Two series of complementary experiments, conducted by our exceptionally qualified team of 11 investigators from eight state-of-the-art laboratories at four institutions, will close critical gaps in the current characterization of the autonomic connectome controlling stomach function. These proposed synergistic anatomical and functional investigations will form the needed foundation for neuromodulation protocols that can correct shortcomings in past, first-generation bioelectronic attempts to ameliorate and monitor gastric disorders. Building on recent advances in mapping of vagal circuits, many reported by our research team, SA 1 will finish inventories of the efferent and afferent terminal phenotypes, analyze their collateral specializations, establish their regional distributions, and identify chemical taxonomies of their target tissues. We will also compare the neural circuitry of the human (and pig, an ideal large animal preclinical proof-of-principle model) stomach with that of the rat model to facilitate future translational extrapolations. The analyses of SA 1 will use a suite of high-definition neural tracing, immunohistochemical and molecular protocols, along with advanced imaging and morphometric techniques, that our team has adapted to autonomic circuits. SA 1 will focus on those elements in gastric neural network that may be most relevant to informing SA 2 and identify additional localized sites in the stomach wall where focal stimulation will have strong therapeutic potential. In functional assessments, SA 2 will identify optimal locations for both highly selective vagal stimulation (VNS) and precise surgical placement between the exit of the vagus from the brainstem and the target sites of the axons within the stomach wall and will determine the best stimulation protocols for augmenting gastric physiology. SA 2 will use state-of-the-art closed-loop stimulator technologies, algorithms, and electrodes (previously designed and robustly proven by investigators on our research team) and assess the reliability, validity, and stability of the VNS by employing a battery (? 6) of acute, short-term, and long-term non-invasive endpoints. The team will use data archiving and resource sharing platforms that are universally accessible to all research and medical communities.

Public Health Relevance

This project will consolidate and extend existing anatomical, molecular, and functional characterizations of the vagus-stomach connectome and identify optimal sites and parameters for disease-controlling vagal neuromodulation. It will evaluate the most applicable functional measures for closed-loop feedback for bioelectronic management of gastric disorders, including gastroparesis, reflux disease, and eating disorders.

National Institute of Health (NIH)
Office of The Director, National Institutes of Health (OD)
Project #
Application #
Study Section
Special Emphasis Panel (AFMI (51))
Program Officer
Qashu, Felicia M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Purdue University
Schools of Arts and Sciences
West Lafayette
United States
Zip Code
Budde, Ryan B; Arafat, Muhammad A; Pederson, Daniel J et al. (2018) Acid reflux induced laryngospasm as a potential mechanism of sudden death in epilepsy. Epilepsy Res 148:23-31
McAllen, Robin M; Shafton, Anthony D; Bratton, Bradford O et al. (2018) Calibration of thresholds for functional engagement of vagal A, B and C fiber groups in vivo. Bioelectron Med (Lond) 1:21-27
Lu, K-H; Cao, J; Oleson, S et al. (2018) Vagus nerve stimulation promotes gastric emptying by increasing pyloric opening measured with magnetic resonance imaging. Neurogastroenterol Motil 30:e13380
Robinson, J Paul (2018) Overview of Flow Cytometry and Microbiology. Curr Protoc Cytom 84:e37
Lu, Kun-Han; Cao, Jiayue; Oleson, Steven Thomas et al. (2017) Contrast-Enhanced Magnetic Resonance Imaging of Gastric Emptying and Motility in Rats. IEEE Trans Biomed Eng 64:2546-2554
Diwakarla, S; Fothergill, L J; Fakhry, J et al. (2017) Heterogeneity of enterochromaffin cells within the gastrointestinal tract. Neurogastroenterol Motil 29: