Characterization of the cerebral cortical representation of heartburn in GERD patients.

Although symptoms arising from the esophagus such as heartburn and pain can at times become challenging clinical problems, esophageal viscerosensation, especially with regard to chemical stimulation in humans, is incompletely understood. Our aims were 1) to characterize and ascertain the reproducibility of cerebral cortical registration of heartburn and 2) to elucidate the differences between these findings and those of esophageal subliminal acid stimulation in asymptomatic controls. We studied 11 gastroesophageal reflux disease (GERD) patients (9 males, 30-55 yr) and 15 healthy controls (8 males, 21-49 yr). Cerebral cortical functional magnetic resonance imaging (fMRI) activity was recorded twice in each subject, during two 5-min intervals of 0.1 N HCl, separated by 5 min of NaCl perfusion. 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 min, 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 sensory/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. 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.

[1]  R W Cox,et al.  Real‐time 3D image registration for functional MRI , 1999, Magnetic resonance in medicine.

[2]  T. Shi,et al.  Morphology of thalamocortical neurons projecting to the primary somatosensory cortex and their relationship to spinothalamic terminals in the squirrel monkey , 1995, The Journal of comparative neurology.

[3]  Anthony K. P. Jones,et al.  Pain processing during three levels of noxious stimulation produces differential patterns of central activity , 1997, Pain.

[4]  B. Vogt,et al.  Pain Processing in Four Regions of Human Cingulate Cortex Localized with Co‐registered PET and MR Imaging , 1996, The European journal of neuroscience.

[5]  D. Schacter,et al.  Can medial temporal lobe regions distinguish true from false? An event-related functional MRI study of veridical and illusory recognition memory , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[6]  Apkar Apkarian,et al.  Thalamocortical connections of the cingulate and insula in relation to nociceptive inputs to the cortex , 1998 .

[7]  E. Carmichael,et al.  SOME SENSORY SYNDROMES IN CHILDREN: INDIFFERENCE TO PAIN AND SENSORY NEUROPATHY , 1959, Journal of neurology, neurosurgery, and psychiatry.

[8]  R P Lesser,et al.  Painful stimuli evoke potentials recorded over the human anterior cingulate gyrus. , 1998, Journal of neurophysiology.

[9]  A. K. Jones,et al.  Cerebral responses to a continual tonic pain stimulus measured using positron emission tomography , 1998, Pain.

[10]  M. Bushnell,et al.  Cortical representation of the sensory dimension of pain. , 2001, Journal of neurophysiology.

[11]  R. Leiguarda,et al.  Asymbolia for pain: A sensory‐limbic disconnection syndrome , 1988, Annals of neurology.

[12]  R. Peyron,et al.  Functional imaging of brain responses to pain. A review and meta-analysis (2000) , 2000, Neurophysiologie Clinique/Clinical Neurophysiology.

[13]  R. Kessler,et al.  Regional cerebral activation in irritable bowel syndrome and control subjects with painful and nonpainful rectal distention. , 2000, Gastroenterology.

[14]  M. L. Wood,et al.  Functional MRI of pain- and attention-related activations in the human cingulate cortex. , 1997, Journal of neurophysiology.

[15]  A. Schnitzler,et al.  Functional Neuroimaging of Visceral Sensation , 2000, Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society.

[16]  K. Davis,et al.  The neural circuitry of pain as explored with functional MRI , 2000, Neurological research.

[17]  M. Torrens.  Co-Planar Stereotaxic Atlas of the Human Brain—3-Dimensional Proportional System: An Approach to Cerebral Imaging, J. Talairach, P. Tournoux. Georg Thieme Verlag, New York (1988), 122 pp., 130 figs. DM 268 , 1990 .

[18]  A Schnitzler,et al.  Somatic and limbic cortex activation in esophageal distention: a functional magnetic resonance imaging study. , 1998, Annals of neurology.

[19]  Michael H. Kutner.  Applied Linear Statistical Models , 1974 .

[20]  R. Shaker,et al.  Cerebral cortical registration of subliminal visceral stimulation. , 2002, Gastroenterology.

[21]  J. Le Bas,et al.  Central processing of rectal pain: a functional MR imaging study. , 1999, AJNR. American journal of neuroradiology.

[22]  Roland Peyron,et al.  Role of Operculoinsular Cortices in Human Pain Processing: Converging Evidence from PET, fMRI, Dipole Modeling, and Intracerebral Recordings of Evoked Potentials , 2002, NeuroImage.

[23]  R W Cox,et al.  Software tools for analysis and visualization of fMRI data , 1997, NMR in biomedicine.

[24]  D. Castell,et al.  Symptomatic gastroesophageal reflux: Incidence and precipitating factors , 1976, The American Journal of Digestive Diseases.

[25]  A. Hobson,et al.  Contribution of central sensitisation to the development of noncardiac chest pain , 2000, The Lancet.

[26]  E. G. Jones,et al.  Chemically distinct compartments of the thalamic VPM nucleus in monkeys relay principal and spinal trigeminal pathways to different layers of the somatosensory cortex , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[27]  Alan C. Evans,et al.  Functional imaging of an illusion of pain , 1996, Nature.

[28]  Alan C. Evans,et al.  Distributed processing of pain and vibration by the human brain , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[29]  Q Aziz,et al.  Central neural mechanisms mediating human visceral hypersensitivity. , 2001, American journal of physiology. Gastrointestinal and liver physiology.

[30]  B. Vogt,et al.  Pain and Stroop interference tasks activate separate processing modules in anterior cingulate cortex , 1998, Experimental Brain Research.

[31]  A. Schnitzler,et al.  Neurophysiology and Functional Neuroanatomy of Pain Perception , 2000, Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society.

[32]  M. Bushnell,et al.  Pain perception: is there a role for primary somatosensory cortex? , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[33]  A Sundin,et al.  Identification of human brain loci processing esophageal sensation using positron emission tomography. , 1997, Gastroenterology.

[34]  R. Cox,et al.  Identification and characterization of cerebral cortical response to esophageal mucosal acid exposure and distention. , 1998, Gastroenterology.

[35]  L. Blackshaw,et al.  Involvement of gastrointestinal mechano- and intestinal chemoreceptors in vagal reflexes: an electrophysiological study. , 1987, Journal of the autonomic nervous system.

[36]  R. J. Seitz,et al.  Somatic and limbic cortex activation in esophageal distention: A functional imaging study , 1998, Annals of neurology.

[37]  A Jesmanowicz,et al.  Swallow-related cerebral cortical activity maps are not specific to deglutition. , 2001, American journal of physiology. Gastrointestinal and liver physiology.

[38]  L. Lundell,et al.  Is the esophageal squamous epithelial barrier function impaired in patients with gastroesophageal reflux disease? , 1999, Scandinavian journal of gastroenterology.

[39]  I. Tracey,et al.  Cortical Processing of Human Somatic and Visceral Sensation , 1999, The Journal of Neuroscience.

[40]  USNR LCDR Otto T. Nebel MC,et al.  Symptomatic gastroesophageal reflux: Incidence and precipitating factors , 2005, The American Journal of Digestive Diseases.

[41]  S Minoshima,et al.  Gastric distention correlates with activation of multiple cortical and subcortical regions. , 2001, Gastroenterology.

[42]  J. Copas,et al.  Applied Linear Statistical Models, 2nd Edition. , 1987 .

[43]  H. Fields,et al.  Pain: Mechanisms and Management , 1989 .