Brain Vascular Signatures in Drug-induced Recurrent Hypoglycemia and Associated Cognitive Dysfunction

ABSTRACT Type 2 diabetes mellitus (T2DM) poses a serious global health issue, affecting millions globally, with a concerning rise in younger age groups. T2DM patients often suffer from hypoglycemia, typically medication- induced, leading to severe consequences and cognitive impairment. Frequent hypoglycemic episodes can give

rise to 'hypoglycemia unawareness,' escalating the risk of severe hypoglycemia and cognitive decline, including dementia. Investigating cognitive alterations induced by hypoglycemia in T2DM patients is complex due to the interplay of vascular responses, brain activity, and cognitive functions. Current functional imaging techniques

can visualize brain vascular parameters but lack compatibility with behavioral assessments, creating a challenge to correlate brain activity with cognitive functions. Our research project aims to unravel the intricate connections between vascular responses and cognitive dysfunction influenced by recurrent hypoglycemia. To achieve this, we will employ a novel head-mounted dual-

modality photoacoustic/ultrasound localization (PAUL) imaging technique. With its exceptional resolution, PAUL imaging allows us to visualize detailed patterns of brain blood flow and blood oxygenation, providing data on par with fMRI. We anticipate that this advanced imaging method will enable the visualization of dynamic changes

in brain vascular signatures during cognitive assessments. Through this innovative approach, we expect to gain valuable insights into the association between hypoglycemia and cognitive impairment. Our approach involves three distinct aims. First, we plan to investigate the effects of various hypoglycemia

conditions on brain vascular responses in anesthetized rats with T2DM. By inducing diabetes in middle-aged rats and employing PAUL imaging, we aim to record vascular responses under varying insulin-induced hypoglycemia levels, frequencies, and recurrent lengths. Second, we will design a lightweight head-mounted

probe for high-quality PAUL imaging of brain vascular responses in freely moving rats, reducing stress during cognitive assessments. Lastly, we aim to scrutinize the brain vascular signatures and cognitive functions in rats with recurrent hypoglycemia. This will involve assessing cognitive behaviors while simultaneously imaging brain

blood flow and oxygenation, alongside monitoring glucose levels.