Project summary: The flow of cerebrospinal fluid (CSF) through the brain is essential for maintaining brain health, and clears metabolic waste products through the glymphatic system. Disruption of this clearance process is associated with multiple neurodegenerative disorders, notably Alzheimer’s disease. Two key mechanisms underlying CSF flow in humans are the respiratory cycle, and coherent neural activity. This project aims to determine whether synergistic drive of respiration and neural activity enhances CSF flow in the human brain. We will test how spontaneous respiration is associated with CSF flow and test whether slower breathing drives higher flow. We will then use respiratory-gated transcutaneous vagal nerve stimulation, a noninvasive neuromodulation technique to stimulate neural activity, integrating both respiratory and neural activity to optimally drive CSF flow. Finally, we will test how respiration and respiratory-gated neurostimulation modulate flow both in the large ventricles, and in the tiny perivascular spaces that are essential for brain clearance, using a new fMRI-based imaging technique with high temporal resolution to measure rhythmic dynamics in perivascular flow. Together, these studies will establish how modulation of respiration and neural activity in concert drives CSF flow through the brain. This work will provide the foundation for future clinical investigations testing whether noninvasive stimulation integrating neural and respiratory rhythms can improve clinical outcomes and protect against development of neurological disorders such as Alzheimer’s disease.