Although symptoms arising from the esophagus such as heartburn and pain can at times become challenging clinical problems, esophageal viscero-sensation, especially with regard to chemical stimulation in humans is incompletely understood. AIMS: i) Characterize and ascertain the reproducibility of cerebral cortical registration of heartburn, ii) elucidate the differences between these findings and those of esophageal subliminal acid stimulation in asymptomatic controls. METHOD: We studied 11 gastro-esophageal reflux disease (GERD) patients (9 male, 30-55 yrs) and 15 healthy controls (8 M, 21-49 yrs). Cerebral cortical functional magnetic resonance imaging (fMRI) activity was recorded twice in each subject, during two 5-min. intervals of 0.1 NHCl, separated by 5-min. of NaCl perfusion. RESULTS: Time from onset of acid perfusion to instant of fMRI signal increase and first report of heartburn averaged 1.60±0.80 and 1.85±0.60 minutes, respectively. Average maximum percent signal increase in the GERD patients (16.3±3.5%) was significantly greater than that of healthy controls (3.8±0.9%) (p<0.01). Temporal fMRI signal characteristics during heartburn were significantly different from those of subliminal acid stimulation in controls (p<0.01). Activated cortical regions included/motor, parieto-occipital, cingulate and prefrontal regions, and the insula. There was 92% concordance between the activated Brodmann areas in repeated studies of GERD patients. CONCLUSIONS: Cortical activity associated with perceived and unperceived esophageal acid exposure in GERD patients and healthy controls, respectively, involves multiple brain regions, but occurs more rapidly and with greater intensity in GERD patients than the activity in response to subliminal acid exposure in healthy controls. The cortical pain-processing pathway seems to be involved in perception of esophageal acid exposure and could explain the variations encountered in clinical practice defining this sensation.