For at least 50 years, scientists have postulated that the various parts of the brain are interconnected based on specific rules governed by the timing of inputs and outputs. Experiments in immature, or developing brains, as well as those investigating how the mature brain forms new memories, have led to the modern maxim, "Neurons that fire together, wire together." In other words, brain cells that are active at the same time are more likely to be related functionally, and thus, through as yet unknown mechanisms, form increasingly stronger communication links, eventually forming permanent coupling via anatomical connections. At least in the developing brain, this occurs via the sprouting of axons that form the conduits for communication between the various parts of the brain. Recent studies have now demonstrated that after injury, such as might occur post stroke or traumatic brain injury (TBI), neurons in the remaining intact brain tissue spontaneously reorganize. One can now conclude that the injured brain is not simply a normal brain with a part removed. It forms completely new networks that allow compensation for lost functions, and thus some limited functional recovery.

The goal of this proposal is to combine the resources of scientists with expertise in brain plasticity after injury as well as engineers with expertise in developing microelectronic circuitry in order to optimize the brain's potential for rewiring after injury. Specifically, this interdisciplinary group will design an implantable electronic circuit that will record neuronal activity in one part of the brain and use these signals to stimulate another part of the brain. This circuit will essentially provide artificial coupling between brain areas that are not normally co-activated. Based on the above-mentioned modern maxim, this artificial coupling should provide the stimulus for new anatomical connections to form, permanently linking the two areas. While such sprouting of new axonal arbors is difficult in a normal brain, we aim to provide the coupling signals in the first month after injury, when axonal re-growth occurs spontaneously.

While this novel approach to brain repair is still in its infancy, and proposed studies will be done exclusively in animal models of TBI, we foresee several patient populations in which this technology could be applied. First, and foremost, this includes the ~1.4 million individuals per year in the U.S. who experience TBI. While the highest incidence of TBI traditionally has been among young people due to automobile accidents, and older adults due to falls, the Iraq and Afghanistan wars have brought about new forms of brain injury due to the exposure of soldiers to improvised explosive devices. In addition, stroke patients could also benefit from the development of such novel therapies. Over 800,000 new strokes occur in the U.S. each year, and this number is rising continually due to the aging population. Other conditions that involve acquired brain injuries would also be amenable to such treatment, such as treatment of individuals with surgical removal of brain tumors. In each of these groups, artificial coupling of remote brain areas may allow more efficient communication to occur in the injured brain, improving motor and cognitive functions. While clinical trials will be necessary to delineate any side effects, the risks are not expected to be any greater than other minor neurosurgical procedures.

At the end of a 4-year time span, we expect to understand the ability to rewire axonal connections in the injured brains of rodents, and to determine whether the approach can be applied safely in non-human primates. Assuming that this novel treatment enhances recovery post TBI, early phase clinical trials could be initiated in 3 to 5 additional years. This timeline will depend upon the ability to obtain FDA approval, support from industry to manufacture an implantable system, obtaining funding to conduct clinical trials, and organizing a clinical trial team. Thus, we foresee the possibility of implementing this approach in patient populations in 10 years.

Aside from the potential to impact clinical populations with TBI, stroke, and brain tumors, this project will have substantial impact on our understanding of the basic brain mechanisms underlying recovery after injury. It will provide significant information about the long-held tenet that neural coupling is guided by synchronous activity in different brain areas. It will test important hypotheses that will guide future research and clinical applications for guiding regenerative growth of nerve fibers after brain injuries.