DESCRIPTION (provided by applicant): Limiting the extent of brain damage after stroke or traumatic brain injury is important to minimize functional deficits. Cortical spreading depression (CoSD) is a repetitive, slow moving wave that appears after brain damage and expands the area of neuronal death after ischemic stroke, hemorrhagic stroke, and traumatic brain injury. CoSD has also been implicated in migraine with aura and concussion. The ability to prevent CoSD would therefore be able to reduce the expansion of brain damage and mitigate symptoms related to CoSD, but pharmacological interventions are systemic and typically have significant side effects. The goal of this project is test the hypothesis that targeted non-invasive brain stimulation can reduce or block CoSD. The hypothesis is based on the idea that the mechanism underlying propagation of CoSD may be countered by the neural effects of transcranial direct current stimulation (tDCS). The propagation of the CoSD wave is mediated in part by an increase in extracellular potassium concentration, which produces a sustained depolarization followed by a period of neuronal inactivity. Cathodal transcranial direct current stimulation (tDCS) produces a widespread hyperpolarization of underlying neurons, and therefore has the potential to 'clamp' the membrane potential of large numbers of neurons and block the CoSD wave. Preliminary data shows that CoSD is blocked by cathodal tDCS. In the first set of proposed experiments, potassium chloride will be applied to the frontal cortex of the anesthetized rat to induce CoSD, and the wave will be recorded in occipital cortex with a translaminar multicontact recording electrode. TDCS will be applied to a cranial electrode placed between the frontal and occipital areas to test the hypothesis that cathodal, but not anodal or sham tDCS will block CoSD..The tDCS current magnitude and electrode size will be varied to determine the optimal conditions under which CoSD can be prevented. The second set of experiments will induce CoSD during tDCS in the same model and will measure local cerebral glucose uptake throughout the entire brain. These experiments will test the hypothesis that cathodal, but not anodal or sham tDCS halts the CoSD wave and protects neurons under and distal to the transcranial electrode from the effects of the CoSD. Moreover, since the whole brain can be analyzed at relatively high resolution, these experiments will evaluate the spatial extent and magnitude of the protective effect across the cortex, as well as to test the hypothesis that cathodal tDCS will reduce the distant effects of CoSD in the midbrain, thalamus, and striatum. Together, these experiments will provide the first evidence that tDCS blocks the CoSD wave and will define the optimal stimulation conditions to do so. Results will provide the basis for clinical trials using tDCS against neurological disorders in which CoSD plays a major role, and will serve as the basis for more complete animal experiments to more fully investigate models of stroke and traumatic brain injury. Given the low cost and portability of tDCS and its ability to target specific brain regions, these data will have direct implications for the treatmen of neurological conditions in which CoSD plays a role.

PUBLIC HEALTH RELEVANCE: Stroke, traumatic brain injury, and multiple other neurological diseases are associated with waves of cortical spreading depression, which can increase the extent of brain damage. The proposed research is relevant to public health because results will lead to the prevention of cortical spreading depression and therefore have the potential to reduce the burden of multiple neurological diseases.