This disclosure relates to implantable neuromodulation systems and methods, and in particular to systems and methods for sensing blood-based parameter changes triggered by neural stimulation and subsequently optimizing the stimulation parameters based on feedback from the sensed blood-based parameter changes. Embodiments are directed to a method that includes delivering neural stimulation to a nerve or artery/nerve plexus based on a first set of stimulation parameters, monitoring a response to the neural stimulation that includes monitoring responses of the nerve or artery/nerve plexus and blood-based parameters of the artery, modifying the first set of the stimulation parameters based on the blood-based parameters to create a second set of stimulation parameters, and delivering the neural stimulation based on the second set of the stimulation parameters.