Friday, May 3, 2024
5/3/2024
PROJECT SUMMARY / ABSTRACT 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. The disease affects younger people and leads to a disproportionate loss of work-years compared to other forms of stroke. Cognitive deficits in survivors of SAH are a major driver of the inability to return to work; however, the factors leading to cognitive deficits—and the question of whether they can be prevented or reversed—are largely unknown. 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. Our group has recently observed that SAH leads to alternations in resting state functional connectivity and behavior in a mouse model of the disease. We hypothesize that these resting state networks could serve as a therapeutic target, independent of other kinds of additional underlying mechanisms (e.g., inflammatory, vascular, cellular, molecular). If we can intervene on these functional networks, then it might be possible to restore normal cognition after brain injury. We will test our hypothesis through the following aims: In Aim 1, we will determine the effect of SAH on functional connectivity and behavior. In Aim 2, we will determine the effect of SAH on structural connectivity. In Aim 3, we will determine the effect of brain stimulation on functional connectivity and cognition. To accomplish the aims, we have assembled a multidisciplinary team to determine potential mechanisms of neurocognitive deficits after SAH that includes expertise in the clinical management of SAH, preclinical mouse models of SAH, in vivo functional optical imaging, mouse MRI, and neuronal circuit manipulation with optogenetics and chemogenetics. The ultimate goal of this proposal is to improve cognitive deficits in survivors of aneurysm rupture. Regardless of our findings, we will gain an understanding of the role of functional networks in cognition following aneurysm rupture. Our hope is that intervening on these networks can lead to an effective therapy. If we are successful, we will lay the groundwork for a cure towards neurocognitive decline following subarachnoid hemorrhage while also contributing to a deeper understanding of the fundamental mechanisms underlying cognition.
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