identify biomarkers differentiating different brain injury subtypes. Serum and plasma will be analyzed for various markers of brain injury and these will be monitored at distinct time points for a full year. Additionally, the study uses a novel eye
tracking algorithm to detect eye movement abnormalities classically associated with concussion
and structural injury. Some participants in the study will receive MRI and CT scans to attempt to better understand both acute and long-term changes to the brain after trauma.
The ultimate goal of the study is to create a multimodal classification scheme for brain injury based on serum markers, eye tracking, and MRI so that therapeutics can be targeted appropriately. Such a classification scheme will help clinicians better understand the physiologic changes that occur after TBI. A secondary goal is to establish better outcome measures for brain injury. It is not enough to tell someone they have a concussion, we want to tell them specifically what is wrong with their brain and ultimately how it can be treated.
Therapeutic trials for brain injury
Recovery after TBI focuses primarily on physical, occupational, and speech therapies to help patients return to their pre-injury status. New studies that are being conducted at HCMC are focused on using interventional devices or therapeutics in the acute phase of injury in an attempt to augment the outcomes with the assistance of additional therapies.
Dr. Gaylan Rockswold has been a pioneer in the study of hyperbaric oxygen therapy (HBOT) for patients with severe traumatic brain injury. Patients often have a high mortality after severe TBI and those who survive often have poor outcomes. There have been significant preclinical and clinical investigations that indicate that HBOT improves outcomes in patients with severe TBI. By increasing oxygen delivery to the brain, HBOT helps reduce secondary injury from hypoxia, thus improving outcomes. Patients with severe TBI may have compromised lung function, either from initial trauma or from acquired pneumonia; thus further information is needed to finetune the treatment paradigm of HBOT. The newest study beingdeveloped at HCMC is a phase II trial, aimed at selecting the combination of HBOT treatment parameters that are most likely to demonstrate improvement in outcomes in a future phase III trial.
Vagus nerve stimulation
Further studies at HCMC aim at treating mild and moderate brain injury using electroceuticals, which stimulate neurons to provoke a response rather than rely on exogenous pharmaceuticals. The vagus nerve has an important regulatory function throughout the body and within the central nervous system. It modulates consciousness via thalamic connections to the cortical surface of the brain. Pre-clinical studies have shown that stimulation of the vagus nerve improves outcomes after traumatic brain injury. There is less inflammation and edema in tissue samples, improved wakefulness, and improved performance on cognition tests. In these studies, however, stimulation requires the surgical placement of a stimulator. While vagal nerve stimulation (VNS) has been done in humans for treatment of seizures and depression,
including those associated with prior TBI, for many years, it has not been done specifically for treatment of TBI. Recently, a hand-held non-invasive device that stimulates the vagus nerve directly through intact skin has been developed. Stimulation of the vagus nerve has the potential to alter the recovery from TBI by improving cerebral blood flow, decreasing inflammation, and improving other symptoms associated with TBI such as depression or seizures. We are launching studies looking at non-invasive VNS for treatment of both moderate and mild TBI.
Abnormal eye movements have been known to be associated 3,000 years. While humans have the ability to move their eyes to look at various objects under their own volition, conjugate eye movements are controlled by centers in the brain stem. This conjugate movement is not voluntary and pressure on the third, fourth, or sixth cranial nerves, or the brain stem, lead to abnormalities in the ability to move the eyes in a conjugate manner. Recent studies suggest that as many as 90 percent of patients with concussion may have
visual abnormalities. Dr. Sarah Rockswold, who is board-certified in physical medicine and rehabilitation, is currently investigating how visual rehabilitation can promote recovery from mild brain injury in a Minnesota state-funded project. Subjects are being enrolled in a prospective trial that includes a comprehensive assessment and visual rehabilitation program. They are subsequently assessed with clinical and radiographic outcome measures in conjunction with investigators at the University of Minnesota.
Brain injury prevention
The Minnesota Healthy Brain Initiative is another study being launched from HCMC’s Brain Injury Research Lab, which aims first to promote public learning about brain health and safety, with secondary goals of collecting normative data from a healthy, non-injured population. Research assistants from our lab will be stationed at the KARE 11 booth at the Minnesota State Fair where attendees from age four on will be offered an opportunity to undergo various cognitive assessments and eye tracking. This data will be used to establish baseline data that can then be compared to patients enrolled in the other clinical trials described earlier. In addition, state fair attendees can retest at various times during their visit, along with having a breath alcohol assessment, to assess the impact of alcohol consumption on their own cognitive function and visuomotor capability. Since alcohol consumption increases risk for trauma, this educational project aims to inform regarding the level of impairment seen after even only a few drinks.
As the busiest level one trauma center in the state, nestled in the heart of the medtech valley, we are uniquely positioned to drive further research in the field of brain injury. While TBI still presents a diagnostic, prognostic, and treatment challenge for physicians and therapists, the collaborative studies being conducted are a launching point for discovery.