Type 2 Diabetes Mellitus (DM2) is a major cause of disability and death, affecting nearly 26 million people in the US. Nearly three quarters of those affected have DM-related damage to their nervous system that can include behavioral and cognitive deficits, and increase the risk of dementia. We seek to advance our understanding of the neurobiological substrate for these cortical brain consequences of DM2 and develop a reliable assay for their early detection and longitudinal assessment. We hypothesize that cognitive dysfunction in DM2 is associated with alterations in cortical brain plasticity that can b demonstrated by trans-cranial magnetic stimulation (TMS). We propose to apply single- and paired-pulse TMS to evaluate cortical reactivity in individuals with DM2 as compared with matched, healthy controls. Mechanisms of cortical plasticity will be further explored by assessing the modulation of cortical reactivity induced by a specific repetitive TMS protocol known as theta burst stimulation (TBS). The comparison of the motor responses induced by single-pulse TMS before and following TBS provides a noninvasive measure of brain plasticity in humans. Cognitive testing and a motor learning task will be used to demonstrate the behavioral correlates of this measure of plasticity. Magnetic resonance imaging and magnetic resonance spectroscopy will provide further insights into the neurobiological substrates of the neurophysiologic findings. Our pilot studies support the feasibility of our approach and provide supportive evidence for our hypothesis. We thus anticipate that data from the proposed study will address an important need for a rapid, noninvasive, reliable and safe method to diagnose, evaluate and follow cortical brain dysfunction in DM2. If successful, TMS-based measures of cortical reactivity and plasticity will provide a reliable and objective assessment of DM2-associated brain dysfunction, and eventually serve as useful biomarkers to evaluate cognitive dysfunction in DM2, inform the development of effective therapies and assess treatment response in future clinical trials.