Real-time imaging of human cortical activity evoked by painful esophageal stimulation

doi:10.1053/j.gastro.2004.12.033

Gastroenterology

Volume 128, Issue 3, March 2005, Pages 610-619

https://doi.org/10.1053/j.gastro.2004.12.033 Get rights and content

Background & aims: Current models of visceral pain processing derived from metabolic brain imaging techniques fail to differentiate between exogenous (stimulus-dependent) and endogenous (non-stimulus-specific) neural activity. The aim of this study was to determine the spatiotemporal correlates of exogenous neural activity evoked by painful esophageal stimulation. Methods: In 16 healthy subjects (8 men; mean age, 30.2 ± 2.2 years), we recorded magnetoencephalographic responses to 2 runs of 50 painful esophageal electrical stimuli originating from 8 brain subregions. Subsequently, 11 subjects (6 men; mean age, 31.2 ± 1.8 years) had esophageal cortical evoked potentials recorded on a separate occasion by using similar experimental parameters. Results: Earliest cortical activity (P1) was recorded in parallel in the primary/secondary somatosensory cortex and posterior insula (∼85 ms). Significantly later activity was seen in the anterior insula (∼103 ms) and cingulate cortex (∼106 ms; P = .0001). There was no difference between the P1 latency for magnetoencephalography and cortical evoked potential (P = .16); however, neural activity recorded with cortical evoked potential was longer than with magnetoencephalography (P = .001). No sex differences were seen for psychophysical or neurophysiological measures. Conclusions: This study shows that exogenous cortical neural activity evoked by experimental esophageal pain is processed simultaneously in somatosensory and posterior insula regions. Activity in the anterior insula and cingulate—brain regions that process the affective aspects of esophageal pain—occurs significantly later than in the somatosensory regions, and no sex differences were observed with this experimental paradigm. Cortical evoked potential reflects the summation of cortical activity from these brain regions and has sufficient temporal resolution to separate exogenous and endogenous neural activity.

Section snippets

Subjects

We recruited 16 healthy volunteers (8 men; mean age, 33.8 ± 2.2 years). All were free of any gastrointestinal, cardiac, or neurological disorders, and none was taking any medication at the time of the study. Informed written consent was obtained from all volunteers, and the local ethics committee approved the experimental protocols.

Electrical stimulation

Esophageal electrical stimulation was performed by using a pair of platinum bipolar ring electrodes (2-mm electrodes with an interelectrode distance of 1 cm) sited 5

Results

There was no significant difference in the age of our male and female subjects (female, 29.4 ± 7.6 years; male, 30.8 ± 2.9 years; P = .66) enrolled in the combined study.

Discussion

The MEG data described herein show for the first time that, after painful electrical stimulation of the esophagus, neural activity initially occurs in parallel within the primary (S1) and secondary (S2) somatosensory cortex and the posterior region of the insular cortex. After this, neural activity is observed within the anterior portion of the insular cortex and throughout the cingulate cortex. Activity in the mid-portion of the cingulate cortex occurs significantly earlier than that observed

References (54)

R. Peyron et al.
Functional imaging of brain responses to pain. A review and meta-analysis (2000)
Neurophysiol Clin
(2000)
W.E. Whitehead et al.
Is rectal pain sensitivity a biological marker for irritable bowel syndromepsychological influences on pain perception
Gastroenterology
(1998)
T.J. Ness et al.
Visceral paina review of experimental studies
Pain
(1990)
K. Casey
Concepts of pain mechanismsthe contribution of functional imaging of the human brain
Prog Brain Res
(2000)
Q. Aziz et al.
Identification of human brain loci processing esophageal sensation using positron emission tomography
Gastroenterology
(1997)
B. Bromm et al.
Neurophysiological evaluation of pain
Electroencephalogr Clin Neurophysiol
(1998)
J.D. Lewine et al.
Clinical electroencephalography and event related potentials
J.D. Lewine et al.
Magnetoencephalography and magnetic source imaging
S. Hollerbach et al.
The magnitude of the central response to esophageal electrical stimulation is intensity dependent
Gastroenterology
(1997)
J. Vrba et al.
Signal processing in magnetoencephalography
Methods
(2001)

H.R. Mertz

Overview of functional gastrointestinal disordersdysfunction of the brain-gut axis

Gastroenterol Clin North Am

(2003)

J. Mackenzie

Some points bearing on the association of sensory disorders and visceral disease

Brain

(1893)

Cited by (81)

Brain Processing of Gastrointestinal Sensory Signaling
2018, Physiology of the Gastrointestinal Tract, Sixth Edition
Visceral information reaches the brain through a diverse array of neural, humoral, and immune pathways, conveying an abundance of ascending visceral information that helps to maintain homeostasis within the gastrointestinal (GI) tract (Johnson and Gebhart). While the vast majority of these physiological processes are subconscious, those that do enter consciousness include sensations such as hunger, satiety, and the urge to defecate. Contrastingly, at the extreme of this GI sensory spectrum is visceral pain, engendered by a complex interaction between the intraluminal milieu and a plethora of host factors that, in turn, comprise the multifaceted neurobehavioral system. The GI sensory spectrum invokes activity in numerous subcortical and cortical structures via projections from vagal and spinal afferents, which cumulatively results in an individual's unique sensory experience (Willis et al. and Derbyshire). This chapter will focus on the processing of GI sensation within the brain in health that results in conscious perception with particular attention being paid to the neuroanatomical representations that have been derived from recent functional neuroimaging studies.
Insights into the mechanisms and the emergence of sex-differences in pain
2016, Neuroscience
Recent studies describe sex and gender as critical factors conditioning the experience of pain and the strategies to respond to it. It is now clear that men and women have different physiological and behavioral responses to pain. Some pathological pain states are also highly sex-specific. This clinical observation has been often verified with animal studies which helped to decipher the mechanisms underlying the observed female hyper-reactivity and hyper-sensitivity to pain states. The role of gonadal hormones in the modulation of pain responses has been a straightforward hypothesis but, if pertinent in many cases, cannot fully account for this complex sensation, which includes an important cognitive component. Clinical and fundamental data are reviewed here with a special emphasis on possible developmental processes giving rise to sex-differences in pain processing.
Age, gender, and women's health and the patient
2016, Gastroenterology
Patients with functional gastrointestinal disorders (FGIDs) often experience distress, reduced quality of life, a perceived lack of validation, and an unsatisfactory experience with health care providers. A health care provider can provide the patient with a framework in which to understand and legitimize their symptoms, remove self-doubt or blame, and identify factors that contribute to symptoms that the patient can influence or control. This framework is implemented with the consideration of important factors that impact FGIDs, such as gender, age, society, and the patient’s perspective. Although the majority of FGIDs, including globus, rumination syndrome, irritable bowel syndrome, bloating, constipation, functional abdominal pain, sphincter of Oddi dyskinesia, pelvic floor dysfunction, and extraintestinal manifestations, are more prevalent in women than in men, functional chest pain, dyspepsia, vomiting, and anorectal pain do not appear to vary by gender. Studies have suggested sex differences in somatic, but not visceral, pain perception, motility, and central processing of visceral pain; although further research is required in autonomic nervous system dysfunction, genetics, and immunologic/microbiome. Gender differences in response to psychological treatments, antidepressants, fiber, probiotics, and anticholinergics have not been studied adequately. However, a greater clinical response to 5-HT₃ antagonists but not 5-HT₄ agonists has been reported in women compared with men.
Evaluation of Esophageal Sensation
2014, Gastrointestinal Endoscopy Clinics of North America
Citation Excerpt :
Cerebral evoked potentials provided the opportunity to separate out exogenous cortical responses (stimulus-dependent activity) from endogenous responses. Activity that occurs after more than 300 milliseconds represents endogenous cortical activity, whereas the activity that occurs up to approximately 300 milliseconds after stimulation represents the exogenous component of esophageal-cortical sensory processing.33,34 The neuroanatomic localization of the stimulated area of the brain during esophageal stimulation may be determined using fMRI and PET.35
Do patients with functional chest pain have neuroplastic reorganization of the pain matrix? A diffusion tensor imaging study
2014, Scandinavian Journal of Pain
In functional chest pain (FCP) of presumed esophageal origin central nervous system hyperexcitability is generally believed to play an important role in pain pathogenesis. However, this theory has recently been challenged. Using magnetic resonance diffusion tensor imaging, the aim was to characterize any microstructural reorganization of the pain neuromatrix in FCP patients.
13 FCP patients and 20 matched healthy controls were studied in a 3T MR scanner. Inclusion criteria were relevant chest pain, normal coronary angiogram and normal upper gastrointestinal evaluation. Apparent diffusion coefficient (ADC) (i.e. mean diffusivity of water) and fractional anisotropy (FA) (i.e. directionality of water diffusion as a measure of fiber organization) values were assessed in the secondary sensory cortex, cingulate cortex, insula, prefrontal cortex, and amygdala.
Overall, including all regions, no difference in ADC and FA values was found between the patients and controls (P = 0.79 and P = 0.23, respectively). Post-hoc tests revealed no difference in ADC and FA values of the individual regions. However, a trend of patients having increased ADC in the mid insula grey matter and increased FA in the mid insula white matter was observed (both P = 0.065).
This explorative study suggests that microstructural reorganization of the central pain neuromatrix may not be present in well-characterized FCP patients.
This finding, together with recent neurophysiologal evidence, challenges the theory of visceral hypersensitivity due to changes in the central nervous system in FCP patients.
Brain networks encoding rectal sensation in type 1 diabetes
2013, Neuroscience
It has been shown that patients with type 1 diabetes mellitus and gastrointestinal (GI) symptoms have abnormal processing of sensory information following stimulation in the oesophagus. In order to find less invasive stimuli to study visceral afferent processing and to further elaborate the gut–brain network in diabetes, we studied brain networks following rectal electrical stimulations.
Twelve type 1 diabetes patients with GI symptoms and twelve healthy controls were included. A standard ambulatory 24-h electrocardiography was performed. 122-channel-evoked brain potentials to electrical stimulation in the rectum were recorded. Brain source-connectivity analysis was done. GI symptoms were assessed with the gastroparesis cardinal symptom index and quality of life (QOL) with SF-36. Any changes in brain source connectivity were correlated to duration of the disease, heart beat-to-beat intervals (RRs), clinical symptoms, and QOL of the patients.
Diabetic patients with GI symptoms showed changes relative to controls in the operculum–cingulate network with the operculum source localized deeper and more anterior (P ⩽ 0.001) and the cingulate source localized more anterior (P = 0.03). The shift of operculum source was correlated with the duration of the disease, severity of GI symptoms, and decreased RR (P < 0.05). The shift of the cingulate source was correlated with the mental QOL (P = 0.04). In healthy controls, the contribution of the cingulate source to the network was higher than the contribution of the operculum source (P ⩽ 0.001), whereas in patients the contribution of the two sources was comparable.
This study gives further evidence for CNS involvement in diabetes. Since network reorganizations were correlated to GI symptoms, irregularities of rectal-evoked potentials can be viewed as a proxy for abnormal bottom-up visceral afferent processing. The network changes might serve as a biomarker for disturbed sensory visceral processing of GI symptoms in diabetes patients.

View all citing articles on Scopus

¹: A.R.H. is funded by the UK Medical Research Council, and S.F.W. is funded by the Lord Dowding Fund for Humane Research. This project also received funding from the Golden Charitable Trust.

View full text

Clinical-alimentary tractReal-time imaging of human cortical activity evoked by painful esophageal stimulation

Section snippets

Subjects

Electrical stimulation

Results

Discussion

Neurophysiol Clin

Gastroenterology

Pain

Prog Brain Res

Gastroenterology

Electroencephalogr Clin Neurophysiol

Gastroenterology

Methods

Clin Neurophysiol

Neuroimage

Am J Gastroenterol

Clin Neurophysiol

Neurophysiol Clin

Biol Psychol

Brain Dev

Neuroimage

Eur J Pain

Neuroimage

Clin Neurophysiol

Neuroimage

Brain Res Brain Res Rev

Brain Res

Gastroenterology

Gastroenterol Clin North Am

Some points bearing on the association of sensory disorders and visceral disease

Brain

Clinical-alimentary tract
Real-time imaging of human cortical activity evoked by painful esophageal stimulation