Determinants of functional brain connectivity after subarachnoid hemorrhage

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PROJECT SUMMARY / ABSTRACT I am a practicing neurointensivist with a background in biochemistry, biophysics, and molecular biology. I seek to become an independent translational neuroscientist so that I can improve outcomes in survivors of brain aneurysm rupture. The proposed research and career development plan leverages the expertise of a mentorship team based at Massachusetts General Hospital and Harvard Medical School to give me the additional skills and experience necessary to obtain an R01 and reach scientific independence. Subarachnoid hemorrhage (SAH) from a ruptured brain aneurysm is a life-changing condition which affects more than 30,000 Americans at a cost of $5.6 billion annually. Even survivors with a good outcome on common outcome scales suffer from persistent cognitive deficits precluding return to work. Studies using fMRI and magnetoencephalography suggest that these cognitive deficits are associated with alterations in resting state functional brain connectivity, an indicator of long range neuronal network integrity. However, a major gap in knowledge remains: it is unclear how the SAH-damaged brain leads to changes in brain connectivity. Based on pilot data and published reports, I propose the hypothesis that early after SAH (i) diffuse neuronal death and axonal/ myelin damage lead to a decrease in global functional connectivity by decreasing the number of structural connections between brain regions and (ii) a phenomenon called spreading depolarization (SD) can cause an increase in local brain connectivity (“too much” connectivity) in the same hemisphere of the SD by increasing mediators of synaptic plasticity. Pilot data suggest that both processes can lead to worse performance on behavioral assessments. I will test this hypothesis in 3 integrated aims. In Aim 1, I will determine the effect of SAH alone on functional connectivity and behavior. In Aim 2, I will determine the effect of early recurrent SDs in the setting of SAH on functional connectivity and behavior. In Aim 3, I will investigate potential mechanisms of altered functional connectivity following SAH with or without SDs. To accomplish the aims, I will use novel mouse models which reconstitute SAH and SDs and allow for in vivo optical and local field potential measures of functional brain connectivity. To take the first steps towards assessing causes of altered connectivity, I will use a combination of immunohistochemistry, molecular tools, and cortico-cortical evoked potentials. Whenever possible, I will make use of innovative non-invasive approaches, for example, in the induction of SDs and in optical measurements of functional connectivity. The ultimate goal of this proposal is to provide me with the experience essential to achieve scientific independence, transition to my own lab, and become the kind of investigator who can find ways to improve neurocognitive outcomes in survivors of aneurysm rupture and other forms of acute brain injury.