Background and Objectives: Central and peripheral neural regulation of swallowing and aero-digestive reflexes is unclear in human neonates. Functional near infrared spectroscopy (NIRS) is a noninvasive method to measure changes in oxy-hemoglobin (HbO) and deoxy-hemoglobin (HbD). Pharyngo-esophageal manometry permits evaluation of aero-digestive reflexes. Modalities were combined to investigate feasibility and to test neonatal fronto-parietal cortical changes during pharyngo-esophageal (visceral) stimulation and/or swallowing. Methods: Ten neonates (45.6±3.0wks PMA, 4.1±0.5kg) underwent novel pharyngo-esophageal manometry concurrent with NIRS. To examine esophagus-brain interactions, we analyzed cortical hemodynamic response (HDR) latency and durations during aerodigestive provocation and esophageal reflexes. Data are presented as mean ± SE or %. Results: HDR rates were 8.84 times more likely with basal spontaneous deglutition compared to sham stimuli (P=0.004). Of 182 visceral stimuli, 95% were analyzable for esophageal responses, 38% for HDR, and 36% for both. Of analyzable HDR (N=70): a) HbO concentration (µmol/L) baseline 1.5±0.7 vs. 3.7±0.7 post- stimulus was significant (P=0.02) b) HbD concentration (µmol/L) between baseline 0.1±0.4 vs. post-stimulus -0.5±0.4 was not significant (P=0.73). c) Hemispheric lateralization was 21% left only, 29% right only, and 50% bilateral. During concurrent esophageal and NIRS responses (N=66): a) Peristaltic reflexes were present in 74% and HDR in 61%. b) HDR was 4.75 times more likely with deglutition reflex vs. secondary peristaltic reflex (P=0.016). Conclusions: Concurrent NIRS with visceral stimulation is feasible in neonates, and fronto-parietal cortical activation is recognized. Deglutition contrasting with secondary peristalsis is related to cortical activation; thus, implicating higher hierarchical aerodigestive protective functional neural networks.