Abstract
Vagus nerve stimulation (VNS) is thought to affect neural activity by recruiting brain-wide release of neuromodulators. VNS is used in treatment-resistant epilepsy, and is increasingly being explored for other disorders, such as depression, and as a cognitive enhancer. However, the promise of VNS is only partially fulfilled due to a lack of mechanistic understanding of the transfer function between stimulation parameters and neuromodulatory response, together with a lack of biosensors for assaying stimulation efficacy in real time. We here develop an approach to VNS in head-fixed mice on a treadmill and show that pupil dilation is a reliable and convenient biosensor for VNS-evoked cortical neuromodulation. In an ‘optimal’ zone of stimulation parameters, current leakage and off-target effects are minimized and the extent of pupil dilation tracks VNS-evoked basal-forebrain cholinergic axon activity in neocortex. Thus, pupil dilation is a sensitive readout of the moment-by-moment, titratable effects of VNS on brain state.
Highlights
Vagus nerve stimulation (VNS) is thought to affect neural activity by recruiting brain-wide release of neuromodulators
In order to determine if vagus nerve stimulation (VNS) results in the release of acetylcholine in the cortex and if this VNS-evoked neuromodulation can be tracked using pupillometry, we developed a VNS approach in head-fixed mice
Because there has not been an established biosensor to titrate stimulation on a patient-bypatient basis, or in real time, optimizations of VNS parameters are made only coarsely, often across months or years based on patient feedback
Summary
Vagus nerve stimulation (VNS) is thought to affect neural activity by recruiting brain-wide release of neuromodulators. Functional neuroimaging in humans and c-fos imaging in rats show VNS-evoked activity in many brain regions, including the amygdala, thalamus, hypothalamus, and cerebral cortex[14,15] This widespread brain activation pattern, together with the functional anatomy of the direct connections of the vagus nerve with the brain, suggests a prominent role for brain-wide neuromodulatory systems in mediating the effects of VNS on the brain. In sensory and motor systems, VNS-evoked cortical neuromodulation is increasingly explored for therapeutic benefits in a Hebbian framework, by temporally pairing VNS with sensory stimulation or movements These studies suggest a prominent role for VNS-evoked basal forebrain acetylcholine release in the neocortex. Noninvasive biosensor(s), which could track the brain’s response to VNS, would allow more systematic optimization of treatment in each patient, and potentially open up avenues for closed-loop, adaptive stimulation strategies that respond in real time to the ongoing dynamics of brain activity[4,9]
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