Review article
Brain processing of esophageal sensation in health and disease

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The pain experience

The experience of pain has two distinct dimensions: sensation and affect [2]. The sensory dimension of pain allows localization of a painful event to the offending body region and evaluation of its intensity. This is the sensory–discriminatory aspect of pain processing. The affective dimension of pain is more complex and comprises several components that combine to produce the emotion of pain.

First, there is the unique unpleasantness associated with pain that is characterized by the use of

Extrinsic esophageal innervation

The esophagus has a dual extrinsic innervation that projects from the CNS. This is provided by the vagus nerve and from spinal visceral afferents housed in the cardiac and splanchnic nerves [6]. The vagus nerve (10th cranial nerve) has an afferent to efferent ratio of 9:1, with 70% to 90% of fibers within the nerve trunk being unmyelinated neurons and the rest being thinly myelinated Aδ-fibers [7], [8], [9]. The majority of esophageal vagal afferent neurons have cell bodies in the nodose

Vagal afferent receptors

Vagal afferents have receptive fields in the mucosal and muscle layers of the esophagus [6]. Mucosal afferents can be classified as mechanoreceptors, chemoreceptors, or thermoreceptors. Polymodal mechanoreceptors that respond to chemical stimuli have also been identified [13]. Most mucosal afferents are unmyelinated C fibers, which are described as “in parallel” because they demonstrate afferent discharge to a mechanical stimulus (ie, stretch) but not to muscle contraction (ie, peristalsis).

Spinal visceral afferents

Spinal visceral afferents constitute 5% to 10% of all fibers in the thoracic and lumbar dorsal nerve roots. Most visceral afferents pass via pre- and para-vertebral ganglia en route to the spinal cord and present collaterals to the prevertebral ganglia [9], [18], [19].

Spinal afferents have their cell bodies in the dorsal root ganglia (DRG), which are located within the cervical, thoracic, and upper lumbar spine. Two types of cell bodies have been identified within the DRG. The majority are

Spinal visceral afferent receptors

Despite the majority of afferents in the mucosa being vagal, some mucosal spinal afferents have been identified. These are mainly chemoreceptors, responsive to changes in pH, osmolality, and various nutrients (eg, glucose). It is thought that these afferents are involved in the regulation of gut reflexes such as motility and secretion. Mucosal spinal afferents that are responsive to thermal stimuli have also been identified [6], [13], [22].

Two types of spinal muscle afferents have been

Ascending tracts and thalamic nuclei

The extrinsic innervation of the esophagus is diffuse and complex. The considerable divergence of esophageal afferents across many spinal segments is coupled with subsequent convergence with visceral afferents from other GI regions and viscerosomatic afferents within the spinal cord [18], [19]. It has been shown that approximately 75% of spinal somatic afferents also respond to visceral stimulation [24].

Visceral afferent transmission predominantly ascends in the spinothalamic tract (STT) and

The cerebral cortex

Despite abundant nociceptive projections from thalamic nuclei to many regions of the cerebral cortex, its role in pain processing remained in doubt for many years [31], [32]. However, animal studies and, more recently, functional brain imaging studies in humans have revealed that the cerebral cortex plays an important role in the sensory–discriminatory and affective components of pain. The following section summarizes the role of the four main cortical regions that have consistently been shown

Electrophysiologic assessment of esophageal afferents in health

The complexities of esophageal innervation have been known for many years, yet it is only in the last 10 years that we have attempted to objectively characterize the neurophysiologic basis of esophageal sensation in humans [1]. Commonly used neurophysiologic techniques have been adapted, allowing us to noninvasively investigate the integrity and characteristics of GI afferent pathways. Our knowledge in this area is slowly expanding.

Neurophysiologists have used evoked potentials (EP) to study

Functional neuroimaging of the esophageal-cortical pain matrix

The scalp-recorded EEP represents a summation of cortical activity related to specific stages in the cortical processing of esophageal sensation and pain. Pain is a result of a complex interaction of many brain regions. This has been demonstrated for somatic pain using metabolic neuroimaging techniques such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), which have revealed pain-related activity within a network of cortical and subcortical structures

Recording esophageal–cortical neuromagnetic activity

Studies have used magnetoencephalography (MEG) to record esophageal cortical neuronal activity [66], [67], [68]. MEG detects the minute magnetic fields generated by groups of active cortical neurons using highly sensitive sensors known as SQUIDS (super conducting quantum interference device). Unlike the electrical signal recorded with EP, which is distorted by all of the structures that lie between the cortical source and the recording electrode, the magnetic field generated by an active group

Constructing a model of the esophageal pain matrix

Combining information from the animal and human studies described above, we can construct a hypothetical model of afferent transmission and CNS processing of esophageal sensation, revealing that somatic and visceral pain processing are similar. Esophageal nociceptive signals are transmitted to the STT and PSDC pathway [73] where this relatively small afferent input converges with viscerosomatic afferents [74] and is conveyed primarily to the ventro-posterior lateral nucleus of the thalamus and

Neurophysiologic profiling of noncardiac chest pain

Although the functional brain imaging techniques described above offer an important insight into the neuroanatomy and function of the cortical structures within the pain matrix, their use as clinically diagnostic techniques in the study of pain remains limited. In contrast, the use of electrophysiologic recording techniques has proved valuable in identifying the contribution of CNS lesions in the generation of somatic pain syndromes [77], [78].

Several GI research groups have used these

Hypersensitivity versus hypervigilance

We propose a simple hypothetical model to explain visceral hypersensitivity in patients with unexplained GI pain. This states that in most patients, injury/inflammation is the principle initiator of central sensitization (CS), which can persist long term, and if there is continuing occult injury then it may lead to chronic pain. It is also possible that CS may be amplified in the presence of cognitive bias (hypervigilance) toward visceral sensation. However, in some patients with visceral

Summary

This case study demonstrates that patients with NCCP can be subclassified on the basis of sensory responsiveness and neurophysiologic profiles. This approach identifies specific abnormalities within the CNS processing of esophageal sensation in individual patients, allowing us to objectively differentiate those with sensitized esophageal afferents from those that are hypervigilant to esophageal sensations. The importance of this approach is to underline that NCCP comprises a heterogeneous group

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