The cingulate and insular cortices are parts of the limbic system that process and modulate GI sensory signals. We hypothesized that sensitization of these two limbic area may operate in esophageal sensitization. Thus, the objective of the study was to elucidate the neurocognitive processing in the cingulate and insular cortices to mechanical stimulation of the proximal esophagus following infusion of acid or phosphate buffer solution (PBS) into the esophagus METHODS: Twenty six studies (14 to acid and 12 to PBS infusion) were performed in 20 healthy subjects (18-35 yr) using high resolution (2.5x2.5x2.5 mm3 voxel size) fMRI. Paradigm-driven, 2-minute fMRI scans were performed during randomly timed 15-sec intervals of proximal esophageal barostatically controlled distentions and rest, before and after 30-min of distal esophageal acid or PBS perfusion (0.1N HCl or 0.1 M PBS at 1ml /min). RESULTS: Following distal esophageal acid infusion, at subliminal and liminal levels of proximal esophageal distentions, the number of activated voxels in both cingulate and insular cortices showed a significant increase compared to pre- acid infusion (p<0.05). No statistically significant change in cortical activity was noted following PBS infusion. CONCLUSIONS: 1) Acid stimulation of the esophagus results in sensitization of the cingulate and insular cortices to subliminal and liminal non-painful mechanical stimulations. 2) These findings can have ramifications with regard to the mechanisms of some esophageal symptoms attributed to reflux disease.