Behaviorally, traumatic brain injury (TBI) or age-related neurodegeneration causes severe depression, anxiety, personality changes, increased aggression, social inappropriateness, and deficits in attention, cognition, sensory processing, and communication. These diseases are also non-genetic risk factors for neurological diseases such as chronic traumatic encephalopathy, Alzheimer's disease, Parkinson's disease, and depression. Dr. Head is using genetic intervention via viral vectors to reverse damage caused by TBI and age-related neurodegeneration, and is the only researcher in the world exploring such an approach. Therapeutic approaches have proven to be unsuccessful, and as a result these long-term disabilities lead to a greater requirement for institutional and long-term care. Therefore, there exists an urgent need for the development of more innovative methods to limit neurodegeneration and improve neurologic function after injury or in the aged brain. Evoking structural and functional neuroplasticity that in turn restores motor and cognitive function days to weeks to months after brain trauma remains a major medical challenge for treating millions of individuals.

The brain is easily the organ we rely on most to regulate the various functions of life, and brain injuries resulting from accidents or aging can prove to be debilitating and have lasting and dire consequences. Dr. Brian P. Head, Associate Professor in the Department of Anesthesia at the University of California, San Diego and at the Veterans Administration San Diego Healthcare System, is using genetic interventions (via viral vector gene therapy) to regenerate neuronal growth after traumatic brain injury (TBI, funded by NINDS) and in the aging brain (funded by VA Merit). Specifically, his research uses a viral vector (AAV) to deliver a neuron-targeted chemical, synapsin, to encourage the expression of caveolin-1 (Cav-1) in neurons, a membrane protein that is essential for membrane formation in most cell membranes. Encouraging expression of this neurochemical will ideally enhance signaling in damaged neural tissue, helping the brain recover damaged neurons and retain cognitive ability. Recovered neurons are not just growing, but also fully functional with regards to neural physiology and behavior, where they were not necessarily before. This research is currently done using murine (mouse) models, but efforts to translate this to human models are in place.

Dr. Head's current research projects use similar gene-based therapies, promoting growth by targeting the re-building of proteins, but work with a number of brain-degenerative conditions:

• Traumatic Brain Injuries (TBI): When an individual suffers a TBI, there is a primary impact zone where the hit occurs, called the primary injury, which usually sees immediate damage and death to tissue. There is a secondary injury that follows which creates a hostile environment of injury where neurons die anywhere from minutes to months later. As the region of brain injury spreads, even more cognitive or motor damage can occur months to years later. Because the primary impact happens immediately, damage is generally unavoidable. Research has indicated though, that damage resulting from the spreading of the secondary injury can in fact, be mitigated or eliminated. Many of the neurons in this secondary region are viable, but die over time. By intervening with genetic-manipulation therapy, it is believed that damaged neurons can not only be protected by promoting growth of the membrane proteins, which are important for synapse formation, but also "sprouting," the growth of axons from a damaged neuron, is encouraged, which re-connects neuronal cells around or through the damaged areas of the brain.

• Age-Related Neurodegeneration: Brain tissue is subject to degeneration through natural processes like aging. Unlike younger individuals, who have more capacity for reinvoking neural plasticity, older individuals show more of a challenge for natural regrowth of neurons. Dr. Head is working to revitalize the young developmental period in older individuals by targeting areas known to exhibit deficits with age. Specifically, short-term memory is often affected as the hippocampus fails to code new memories. MRIs shows structural as well as functional deficits, and Dr. Head and his team have seen success targeting the hippocampus, which codes new memories.

• Alzheimer's: Treatment for Alzheimer's is similar to treatment for age-related neurodegeneration because it is not brought about by a traumatic injury. In patients with Alzheimer's, loss of neuron connections can occur for years before being diagnosed. Trying to reinvoke plasticity and growth in viable neurons to reform functional connections in Alzheimer's patients is similar to jump starting a car battery; once it is started, the car will run on its own. Once the neurons sprout new dendrites (finger-like structures that connect brain cells to one another), the brain tends to prune and refine these connections to re-establish functional activity. The "jump-start" is what Dr. Head is providing through his gene therapy--after the jump is applied, the brain has proven it will heal itself.