Ann. N.Y. Acad. Sci. ISSN 0077-8923
A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S Issue: The 12th OESO World Conference: Cancers of the Esophagus
Neurophysiology of the esophagus Christina Brock,1 Anne Brokjær,2 Asbjørn Mohr Drewes,1 Adam D. Farmer,3 Jens Brøndum Frøkjær,4,5 Hans Gregersen,2 and Christian Lottrup1 1 Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark. 2 Department of Health Science and Technology, Aalborg University Hospital, Aalborg, Denmark. 3 Centre for Digestive Diseases, Blizard Institute of Cell & Molecular Science, Wingate Institute of Neurogastroenterology, Barts and the London School of Medicine & Dentistry, Queen Mary University of London, London, United Kingdom. 4 Mech-Sense, Department of Radiology, Aalborg University Hospital, Aalborg, Denmark. 5 Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
Address for correspondence: [email protected]
The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on the methods and characteristics of esophageal afferents in humans; the pitfalls in characterization of mechanosensitive afferents; the sensitization of esophageal afferents in human studies; the brain source modeling in the understanding of the esophagus–brain axis; the use of evoked brain potentials in the esophagus; and measuring descending inhibition in animal and human studies. Keywords: neurophysiology; esophageal afferents; mechanosensitive; esophagus–brain axis; evoked brain potential; descending inhibition; OESO
Concise summary Esophageal pain and other sensory symptoms in the clinical settings are often blurred by confounders that make evaluation difficult. Afferent characteristics and modulation of their response, such as with drugs, can be explored by means of human experimental pain models that allow the possibility of controlling the duration, the intensity, and the nature of the pain stimulus. The main advantage of the model is that it allows a differentiated assessment of superficial and deep structures of the esophageal wall and activation of different receptors, nerve fibers, and peripheral as well as central pain mechanisms. The new models mimic mechanisms and symptoms in the clinical settings and may help us to understand and treat patients with diseases of the esophagus. The gastrointestinal (GI) tract is characterized by (1) a layered structure, (2) anisotropic behavior, (3) large (finite) deformations and nonlinear stress– strain relations, (4) viscoelastic behavior, and (5) muscle-generated forces. The possibilities for mechanical studies in vivo are limited by difficult access to the organ and lack of proper technology. Most researchers adhere to balloon distension, but pressure
is not identical to the force applied to the wall and changes in volume may not reflect true deformation of the wall. Moreover, pressure and volume are luminal measurements, while the mechanosensitive afferents are located in the GI wall. The most advanced and practically useful balloon distension technology for the GI tract is impedance planimetry, which was further developed into the multimodal probe, where the distension (mechanical) stimulus is combined with acid and thermal stimuli. Other modifications of impedance planimetry are the Hoff probe for evaluation of mechanical and ischemic pain mechanisms and the functional luminal imaging probes (FLIP) for detailed analysis of sphincter lumen geometry from measurements of serial crosssections (i.e., the distribution of the volume will be known). Combined with imaging, it may even be possible to obtain information about the wall thickness. Current technology still needs improvement. Development should aim for improving spatial and temporal resolution and increasing sensitivity and specificity. Esophageal pain is a complex phenomenon with sensory–discriminative, affective–motivational, and cognitive–evaluative components. The concept of
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visceral hypersensitivity has become the germane pathophysiological hypothesis over the last 30 years. Identification of the molecular basis of visceral hypersensitivity has not been completely elucidated; several peripheral and central mechanisms have been proposed. There have been some important recent advances in our understanding of the underlying molecular features of peripheral sensitization, and among the most intensively studied mechanisms is the transient receptor potential vallinoid receptor (TRPV1), postulated to play an important role in mechanotransduction within the GI tract. There is accumulating evidence in humans linking increased TRPV1 expression with visceral hypersensitivity, leading to considerable interest in the development of TRPV1 antagonists. The concept of central sensitization has been demonstrated in a reproducible human esophageal model in which hydrochloric acid is infused into the distal esophagus. The N-methyl-d-aspartate (NMDA) receptor has been proposed as a critical molecular factor in the development and maintenance of central sensitization, through interactions occurring at the spinal dorsal horn. Pioneering work from the Drewes group in Aalborg has led to the development and validation of a multimodal esophageal stimulation paradigm that is providing novel insights into controlled stimulation of the superficial and deep layers of the esophageal mucosa. Electroencephalography (EEG) recordings can be used for cortical evoked potentials (EPs) assessing the electrical brain responses following a timelocked stimulus (i.e., painful electrical stimulation in the esophagus). However, their main disadvantage is a poor spatial resolution of the signal in contrast to high temporal resolution. Inverse brain source modeling is based on the idea that the groups of neurons that generate surface potentials can be modeled by equivalent-current dipoles. Hence, mathematical algorithms make it possible to calculate the location, orientation, and strength of dipolar source locations. This method offers the opportunity to study pain-specific activation dynamically, as it reflects the sequential activation of the neuronal pain networks underlying the EPs. One of the major limitations of inverse modeling has been the instability of algorithms in modeling several simultaneously active sources or sources in deep-brain structures such as the thalamus or brain stem. To bypass these problems, signal-decomposition meth58
ods have been developed, separating the signal into a sum of waveforms, whereby signals corresponding to specific evoked brain activity can be separated from artifacts and noise. Once the signals are decomposed, inverse modeling can be applied on each of the retrieved waveforms. Recently, multichannel matching pursuit has been introduced, decomposing the EPs data into a sum of waveforms, each of them being defined in time, frequency, and space. EEG has a relatively poor spatial resolution even though various inverse modeling algorithms and signal decomposition procedures have overcome this limitation to some extent. The position of the original brain sources does not represent the accurate position but rather the “center of gravity” of brain activity. Taken together, spontaneous EEG and EPs provide complimentary information about the modulation of the central nervous system after painful stimuli. The resting-stage EEG oscillates in certain frequency bands associated with specific brain functions such as pain perception and attention to pain. In contrast to the spontaneous EEG, EPs present the time-locked response to an external stimulus. They have been used to explore the pathogenesis of different diseases of the esophagus such as functional chest pain (FCP). Multichannel EEG recordings combined with inverse modeling can determine the location of brain centers underlying EPs. To bypass the instability of algorithms to model several simultaneously active sources and sources in deep brain structures, signal decomposition methods have been developed in order to separate the signal into a sum of waveforms. The stability and temporal resolution of the EPs and source modeling validates their use in patient studies, and may allow for a better understanding of how esophageal pain is processed in the brain. Pain control in humans includes several levels of pain modulation. One of the unique inhibitory mechanisms is the phenomenon termed diffuse noxious inhibitory control (DNIC), which results from the physiological activation of brain structures putatively involved in descending inhibition and reduces the pain perception from a primary stimulus. It can be induced experimentally by heterotopic tonic pain stimuli outside the receptive field of the primary stimulus. In animal studies, lesions of the dorsal reticular nucleus in the caudal medulla strongly reduced DNIC, and it has thus been
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proposed that the dorsal reticular nucleus is exclusively inhibitory. However, other studies have proposed that it is also involved in descending facilitation. In humans, the reticular systems in the brain stem, and probably in the spinoreticular tracts, are also believed to be key neuronal links in the loop
subserving DNIC. The term disinhibition describes an impairment of human descending pain control, involving either inhibitory or facilitating mechanisms or both. Disinhibition has been proposed to potentially underlie the pathogenesis in chronic somatic and visceral pain.
1. Methods and characteristics of esophageal afferents in humans
only represents a limited part of the pain experience. Therefore, a variety of stimulus modalities are required. This was the rationale for development of the multimodal pain model for the esophagus.4 The main advantage of the model is that it allows a differentiated assessment of superficial and deep structures of the esophageal wall and the activation of different receptors, nerve fibers, and peripheral as well as central pain mechanisms. The model has proved to be robust and reliable across experimental sessions, and validity was confirmed in a series of studies where it was used to explore the pathophysiology of esophageal disorders such as erosive and nonerosive reflux disease (NERD), FCP, and Barrett’s esophagus (BE).5,6 The model has also been successful in the testing of new and existing drugs.3 In conclusion, experimental pain models have developed rapidly over the last decade and have provided valuable information about esophageal afferent activation as well as symptoms in health and disease. Although experimental pain also has limitations, the new models mimic mechanisms and symptoms in the clinical settings and may help us to understand and treat patients with diseases of the esophagus. 2. What are the pitfalls in characterization of mechanosensitive afferents in vivo?
Asbjørn Mohr Drewes, Anne Brokjær, and Christian Lottrup [email protected] Esophageal pain and other sensory symptoms in clinical settings are often blurred by confounders that make evaluation difficult. Hence, fear and anxiety, together with factors such as job situation, physical activity, and previous experience, interfere with assessment of pain and make evaluation of treatment difficult.1,2 This is mainly due to the difficulties in localization of visceral pain and variability in patterns of referred pain to somatic structures.1,3 To help us understand the nature of esophageal afferents, experimental methods to evoke and assess sensations after esophageal stimulation under controlled circumstances are advantageous. Afferent characteristics and modulation of their response, such as with drugs, can be explored by means of human experimental pain models. In clear contrast to clinical pain, experimental pain models allow the possibility of controlling the duration, the intensity, and the nature of the pain stimulus. In the models, we consider the pain system as a black box, but when the stimulus gives the same outcome in repeated experiments, the model is stable and helps us understand mechanisms and treatment.3 Different models have been developed for stimulation of the esophagus. Most have relied on chemical activation of the nociceptors with acid or on distension using balloons, but other models have relied on electrical stimulation. The models have now been refined to use other chemicals such as capsaicin, thermal stimulation, endoscopy, and overtubes. However, clinical pain is the end result of many chemical and electrical components activating esophageal afferents, and it is obvious that the reaction to a single stimulus of a certain modality (such as distension of the esophagus with a balloon)
Hans Gregersen [email protected] A well-functioning digestive system is dependent on internal and external neural feedback mechanisms. If the feedback mechanisms fail, the digestive function will be disordered and the patients will experience symptoms. The function of the digestive tract has been studied in vivo and in vitro using several methodological set-ups and technologies. Many studies have focused on mechanosensory responses. The present review will focus on pitfalls related to current technologies for mechanosensory studies in vivo on humans and animals.
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Figure 1. The sketch shows a piece of intestine with mechanoreceptors and afferent nerves (green lines). P denotes the pressure that distends and deforms the wall. r, l, and c denote the radial, longitudinal, and circumferential directions.
Scientists may reach erroneous conclusions from the collection, analysis, and interpretation of data. In the context of this paper, pitfalls relate to technology such as balloon distension in the gut and stimulation of in vitro preparations with von Frey hair; methodology related to the distension protocol owing to time-dependent viscoelastic effects; and misinterpretation of data related to the mechanical stimulus, the mechanical environment, and the afferent response. From extensive review of the literature on GI mechanosensory studies, it seems that selection of improper technology and a lack of knowledge of even simple mechanical terms are quite frequent, which leads to misinterpretation and erroneous conclusions.7–9 Most problems relate to misunderstanding of (1) the relationships among organ geometry, tissue structure, mechanical properties, muscle contractile properties, and afferent signaling and (2) the forces and deformation imposed by balloon distension (or other mechanical stimulus). To understand how the mechanosensitive afferents react, we must first understand the mechanical environment they are embedded in and how they react to mechanical stimuli (Fig. 1). Second, we must understand nerve conduction and pathways, and finally we must understand how the brain interprets the signaling as symptoms. This review focuses on the mechanical aspects. The GI tract is 60
complex, with irregular geometry and many building components, with cells and fibers arranged in specific patterns in each layer. In brief, the GI tract is characterized by7,8 (1) a layered structure; (2) anisotropic behavior (different properties in different directions); (3) large (finite) deformations and nonlinear stress–strain relations; (4) viscoelastic behavior; and (5) muscle-generated forces. In in vivo studies, it is impossible to obtain detailed data covering all these issues. The possibilities for mechanical studies in vivo are limited by difficult access to the organ and lack of proper technology. Most researchers adhere to balloon distension, which is a simple way to obtain data on the distending force and deformation or proxies thereof. However, balloon distension studies are often flawed. In most studies, pressure and volume are measured, but pressure is not identical to the force applied to the wall, and changes in volume may not reflect true deformation of the wall (Fig. 2). In this regard, it is important to recognize that pressure and volume are luminal measurements, while the mechanosensitive afferents are located in the GI wall. Pressure needs to be converted to stress or tension, which requires more advanced technology and analysis. Deformation must also be assessed by more advanced technology, since measurement of volume does not provide information about the distribution of the volume. Thus, increasing balloon volume may merely elongate the balloon rather than impose a stretch of the wall to stimulate mechanosensors (Fig. 2). The most advanced and practically useful balloon distension technologies for the GI tract include impedance planimetry, which was further developed into the multimodal probe, where the distension (mechanical) stimulus is combined with acid and thermal stimuli;10 the Hoff probe for evaluation of mechanical as well as ischemic pain mechanisms;11,12 and FLIP for detailed analysis of sphincter lumen geometry.13 With these technologies, the investigator gains information at cross-sectional levels (i.e., the distribution of the volume will be known). Combined with imaging, it may even be possible to obtain information about the wall thickness, but often the data are of poor quality with low resolution and cumbersome analysis. Current technology still needs improvement, and development should aim for improving spatial and temporal resolution and increasing
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Figure 2. Sketch showing distending balloon. Arrows illustrate forces. As a result of the stiffness of the wall, the balloon will elongate when filled rather than stretching the wall and receptors. Elongation will result in underestimation of the radius, inducing errors in calculation of mechanical parameters. Hence, distribution of volume in the balloon must be taken into account.
sensitivity and specificity, to be accurate and reproducible. Furthermore, useful end points must be selected as relevant biomarkers for scientific or clinical use. In conclusion, to conduct valid future studies, control of the mechanical stimulus is needed, in terms of knowing the distending forces and deformation, but also with use of proper protocols that take viscoelastic effects into consideration. In addition, the investigator must understand the structural and mechanical environment for the afferents (location, direction, oxygen supply, and tissue properties), and at the same time must be able to quantitate the measures of sensation. 3. What do we know about sensitization of esophageal afferents from human studies? Adam D. Farmer [email protected] Introduction Esophageal pain is a complex phenomenon with sensory–discriminative, affective–motivational, and cognitive–evaluative components. In particular, esophageal pain and discomfort is a common complaint, encompassing a continuum of disorders ranging from those where inflammation is present, as in erosive esophagitis (EE), to those in which inflammation is not demonstrable, as in functional esophageal disorders such as FCP or noncardiac chest pain (NCCP). Not surprisingly, the symptom burden exerted by esophageal pain per se causes a significant reduction in quality of life, and patients often have recourse to disproportionately high healthcare utilization and are frequently recalcitrant to standard therapies.14
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Esophageal hypersensitivity Within the functional esophageal disorders, the concept of visceral hypersensitivity has become the germane pathophysiological hypothesis over the last 30 years. For instance, Richter et al. demonstrated that, in comparison to healthy controls, a high percentage of patients with NCCP reported pain to intraluminal esophageal balloon distension.15 Nasr et al. further examined the role of esophageal hypersensitivity in the pathogenesis of NCCP and showed that 75% of patients demonstrated features consistent with esophageal hypersensitivity, with lower distension volumes seen at sensory threshold level, discomfort level, and pain tolerance threshold (Fig. 3).16 Similarly, in a more recent study, we have shown that patients with FCP/NCCP are hypersensitive to balloon distension (Fig. 3).17 However, the simple balloon distension paradigm lacks the sensitivity and specificity to make it a clinically useful diagnostic modality. Thus, considerable effort has been directed at the identification of the molecular basis of visceral hypersensitivity, and several peripheral and central mechanisms have been proposed. Peripheral mechanisms of esophageal pain While it is beyond the scope of this paper to review all of the mechanisms examined to date in the literature, there have been some important recent advances in our understanding of the underlying molecular features of peripheral sensitization. Among the most intensively studied mechanisms is TRPV, an ion channel that serves a diverse range of sensory functions such as temperature sensing and hearing. The TRPV1 receptor was first identified and cloned in the late 1990s and is ubiquitously expressed on small to medium-sized neurons. The TRPV1 receptor may be activated by capsaicin and heat and is postulated to play an important role in mechanotransduction within the GI tract.18 Upon activation, the TRPV1 receptor evokes a burning sensation and pain, and when associated with concomitant release of substance P, neurogenic inflammation may occur. Notably, hydrogen ions strongly potentiate this activation, and, not surprisingly, this ion channel has been widely studied in EE. There is accumulating evidence in humans linking increased TRPV1 expression with visceral hypersensitivity, leading to considerable interest in the development of TRPV1 antagonists. Krarup et al. reported a randomized, placebo-controlled,
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Figure 3. Balloon-distension studies in NCCP/FCP patients demonstrating visceral hypersensitivity to intraesophageal balloon distension. (A) Nasr et al. demonstrated that patients with NCCP have lower sensory, discomfort, and pain tolerance thresholds than healthy controls to a stepwise distension protocol.16 (B) We have recently replicated these results, demonstrating that patients with NCCP have lowered pain tolerance thresholds to a rapid ramp distension protocol. *P < 0.01.
double-blinded cross-over study investigating the effect of a TRPV1 antagonist (AZD1386) on experimentally induced esophageal pain. While pain sensitivity to modalities such as mechanical and chemical stimulation was unaffected, AZD1386 did increase pain thresholds to heat stimuli within the esophagus.19 Central mechanisms of esophageal pain Sarkar et al. demonstrated the concept of central sensitization in a reproducible human esophageal model in which hydrochloric acid is infused into the distal esophagus.20 Pain thresholds to electrical stimulation were not only reduced in the acid-exposed distal region but also in the adjacent unexposed proximal region, thereby suggesting the development of secondary hyperalgesia and central sensitization. The NMDA receptor has been proposed as a critical molecular factor in the development and maintenance of central sensitization, 62
through interactions occurring at the spinal dorsal horn.21 Interestingly, antagonism of the NMDA receptor with ketamine can prevent the development of central sensitization within the esophagus, although tolerability has limited its use in the clinical environment.22 Pioneering work from the Drewes group in Aalborg, Denmark has led to the development and validation of a multimodal esophageal stimulation paradigm, encompassing balloon distension and thermal and electrical stimulation, which is providing novel insights into controlled stimulation of the superficial and deep layers of the esophageal mucosa.4 Conclusions Esophageal pain remains a common, complex, and incompletely understood phenomenon. While advances have been made in elucidating the underlying pathophysiological mechanisms, derived from
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Figure 4. The concept of inverse brain source modeling. Based on the surface potentials in multichannel EEG recordings of evoked potentials (left), mathematical algorithms make it possible to calculate backwards into the brain with estimation of location, orientation, and strength of dipolar source locations (right). The model is here illustrated with two original pain-evoked electrical dipoles in the insula and the subsequent calculated electrical sources.
research across a diverse range of clinical disorders, further work is needed to translate these findings into improvements in patient outcomes.
of EEG recordings. To address this problem, advanced mathematics and signal-analysis algorithms have been developed, known as inverse modeling.
Acknowledgments A.D.F. was funded by a Medical Research Council project Grant MGAB1A1R.
Inverse brain source modeling Inverse brain source modeling is based on the idea that the groups of neurons that generate surface potentials can be modeled by equivalent-current dipoles. Hence, based on the surface potential in the multiple-channel recordings of EPs, mathematical algorithms make it possible to calculate the location, orientation, and strength of dipolar source locations (Fig. 4). The recorded signal is a mixture of multiple electrical sources with multiple localizations inside the brain. EPs with inverse source modeling have been used to explore the pain matrix following experimental visceral pain in healthy volunteers and different visceral diseases. This method provides an opportunity to study pain-specific activation dynamically, as it reflects the sequential activation of neuronal pain networks underlying the EPs. There are commercial software and freeware available for inverse source modeling: the most commonly used are EEGLAB (Matlab, The MathWorks Inc., Natick, MA), BESA (MEGIS Software GmbH, Gr¨afelfing, Germany), and CURRY (Compumedics, El Paso, TX).
4. Can brain source modeling be used to understand the esophagus–brain axis? Jens Brøndum Frøkjær, Christina Brock, and Asbjørn Mohr Drewes [email protected] Introduction Detailed knowledge of how the brain processes sensory information from visceral structures such as the esophagus is important in our understanding of the underlying complexity of pain mechanisms. EEG measures the electrical brain activity directly with a temporal resolution of milliseconds through scalp electrodes. EEG recordings can be used for cortical EPs assessing the electrical brain responses following a time-locked stimulus (i.e., painful electrical stimulation in the esophagus). However, the recorded EPs are generated from mixtures of multiple electrical currents generated by groups of neurons in the brain. Hence, owing to distortion of the electrical signal through meninges, skull, bone, and skin, the EPs have bad spatial resolution, as it is very difficult to predict the location and other properties of brain sources generating the signal. This poor spatial resolution of the signal is in contrast to the high temporal resolution, the main disadvantage
Clinical studies of upper-gut disorders In a study of healthy subjects, based on the BESA algorithm, EPs to electrical stimulation of the upper gut were explained by bilateral brain sources in the SII, insular cortices, and a single dipole in the anterior cingulate cortex.23 A viscerotopic
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organization of the different gut segments was seen in the brain, thus revealing a “visceral homunculus” mimicking that seen for the somatic sensory system. After experimental acid sensitization of the esophagus in healthy subjects, a posterior shift and a latency reduction of the anterior cingulate cortex dipole was seen.24 This finding may translate to the clinic, where patients with NERD often feel unpleasant chest sensations and pain despite the fact that a normal esophagus is evident at endoscopy.25 Hence, the symptoms in these patients may be partly explained by alterations in the central processing of visceral pain. A modification of bilateral insular dipole localization was seen in patients with painful chronic pancreatitis following upper-gut stimulation.25,26 As the upper gut and pancreas share the same afferent neuronal pathways, these findings likely represent a reorganization of the visceral cortical projections induced by recurrent and long-standing pain attacks due to pancreatitis. This parallels findings from somatic pain studies, where reorganization of the cortical pain matrix has been commonly reported.27 In a study of diabetes patients with autonomic neuropathy and GI symptoms, the evoked brain potentials to painful esophageal stimulation were analyzed using the fixed Multiple Signal Classification (MUSIC) algorithm in CURRY.28 The patients had a posterior shift of the anterior cingulate cortex dipole and additional sources close to the posterior insula and medial frontal gyrus. This indicates that central neuronal reorganization may contribute to our understanding of the GI symptoms in these patients.
mon approaches for signal decomposition are blind source-separation algorithms such as independent component analysis (ICA) and second-order blind identification (SOBI).29 ICA has been used to study sequential brain activation and cross talk between brain centers following electrical stimulation of the esophagus in healthy subjects.29 Recently, multichannel matching pursuit (MMP) has been introduced, decomposing the EP data into a sum of waveforms (usually termed atoms), each of them being defined in time, frequency, and space. We showed that inverse modeling on MMP atoms is superior to inverse modeling on instantaneous EP data, ICA, and SOBI components, with high accuracy in localizing superficial, deep, and simultaneously active sources.29,30 Recently, we used inverse modeling with MMP to study the effects of morphine on painful esophageal EPs in healthy subjects, where the brain source shifted frontally in atoms in the ␦-band due to morphine, whereas the source was stable in the placebo condition.31
Technical considerations and further development One of the major limitations with inverse modeling has been the instability of algorithms in modeling several simultaneously active sources or sources in deep-brain structures such as the thalamus or brain stem. To bypass these problems, signaldecomposition methods have been developed that separate the signal into a sum of waveforms, whereby signals corresponding to specific evoked brain activity can be separated from artifacts and noise. Once the signals are decomposed, inverse modeling, as explained above, can be applied on each of the retrieved waveforms. Some of the most com-
Although EEG methods also have many limitations—some of them shared with functional magnetic resonance imaging—they are generally highly available, relatively easy to use, and inexpensive.32,33 The main advantage is the high temporal resolution, which allows assessment of primary pain processing, including sequential activation and analysis of coherence and cross talk between brain centers. However, EEG has a relatively poor spatial resolution, although various inverse modeling algorithms and signal decomposition procedures have overcome this limitation to some extent. Even though multichannel EEG, cerebral EPs, and inverse modeling of the brain
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Conclusion EEG and EPs have excellent temporal resolution, and, combined with new state-of-the-art mathematical inverse source modeling, they allow us to look into the brain networks giving rise to the EPs. This may be a promising approach and the way forward to understanding brain dynamics in response to visceral pain. 5. What can evoked brain potentials be used for in the esophagus? Asbjørn Mohr Drewes, Christina Brock, and Jens Brøndum Frøkjær [email protected]
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Figure 5. Schematic representation of an evoked brain potential following painful stimulation of the esophagus. The potential is an average of repeated and identical stimulations. The cortical processing of the painful stimuli is traditionally assessed as amplitude and latency characteristics of both negative and positive peaks denoted N1, P1, N2, and P2.
sources offers a noninvasive approach to study brain activity with time resolution on a millisecond scale, it must not be overlooked that the position of the original brain sources does not represent the accurate position but rather the “center of gravity” of brain activity. The resting EEG is typically used to study the pathophysiology of pain in chronic pain patients, while EPs are used to study the nociceptive pain response, including the sequential brain activation following esophageal stimulation.24 Taken together, spontaneous EEG and EPs provide complimentary information about the modulation of the central nervous system after painful stimuli. In spite of the chaotic nature of the signals, it has been shown that the resting-stage EEG oscillates in certain frequency bands associated with specific brain functions such as pain perception and attention to pain. EEG changes to experimental pain have been described in several studies of somatic tissues, but no studies were done in volunteers or patients with esophageal pain. In contrast to the spontaneous EEG, the EPs present the time-locked response to an external stimulus. As this response is highly influenced by the sequential activation of distinct brain centers, the morphology of the EP is different from the spontaneous EEG (Fig. 5). The EP is characterized by several peaks of both negative and positive polarity, and may be quantified by the peak
amplitudes and latencies. Although simplified, the amplitudes represent the number of synchronous activated neurons, while the latency represents the delay in activation due to corticocortical connections. For example, we stimulated the acid-perfused area in the lower esophagus and found a reduction of the EP latency reflecting a central neuronal sensitization.24 The EPs have also been used to explore the pathogenesis of different diseases of the esophagus such as FCP. In a series of studies, these patients were found to have reduced latencies to painful electrical stimuli in the esophagus and the sternal skin. Furthermore, lower amplitude of the deflections was found, suggesting over-reporting and increased perception or a strong thalamic gate. Finally, Hobson et al. showed that there might be distinct patient groups lumped together under the common name of functional (or noncardiac) chest pain. Whereas most patients demonstrated hypersensitivity to electrical stimulation of the esophagus, some are sensitized with short latency (as shown after acid perfusion of the esophagus in healthy volunteers), whereas some were hypervigilant and overreporting, with long P1 latency and reduced amplitude.34 Multichannel EEG recordings combined with inverse modeling can determine the location of brain centers underlying EPs. This method provides an
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opportunity to dynamically study pain-specific cortical activation, as it reflects the sequential activation of neuronal pain networks. There are a number of commercial software and freeware available for inverse modeling of the EPs. However, one of the major limitations with inverse modeling has been the instability of algorithms in modeling several simultaneously active sources and sources in deep-brain structures such as the thalamus or brain stem. To bypass these problems, signal decomposition methods have been developed in order to separate the signal into a sum of waveforms, whereby signals corresponding to specific evoked brain activity can be separated from artifacts and noise. Some of the most common approaches for signal decomposition are blind source-separation algorithms such as independent component analysis and second-order blind identification. Drewes et al. have successfully used signal decomposition with independent component analysis to study EPs and sequential brain activation and cross talk between brain centers following electrical stimulation of the esophagus in healthy controls.29 Recently, multichannel matching pursuit was introduced, which decomposes the EP data into a sum of waveforms (usually termed atoms), each of them being defined in time, frequency, and space. Analysis on these atoms is superior to inverse modeling on instantaneous EP data and other signal decomposition methods.30 This has been used in modeling of the analgesic response to esophageal pain as well as in diabetic neuropathy. For a short review, the reader is referred to Ref. 35. In conclusion, the stability and temporal resolution of the EPs and source modeling validates their use in patient studies, and may pave the road for a better understanding of how esophageal pain is processed in the brain.
ever, it has become evident that pain control in man includes several levels of pain modulation. Diffuse noxious inhibitory control One of the unique inhibitory mechanisms is the phenomenon termed DNIC. Neurons within the dorsal horn of the spinal cord are strongly inhibited in response to a conditioning noxious tonic stimulus applied on a heterotopic location. Hence, DNIC reduces the pain perception from a primary stimulus, and can be induced experimentally by heterotopic tonic pain stimuli outside the receptive field of the primary stimulus.36,37 In other words, DNIC underlies the phrase “pain inhibits pain.” DNIC influences only convergent neurons: other cell types located in the dorsal horn, such as specific nociceptive neurons in lamina I and II, are not affected by this type of control.38 The inhibition is extremely potent, affects all the activities of the convergent neurons, and persists, sometimes for several minutes, after the removal of the conditioning stimulus. DNIC results from the physiological activation of brain structures putatively involved in descending inhibition.
Christina Brock, Jens Brøndum Frøkjær, and Asbjørn Mohr Drewes [email protected]
Measurement of descending inhibition in animals The classical knowledge of DNIC derives from animal studies where direct nerve recordings can be obtained before, during, and after the heterotopic stimulation. From these experiments it is known that lesions of the following structures did not modify DNIC: the periaqueductal gray, the cuneiform nucleus, the parabrachial area, the locus coeruleus/subcoeruleus, or the rostral ventromedial medulla (RVM) including the raphe magnus, the gigantocellularis, and the paragigantocellularis nuclei. By contrast, lesions of the dorsal raphe nucleus (DRN) in the caudal medulla strongly reduced DNIC.39,40 Thus, it has been proposed that DRN is exclusively inhibitory.41 However, other studies have proposed that DRN is also involved in descending facilitation.42 The classical animal studies examining DNIC show inhibition of spinal dorsal horn neurons following noxious heterotopic stimuli.43,44
The pain experience originating from the esophagus is multifaceted and complex. The perception is continuously modulated by inhibitory and facilitatory mechanisms. Most research on descending pain control originates in animal experiments, where the involved mechanisms are clearly described. How-
Measurements of descending inhibition in humans In humans, the reticular systems in the brain stem, and probably in the spinoreticular tracts, are also believed to be key neuronal links in the loop subserving DNIC.45 Neurons within the DRN are multiceptive
6. How can descending inhibition be measured in animal and human studies?
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neurons that have the whole body as receptive field, and the descending projections involved in DNIC terminate in the dorsal horn at all levels of the spinal cord.46 The involvement of supraspinal structures is supported by a study that showed that psychological parameters can shape the DNIC response, as it has been shown that expectation of hyperalgesia completely blocks the DNIC effect.47 An experimental study showed decreased pain-detection threshold to esophageal electrical stimulation after chemical perfusion of the distal esophagus with hydrochloride acid and capsaicin. This may likely be caused by DNIC induction following the chemical perfusion.48 Another means of assessing DNIC could involve a test stimulus applied to the esophagus while a conditioning stimulus is applied (e.g., by immersing the hand or foot into cooled water either at a fixed temperature or individually adjusted to tolerance threshold). Disinhibition The term disinhibition describes an impairment of the human descending pain control involving either inhibitory or facilitatory mechanisms or both. Disinhibition has been proposed to potentially underlie the pathogenesis in chronic somatic and visceral pain.49 Only limited information exists regarding disinhibition in painful esophageal and GI diseases, but some evidence has been shown in patients suffering from chronic pancreatitis and irritable bowel syndrome. Conclusion A thorough investigation of esophageal pain should ideally not only focus on the ascending transmission and activation, but look at the interplay between ascending and descending mechanisms. New experimental protocols, which include descending control mechanisms, may be a promising approach to understand the brain dynamics in response to esophageal organic and functional pain. Conflicts of interest The authors declare no conflicts of interest. References 1. Drewes, A.M., H. Gregersen & L. Arendt-Nielsen. 2003. Experimental pain in gastroenterology. A reappraisal of human studies. Scand. J. Gastroenterol. 38: 1115–1130.
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2. Olesen, A.E., T. Andresen, C. Staahl & A.M. Drewes. 2012. Human experimental pain models for assessing the therapeutic efficacy of analgesic drugs. Pharm. Rev. 64: 722–779. 3. Drewes, A.M., L. Arendt-Nielsen, J.H. Jensen, et al. 1997. Experimental pain in the stomach: a model based on electrical stimulation guided by gastroscopy. Gut 41: 753–757. 4. Drewes, A.M., K.-S. Schipper, G. Dimcevski, et al. 2002. Multimodal assessment of pain in the oesophagus: a new experimental model. Am. J. Physiol. Gastrointest. Liver Physiol. 283: G95–G103. 5. Drewes, A.M., H. Reddy, J. Pedersen, et al. 2006. Multimodal pain stimulations in patients with grade B oesophagitis. Gut 55: 926–932. 6. Drewes, A.M. & H. Gregersen. 2006. Multimodal pain stimulation of the gastrointestinal tract. World J. Gastroenterol. 12: 2477–2486. 7. Gregersen, H. 2002. Biomechanics of the Gastrointestinal Tract. London: Springer-Verlag. 8. Gregersen, H. & G.S. Kassab. 1996. Biomechanics of the gastrointestinal tract. Neurogastroenterol. Motil. 8: 277–297. 9. Gregersen, H., A.M. Drewes, B.P. McMahon & D. Liao. 2006. Balloon-distension studies in the gastrointestinal tract: current role. Dig. Dis. 24: 286–296. 10. Drewes, A.M., H. Reddy, J. Pedersen, et al. 2006. Multimodal pain stimulations in patients with grade B oesophagitis. Gut 55: 926–932. 11. Hoff, D.A., H. Gregersen, S. Odegaard, et al. 2010. Sensation evoked by oesophageal distension in functional chest pain patients depends on mechanical stress rather than on ischaemia. Neurogastroenterol. Motil. 22: 1170– 1176. 12. Hoff, D.A., H. Gregersen, S. Odegaard, et al. 2010. Mechanosensation and mucosal blood perfusion in the esophagus of healthy volunteers studied with a multimodal device incorporating laser Doppler flowmetry and endosonography. Dig. Dis. Sci. 55: 312–320. 13. McMahon, B.P., J.B. Frøkjær, P. Kunwald, et al. 2007. The Functional Lumen Imaging Probe (FLIP) for evaluation of the esophagogastric junction. Am. J. Physiol. 292: G377– G384. 14. Achem, S.R. 2008. Noncardiac chest pain-treatment approaches. Gastroenterol. Clin. North Am. 37: 859–878, ix. 15. Richter, J.E., C.F. Barish & D.O. Castell. 1986. Abnormal sensory perception in patients with esophageal chest pain. Gastroenterology 91: 845–852. 16. Nasr, I. et al. 2010. Investigation of esophageal sensation and biomechanical properties in functional chest pain. Neurogastroenterol. Motil. 22: 520–526, e116. 17. Farmer, A.D. et al. 2013. Psychophysiological responses to visceral and somatic pain in functional chest pain identify clinically relevant pain clusters. Neurogastroenterol. Motil. 26: 139–148. 18. Holzer, P. 2004. TRPV1 and the gut: from a tasty receptor for a painful vanilloid to a key player in hyperalgesia. Eur. J. Pharmacol. 500: 231–241. 19. Krarup, A.L. et al. 2011. Randomised clinical trial: the efficacy of a transient receptor potential vanilloid 1 antagonist AZD1386 in human oesophageal pain. Aliment. Pharmacol. Ther. 33: 1113–1122.
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20. Sarkar, S. et al. 2000. Contribution of central sensitisation to the development of non-cardiac chest pain. Lancet 356: 1154–1159. 21. Grundy, D. et al. 2006. Fundamentals of neurogastroenterology: basic science. Gastroenterology 130: 1391–1411. 22. Willert, R.P. et al. 2004. The development and maintenance of human visceral pain hypersensitivity is dependent on the N-methyl-D-aspartate receptor. Gastroenterology 126: 683– 692. 23. Drewes, A.M., G. Dimcevski , S.A. Sami, et al. 2006. The “human visceral homunculus” to pain evoked in the oesophagus, stomach, duodenum and sigmoid colon. Exp. Brain Res. 174: 443–452. 24. Sami, S.A., P. Rossel, G. Dimcevski, et al. 2006. Cortical changes to experimental sensitization of the human esophagus. Neuroscience 140: 269–279. 25. Dimcevski, G., S.A. Sami, P. Funch-Jensen, et al. 2007. Pain in chronic pancreatitis: the role of reorganization in the central nervous system. Gastroenterology 132: 1546–1556. 26. Olesen, S.S., J.B. Frokjaer, D. Lelic, et al. 2011. Painassociated adaptive cortical reorganisation in chronic pancreatitis. Pancreatology 10: 742–751. 27. Flor, H., T. Elbert, S. Knecht, et al. 1995. Phantom-limb pain as a perceptual correlate of cortical reorganization following arm amputation. Nature 375: 482–484. 28. Frokjaer, J.B., L.L. Egsgaard, C. Graversen, et al. 2011. Gastrointestinal symptoms in type-1 diabetes: is it all about brain plasticity? Eur. J. Pain 15: 249–257. 29. Drewes, A.M., S.A. Sami, G. Dimcevski, et al. 2006. Cerebral processing of painful oesophageal stimulation: a study based on independent component analysis of the EEG. Gut 55: 619–629. 30. Lelic, D., M. Gratkowski, M. Valeriani, et al. 2009. Inverse modeling on decomposed electroencephalographic data: a way forward? J. Clin. Neurophysiol. 26: 227–235. 31. Lelic, D., A.E. Olesen, C. Brock, et al. 2012. Advanced pharmaco-EEG reveals morphine induced changes in the brain’s pain network. J. Clin. Neurophysiol. 29: 219–225. 32. Schleim, S. & J.P. Roiser. 2009. fMRI in translation: the challenges facing real-world applications. Front Hum. Neurosci. 63: 1–7. 33. Robinson, M.E., R. Staud & D.D. Price. 2013. Pain measurement and brain activity: will neuroimages replace pain ratings? J. Pain 14: 323–327. 34. Hobson, A.R., P.L. Furlong, S. Sarkar, et al. 2006. Neurophysiologic assessment of esophageal sensory processing in noncardiac chest pain. Gastroenterology 130: 80–88.
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35. Frøkjær, J.B., S.S. Olesen, C. Graversen, et al. 2011. Neuroimaging of the human visceral pain system—a methodological review. Scand. J. Pain 2: 95–104. 36. Song, G.H., V. Venkatraman & K.Y. Ho. 2006. Cortical effects of anticipation and endogenous modulation of visceral pain assessed by functional brain MRI in irritable bowel syndrome patients and healthy controls. Pain 126: 79–90. 37. Wilder-Smith, C.H., G. Song, K.G. Yeoh & K.Y. Ho. 2008. Activating endogenous visceral pain modulation: a comparison of heterotopic stimulation methods in healthy controls. Eur. J. Pain. 13: 836–842. 38. Lautenbacher, S., S. Roscher & F. Strian. 2002. Inhibitory effects do not depend on the subjective experience of pain during heterotopic noxious conditioning stimulation (HNCS): a contribution to the psychophysics of pain inhibition. Eur. J. Pain 6: 365–374. 39. Le Bars, D. 2002. The whole body receptive field of dorsal horn multireceptive neurones. Brain Res. Rev. 40: 29–44. 40. Villanueva, L. & D. Le Bars. 1995. The activation of bulbospinal controls by peripheral nociceptive inputs: diffuse noxious inhibitory controls. Biol. Res. 28: 113–125. 41. Bouhassira, D., L. Villanueva, Z. Bing & B.D. Le. 1992. Involvement of the subnucleus reticularis dorsalis in diffuse noxious inhibitory controls in the rat. Brain Res. 595: 353– 357. 42. Lima, D. & A. Almeida. 2002. The medullary dorsal reticular nucleus as a pronociceptive centre of the pain control system. Prog. Neurobiol. 66: 81–108. 43. Dickenson, A.H. & D. Le Bars. 1987. Supraspinal morphine and descending inhibitions acting on the dorsal horn of the rat. J. Physiol. 384: 81–107. 44. Millan, D.J. 2002. Descending control of pain. Prog. Neurobiol. 66: 355–474. 45. de Broucker, T., P. Cesaro, J.C. Willer & B.D. Le. 1990. Diffuse noxious inhibitory controls in man. Involvement of the spinoreticular tract. Brain 113(Pt 4): 1223–1234. 46. Pud, D., Y. Granovsky & D. Yarnitsky. 2009. The methodology of experimentally induced diffuse noxious inhibitory control (DNIC)-like effect in humans. Pain 144: 16–19. 47. Goffaux, P., W.J. Redmond, P. Rainville & S. Marchand. 2007. Descending analgesia–when the spine echoes what the brain expects. Pain 130: 137–143. 48. Brock, C., T. Andresen & J.B. Frokjaer. 2010. Central pain mechanisms following combined acid and capsaicin perfusion of the human oesophagus. Eur. J. Pain 14: 273–281. 49. Mitchell, L.A., R.A. MacDonald & E.E. Brodie. 2004. Temperature and the cold pressor test. J. Pain 5: 233–237.
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A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S Issue: The 12th OESO World Conference: Cancers of the Esophagus
Neurophysiology of the esophagus Christina Brock,1 Anne Brokjær,2 Asbjørn Mohr Drewes,1 Adam D. Farmer,3 Jens Brøndum Frøkjær,4,5 Hans Gregersen,2 and Christian Lottrup1 1 Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark. 2 Department of Health Science and Technology, Aalborg University Hospital, Aalborg, Denmark. 3 Centre for Digestive Diseases, Blizard Institute of Cell & Molecular Science, Wingate Institute of Neurogastroenterology, Barts and the London School of Medicine & Dentistry, Queen Mary University of London, London, United Kingdom. 4 Mech-Sense, Department of Radiology, Aalborg University Hospital, Aalborg, Denmark. 5 Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
Address for correspondence: [email protected]
The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on the methods and characteristics of esophageal afferents in humans; the pitfalls in characterization of mechanosensitive afferents; the sensitization of esophageal afferents in human studies; the brain source modeling in the understanding of the esophagus–brain axis; the use of evoked brain potentials in the esophagus; and measuring descending inhibition in animal and human studies. Keywords: neurophysiology; esophageal afferents; mechanosensitive; esophagus–brain axis; evoked brain potential; descending inhibition; OESO
Concise summary Esophageal pain and other sensory symptoms in the clinical settings are often blurred by confounders that make evaluation difficult. Afferent characteristics and modulation of their response, such as with drugs, can be explored by means of human experimental pain models that allow the possibility of controlling the duration, the intensity, and the nature of the pain stimulus. The main advantage of the model is that it allows a differentiated assessment of superficial and deep structures of the esophageal wall and activation of different receptors, nerve fibers, and peripheral as well as central pain mechanisms. The new models mimic mechanisms and symptoms in the clinical settings and may help us to understand and treat patients with diseases of the esophagus. The gastrointestinal (GI) tract is characterized by (1) a layered structure, (2) anisotropic behavior, (3) large (finite) deformations and nonlinear stress– strain relations, (4) viscoelastic behavior, and (5) muscle-generated forces. The possibilities for mechanical studies in vivo are limited by difficult access to the organ and lack of proper technology. Most researchers adhere to balloon distension, but pressure
is not identical to the force applied to the wall and changes in volume may not reflect true deformation of the wall. Moreover, pressure and volume are luminal measurements, while the mechanosensitive afferents are located in the GI wall. The most advanced and practically useful balloon distension technology for the GI tract is impedance planimetry, which was further developed into the multimodal probe, where the distension (mechanical) stimulus is combined with acid and thermal stimuli. Other modifications of impedance planimetry are the Hoff probe for evaluation of mechanical and ischemic pain mechanisms and the functional luminal imaging probes (FLIP) for detailed analysis of sphincter lumen geometry from measurements of serial crosssections (i.e., the distribution of the volume will be known). Combined with imaging, it may even be possible to obtain information about the wall thickness. Current technology still needs improvement. Development should aim for improving spatial and temporal resolution and increasing sensitivity and specificity. Esophageal pain is a complex phenomenon with sensory–discriminative, affective–motivational, and cognitive–evaluative components. The concept of
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visceral hypersensitivity has become the germane pathophysiological hypothesis over the last 30 years. Identification of the molecular basis of visceral hypersensitivity has not been completely elucidated; several peripheral and central mechanisms have been proposed. There have been some important recent advances in our understanding of the underlying molecular features of peripheral sensitization, and among the most intensively studied mechanisms is the transient receptor potential vallinoid receptor (TRPV1), postulated to play an important role in mechanotransduction within the GI tract. There is accumulating evidence in humans linking increased TRPV1 expression with visceral hypersensitivity, leading to considerable interest in the development of TRPV1 antagonists. The concept of central sensitization has been demonstrated in a reproducible human esophageal model in which hydrochloric acid is infused into the distal esophagus. The N-methyl-d-aspartate (NMDA) receptor has been proposed as a critical molecular factor in the development and maintenance of central sensitization, through interactions occurring at the spinal dorsal horn. Pioneering work from the Drewes group in Aalborg has led to the development and validation of a multimodal esophageal stimulation paradigm that is providing novel insights into controlled stimulation of the superficial and deep layers of the esophageal mucosa. Electroencephalography (EEG) recordings can be used for cortical evoked potentials (EPs) assessing the electrical brain responses following a timelocked stimulus (i.e., painful electrical stimulation in the esophagus). However, their main disadvantage is a poor spatial resolution of the signal in contrast to high temporal resolution. Inverse brain source modeling is based on the idea that the groups of neurons that generate surface potentials can be modeled by equivalent-current dipoles. Hence, mathematical algorithms make it possible to calculate the location, orientation, and strength of dipolar source locations. This method offers the opportunity to study pain-specific activation dynamically, as it reflects the sequential activation of the neuronal pain networks underlying the EPs. One of the major limitations of inverse modeling has been the instability of algorithms in modeling several simultaneously active sources or sources in deep-brain structures such as the thalamus or brain stem. To bypass these problems, signal-decomposition meth58
ods have been developed, separating the signal into a sum of waveforms, whereby signals corresponding to specific evoked brain activity can be separated from artifacts and noise. Once the signals are decomposed, inverse modeling can be applied on each of the retrieved waveforms. Recently, multichannel matching pursuit has been introduced, decomposing the EPs data into a sum of waveforms, each of them being defined in time, frequency, and space. EEG has a relatively poor spatial resolution even though various inverse modeling algorithms and signal decomposition procedures have overcome this limitation to some extent. The position of the original brain sources does not represent the accurate position but rather the “center of gravity” of brain activity. Taken together, spontaneous EEG and EPs provide complimentary information about the modulation of the central nervous system after painful stimuli. The resting-stage EEG oscillates in certain frequency bands associated with specific brain functions such as pain perception and attention to pain. In contrast to the spontaneous EEG, EPs present the time-locked response to an external stimulus. They have been used to explore the pathogenesis of different diseases of the esophagus such as functional chest pain (FCP). Multichannel EEG recordings combined with inverse modeling can determine the location of brain centers underlying EPs. To bypass the instability of algorithms to model several simultaneously active sources and sources in deep brain structures, signal decomposition methods have been developed in order to separate the signal into a sum of waveforms. The stability and temporal resolution of the EPs and source modeling validates their use in patient studies, and may allow for a better understanding of how esophageal pain is processed in the brain. Pain control in humans includes several levels of pain modulation. One of the unique inhibitory mechanisms is the phenomenon termed diffuse noxious inhibitory control (DNIC), which results from the physiological activation of brain structures putatively involved in descending inhibition and reduces the pain perception from a primary stimulus. It can be induced experimentally by heterotopic tonic pain stimuli outside the receptive field of the primary stimulus. In animal studies, lesions of the dorsal reticular nucleus in the caudal medulla strongly reduced DNIC, and it has thus been
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proposed that the dorsal reticular nucleus is exclusively inhibitory. However, other studies have proposed that it is also involved in descending facilitation. In humans, the reticular systems in the brain stem, and probably in the spinoreticular tracts, are also believed to be key neuronal links in the loop
subserving DNIC. The term disinhibition describes an impairment of human descending pain control, involving either inhibitory or facilitating mechanisms or both. Disinhibition has been proposed to potentially underlie the pathogenesis in chronic somatic and visceral pain.
1. Methods and characteristics of esophageal afferents in humans
only represents a limited part of the pain experience. Therefore, a variety of stimulus modalities are required. This was the rationale for development of the multimodal pain model for the esophagus.4 The main advantage of the model is that it allows a differentiated assessment of superficial and deep structures of the esophageal wall and the activation of different receptors, nerve fibers, and peripheral as well as central pain mechanisms. The model has proved to be robust and reliable across experimental sessions, and validity was confirmed in a series of studies where it was used to explore the pathophysiology of esophageal disorders such as erosive and nonerosive reflux disease (NERD), FCP, and Barrett’s esophagus (BE).5,6 The model has also been successful in the testing of new and existing drugs.3 In conclusion, experimental pain models have developed rapidly over the last decade and have provided valuable information about esophageal afferent activation as well as symptoms in health and disease. Although experimental pain also has limitations, the new models mimic mechanisms and symptoms in the clinical settings and may help us to understand and treat patients with diseases of the esophagus. 2. What are the pitfalls in characterization of mechanosensitive afferents in vivo?
Asbjørn Mohr Drewes, Anne Brokjær, and Christian Lottrup [email protected] Esophageal pain and other sensory symptoms in clinical settings are often blurred by confounders that make evaluation difficult. Hence, fear and anxiety, together with factors such as job situation, physical activity, and previous experience, interfere with assessment of pain and make evaluation of treatment difficult.1,2 This is mainly due to the difficulties in localization of visceral pain and variability in patterns of referred pain to somatic structures.1,3 To help us understand the nature of esophageal afferents, experimental methods to evoke and assess sensations after esophageal stimulation under controlled circumstances are advantageous. Afferent characteristics and modulation of their response, such as with drugs, can be explored by means of human experimental pain models. In clear contrast to clinical pain, experimental pain models allow the possibility of controlling the duration, the intensity, and the nature of the pain stimulus. In the models, we consider the pain system as a black box, but when the stimulus gives the same outcome in repeated experiments, the model is stable and helps us understand mechanisms and treatment.3 Different models have been developed for stimulation of the esophagus. Most have relied on chemical activation of the nociceptors with acid or on distension using balloons, but other models have relied on electrical stimulation. The models have now been refined to use other chemicals such as capsaicin, thermal stimulation, endoscopy, and overtubes. However, clinical pain is the end result of many chemical and electrical components activating esophageal afferents, and it is obvious that the reaction to a single stimulus of a certain modality (such as distension of the esophagus with a balloon)
Hans Gregersen [email protected] A well-functioning digestive system is dependent on internal and external neural feedback mechanisms. If the feedback mechanisms fail, the digestive function will be disordered and the patients will experience symptoms. The function of the digestive tract has been studied in vivo and in vitro using several methodological set-ups and technologies. Many studies have focused on mechanosensory responses. The present review will focus on pitfalls related to current technologies for mechanosensory studies in vivo on humans and animals.
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Figure 1. The sketch shows a piece of intestine with mechanoreceptors and afferent nerves (green lines). P denotes the pressure that distends and deforms the wall. r, l, and c denote the radial, longitudinal, and circumferential directions.
Scientists may reach erroneous conclusions from the collection, analysis, and interpretation of data. In the context of this paper, pitfalls relate to technology such as balloon distension in the gut and stimulation of in vitro preparations with von Frey hair; methodology related to the distension protocol owing to time-dependent viscoelastic effects; and misinterpretation of data related to the mechanical stimulus, the mechanical environment, and the afferent response. From extensive review of the literature on GI mechanosensory studies, it seems that selection of improper technology and a lack of knowledge of even simple mechanical terms are quite frequent, which leads to misinterpretation and erroneous conclusions.7–9 Most problems relate to misunderstanding of (1) the relationships among organ geometry, tissue structure, mechanical properties, muscle contractile properties, and afferent signaling and (2) the forces and deformation imposed by balloon distension (or other mechanical stimulus). To understand how the mechanosensitive afferents react, we must first understand the mechanical environment they are embedded in and how they react to mechanical stimuli (Fig. 1). Second, we must understand nerve conduction and pathways, and finally we must understand how the brain interprets the signaling as symptoms. This review focuses on the mechanical aspects. The GI tract is 60
complex, with irregular geometry and many building components, with cells and fibers arranged in specific patterns in each layer. In brief, the GI tract is characterized by7,8 (1) a layered structure; (2) anisotropic behavior (different properties in different directions); (3) large (finite) deformations and nonlinear stress–strain relations; (4) viscoelastic behavior; and (5) muscle-generated forces. In in vivo studies, it is impossible to obtain detailed data covering all these issues. The possibilities for mechanical studies in vivo are limited by difficult access to the organ and lack of proper technology. Most researchers adhere to balloon distension, which is a simple way to obtain data on the distending force and deformation or proxies thereof. However, balloon distension studies are often flawed. In most studies, pressure and volume are measured, but pressure is not identical to the force applied to the wall, and changes in volume may not reflect true deformation of the wall (Fig. 2). In this regard, it is important to recognize that pressure and volume are luminal measurements, while the mechanosensitive afferents are located in the GI wall. Pressure needs to be converted to stress or tension, which requires more advanced technology and analysis. Deformation must also be assessed by more advanced technology, since measurement of volume does not provide information about the distribution of the volume. Thus, increasing balloon volume may merely elongate the balloon rather than impose a stretch of the wall to stimulate mechanosensors (Fig. 2). The most advanced and practically useful balloon distension technologies for the GI tract include impedance planimetry, which was further developed into the multimodal probe, where the distension (mechanical) stimulus is combined with acid and thermal stimuli;10 the Hoff probe for evaluation of mechanical as well as ischemic pain mechanisms;11,12 and FLIP for detailed analysis of sphincter lumen geometry.13 With these technologies, the investigator gains information at cross-sectional levels (i.e., the distribution of the volume will be known). Combined with imaging, it may even be possible to obtain information about the wall thickness, but often the data are of poor quality with low resolution and cumbersome analysis. Current technology still needs improvement, and development should aim for improving spatial and temporal resolution and increasing
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Figure 2. Sketch showing distending balloon. Arrows illustrate forces. As a result of the stiffness of the wall, the balloon will elongate when filled rather than stretching the wall and receptors. Elongation will result in underestimation of the radius, inducing errors in calculation of mechanical parameters. Hence, distribution of volume in the balloon must be taken into account.
sensitivity and specificity, to be accurate and reproducible. Furthermore, useful end points must be selected as relevant biomarkers for scientific or clinical use. In conclusion, to conduct valid future studies, control of the mechanical stimulus is needed, in terms of knowing the distending forces and deformation, but also with use of proper protocols that take viscoelastic effects into consideration. In addition, the investigator must understand the structural and mechanical environment for the afferents (location, direction, oxygen supply, and tissue properties), and at the same time must be able to quantitate the measures of sensation. 3. What do we know about sensitization of esophageal afferents from human studies? Adam D. Farmer [email protected] Introduction Esophageal pain is a complex phenomenon with sensory–discriminative, affective–motivational, and cognitive–evaluative components. In particular, esophageal pain and discomfort is a common complaint, encompassing a continuum of disorders ranging from those where inflammation is present, as in erosive esophagitis (EE), to those in which inflammation is not demonstrable, as in functional esophageal disorders such as FCP or noncardiac chest pain (NCCP). Not surprisingly, the symptom burden exerted by esophageal pain per se causes a significant reduction in quality of life, and patients often have recourse to disproportionately high healthcare utilization and are frequently recalcitrant to standard therapies.14
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Esophageal hypersensitivity Within the functional esophageal disorders, the concept of visceral hypersensitivity has become the germane pathophysiological hypothesis over the last 30 years. For instance, Richter et al. demonstrated that, in comparison to healthy controls, a high percentage of patients with NCCP reported pain to intraluminal esophageal balloon distension.15 Nasr et al. further examined the role of esophageal hypersensitivity in the pathogenesis of NCCP and showed that 75% of patients demonstrated features consistent with esophageal hypersensitivity, with lower distension volumes seen at sensory threshold level, discomfort level, and pain tolerance threshold (Fig. 3).16 Similarly, in a more recent study, we have shown that patients with FCP/NCCP are hypersensitive to balloon distension (Fig. 3).17 However, the simple balloon distension paradigm lacks the sensitivity and specificity to make it a clinically useful diagnostic modality. Thus, considerable effort has been directed at the identification of the molecular basis of visceral hypersensitivity, and several peripheral and central mechanisms have been proposed. Peripheral mechanisms of esophageal pain While it is beyond the scope of this paper to review all of the mechanisms examined to date in the literature, there have been some important recent advances in our understanding of the underlying molecular features of peripheral sensitization. Among the most intensively studied mechanisms is TRPV, an ion channel that serves a diverse range of sensory functions such as temperature sensing and hearing. The TRPV1 receptor was first identified and cloned in the late 1990s and is ubiquitously expressed on small to medium-sized neurons. The TRPV1 receptor may be activated by capsaicin and heat and is postulated to play an important role in mechanotransduction within the GI tract.18 Upon activation, the TRPV1 receptor evokes a burning sensation and pain, and when associated with concomitant release of substance P, neurogenic inflammation may occur. Notably, hydrogen ions strongly potentiate this activation, and, not surprisingly, this ion channel has been widely studied in EE. There is accumulating evidence in humans linking increased TRPV1 expression with visceral hypersensitivity, leading to considerable interest in the development of TRPV1 antagonists. Krarup et al. reported a randomized, placebo-controlled,
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Figure 3. Balloon-distension studies in NCCP/FCP patients demonstrating visceral hypersensitivity to intraesophageal balloon distension. (A) Nasr et al. demonstrated that patients with NCCP have lower sensory, discomfort, and pain tolerance thresholds than healthy controls to a stepwise distension protocol.16 (B) We have recently replicated these results, demonstrating that patients with NCCP have lowered pain tolerance thresholds to a rapid ramp distension protocol. *P < 0.01.
double-blinded cross-over study investigating the effect of a TRPV1 antagonist (AZD1386) on experimentally induced esophageal pain. While pain sensitivity to modalities such as mechanical and chemical stimulation was unaffected, AZD1386 did increase pain thresholds to heat stimuli within the esophagus.19 Central mechanisms of esophageal pain Sarkar et al. demonstrated the concept of central sensitization in a reproducible human esophageal model in which hydrochloric acid is infused into the distal esophagus.20 Pain thresholds to electrical stimulation were not only reduced in the acid-exposed distal region but also in the adjacent unexposed proximal region, thereby suggesting the development of secondary hyperalgesia and central sensitization. The NMDA receptor has been proposed as a critical molecular factor in the development and maintenance of central sensitization, 62
through interactions occurring at the spinal dorsal horn.21 Interestingly, antagonism of the NMDA receptor with ketamine can prevent the development of central sensitization within the esophagus, although tolerability has limited its use in the clinical environment.22 Pioneering work from the Drewes group in Aalborg, Denmark has led to the development and validation of a multimodal esophageal stimulation paradigm, encompassing balloon distension and thermal and electrical stimulation, which is providing novel insights into controlled stimulation of the superficial and deep layers of the esophageal mucosa.4 Conclusions Esophageal pain remains a common, complex, and incompletely understood phenomenon. While advances have been made in elucidating the underlying pathophysiological mechanisms, derived from
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Figure 4. The concept of inverse brain source modeling. Based on the surface potentials in multichannel EEG recordings of evoked potentials (left), mathematical algorithms make it possible to calculate backwards into the brain with estimation of location, orientation, and strength of dipolar source locations (right). The model is here illustrated with two original pain-evoked electrical dipoles in the insula and the subsequent calculated electrical sources.
research across a diverse range of clinical disorders, further work is needed to translate these findings into improvements in patient outcomes.
of EEG recordings. To address this problem, advanced mathematics and signal-analysis algorithms have been developed, known as inverse modeling.
Acknowledgments A.D.F. was funded by a Medical Research Council project Grant MGAB1A1R.
Inverse brain source modeling Inverse brain source modeling is based on the idea that the groups of neurons that generate surface potentials can be modeled by equivalent-current dipoles. Hence, based on the surface potential in the multiple-channel recordings of EPs, mathematical algorithms make it possible to calculate the location, orientation, and strength of dipolar source locations (Fig. 4). The recorded signal is a mixture of multiple electrical sources with multiple localizations inside the brain. EPs with inverse source modeling have been used to explore the pain matrix following experimental visceral pain in healthy volunteers and different visceral diseases. This method provides an opportunity to study pain-specific activation dynamically, as it reflects the sequential activation of neuronal pain networks underlying the EPs. There are commercial software and freeware available for inverse source modeling: the most commonly used are EEGLAB (Matlab, The MathWorks Inc., Natick, MA), BESA (MEGIS Software GmbH, Gr¨afelfing, Germany), and CURRY (Compumedics, El Paso, TX).
4. Can brain source modeling be used to understand the esophagus–brain axis? Jens Brøndum Frøkjær, Christina Brock, and Asbjørn Mohr Drewes [email protected] Introduction Detailed knowledge of how the brain processes sensory information from visceral structures such as the esophagus is important in our understanding of the underlying complexity of pain mechanisms. EEG measures the electrical brain activity directly with a temporal resolution of milliseconds through scalp electrodes. EEG recordings can be used for cortical EPs assessing the electrical brain responses following a time-locked stimulus (i.e., painful electrical stimulation in the esophagus). However, the recorded EPs are generated from mixtures of multiple electrical currents generated by groups of neurons in the brain. Hence, owing to distortion of the electrical signal through meninges, skull, bone, and skin, the EPs have bad spatial resolution, as it is very difficult to predict the location and other properties of brain sources generating the signal. This poor spatial resolution of the signal is in contrast to the high temporal resolution, the main disadvantage
Clinical studies of upper-gut disorders In a study of healthy subjects, based on the BESA algorithm, EPs to electrical stimulation of the upper gut were explained by bilateral brain sources in the SII, insular cortices, and a single dipole in the anterior cingulate cortex.23 A viscerotopic
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organization of the different gut segments was seen in the brain, thus revealing a “visceral homunculus” mimicking that seen for the somatic sensory system. After experimental acid sensitization of the esophagus in healthy subjects, a posterior shift and a latency reduction of the anterior cingulate cortex dipole was seen.24 This finding may translate to the clinic, where patients with NERD often feel unpleasant chest sensations and pain despite the fact that a normal esophagus is evident at endoscopy.25 Hence, the symptoms in these patients may be partly explained by alterations in the central processing of visceral pain. A modification of bilateral insular dipole localization was seen in patients with painful chronic pancreatitis following upper-gut stimulation.25,26 As the upper gut and pancreas share the same afferent neuronal pathways, these findings likely represent a reorganization of the visceral cortical projections induced by recurrent and long-standing pain attacks due to pancreatitis. This parallels findings from somatic pain studies, where reorganization of the cortical pain matrix has been commonly reported.27 In a study of diabetes patients with autonomic neuropathy and GI symptoms, the evoked brain potentials to painful esophageal stimulation were analyzed using the fixed Multiple Signal Classification (MUSIC) algorithm in CURRY.28 The patients had a posterior shift of the anterior cingulate cortex dipole and additional sources close to the posterior insula and medial frontal gyrus. This indicates that central neuronal reorganization may contribute to our understanding of the GI symptoms in these patients.
mon approaches for signal decomposition are blind source-separation algorithms such as independent component analysis (ICA) and second-order blind identification (SOBI).29 ICA has been used to study sequential brain activation and cross talk between brain centers following electrical stimulation of the esophagus in healthy subjects.29 Recently, multichannel matching pursuit (MMP) has been introduced, decomposing the EP data into a sum of waveforms (usually termed atoms), each of them being defined in time, frequency, and space. We showed that inverse modeling on MMP atoms is superior to inverse modeling on instantaneous EP data, ICA, and SOBI components, with high accuracy in localizing superficial, deep, and simultaneously active sources.29,30 Recently, we used inverse modeling with MMP to study the effects of morphine on painful esophageal EPs in healthy subjects, where the brain source shifted frontally in atoms in the ␦-band due to morphine, whereas the source was stable in the placebo condition.31
Technical considerations and further development One of the major limitations with inverse modeling has been the instability of algorithms in modeling several simultaneously active sources or sources in deep-brain structures such as the thalamus or brain stem. To bypass these problems, signaldecomposition methods have been developed that separate the signal into a sum of waveforms, whereby signals corresponding to specific evoked brain activity can be separated from artifacts and noise. Once the signals are decomposed, inverse modeling, as explained above, can be applied on each of the retrieved waveforms. Some of the most com-
Although EEG methods also have many limitations—some of them shared with functional magnetic resonance imaging—they are generally highly available, relatively easy to use, and inexpensive.32,33 The main advantage is the high temporal resolution, which allows assessment of primary pain processing, including sequential activation and analysis of coherence and cross talk between brain centers. However, EEG has a relatively poor spatial resolution, although various inverse modeling algorithms and signal decomposition procedures have overcome this limitation to some extent. Even though multichannel EEG, cerebral EPs, and inverse modeling of the brain
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Conclusion EEG and EPs have excellent temporal resolution, and, combined with new state-of-the-art mathematical inverse source modeling, they allow us to look into the brain networks giving rise to the EPs. This may be a promising approach and the way forward to understanding brain dynamics in response to visceral pain. 5. What can evoked brain potentials be used for in the esophagus? Asbjørn Mohr Drewes, Christina Brock, and Jens Brøndum Frøkjær [email protected]
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Figure 5. Schematic representation of an evoked brain potential following painful stimulation of the esophagus. The potential is an average of repeated and identical stimulations. The cortical processing of the painful stimuli is traditionally assessed as amplitude and latency characteristics of both negative and positive peaks denoted N1, P1, N2, and P2.
sources offers a noninvasive approach to study brain activity with time resolution on a millisecond scale, it must not be overlooked that the position of the original brain sources does not represent the accurate position but rather the “center of gravity” of brain activity. The resting EEG is typically used to study the pathophysiology of pain in chronic pain patients, while EPs are used to study the nociceptive pain response, including the sequential brain activation following esophageal stimulation.24 Taken together, spontaneous EEG and EPs provide complimentary information about the modulation of the central nervous system after painful stimuli. In spite of the chaotic nature of the signals, it has been shown that the resting-stage EEG oscillates in certain frequency bands associated with specific brain functions such as pain perception and attention to pain. EEG changes to experimental pain have been described in several studies of somatic tissues, but no studies were done in volunteers or patients with esophageal pain. In contrast to the spontaneous EEG, the EPs present the time-locked response to an external stimulus. As this response is highly influenced by the sequential activation of distinct brain centers, the morphology of the EP is different from the spontaneous EEG (Fig. 5). The EP is characterized by several peaks of both negative and positive polarity, and may be quantified by the peak
amplitudes and latencies. Although simplified, the amplitudes represent the number of synchronous activated neurons, while the latency represents the delay in activation due to corticocortical connections. For example, we stimulated the acid-perfused area in the lower esophagus and found a reduction of the EP latency reflecting a central neuronal sensitization.24 The EPs have also been used to explore the pathogenesis of different diseases of the esophagus such as FCP. In a series of studies, these patients were found to have reduced latencies to painful electrical stimuli in the esophagus and the sternal skin. Furthermore, lower amplitude of the deflections was found, suggesting over-reporting and increased perception or a strong thalamic gate. Finally, Hobson et al. showed that there might be distinct patient groups lumped together under the common name of functional (or noncardiac) chest pain. Whereas most patients demonstrated hypersensitivity to electrical stimulation of the esophagus, some are sensitized with short latency (as shown after acid perfusion of the esophagus in healthy volunteers), whereas some were hypervigilant and overreporting, with long P1 latency and reduced amplitude.34 Multichannel EEG recordings combined with inverse modeling can determine the location of brain centers underlying EPs. This method provides an
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opportunity to dynamically study pain-specific cortical activation, as it reflects the sequential activation of neuronal pain networks. There are a number of commercial software and freeware available for inverse modeling of the EPs. However, one of the major limitations with inverse modeling has been the instability of algorithms in modeling several simultaneously active sources and sources in deep-brain structures such as the thalamus or brain stem. To bypass these problems, signal decomposition methods have been developed in order to separate the signal into a sum of waveforms, whereby signals corresponding to specific evoked brain activity can be separated from artifacts and noise. Some of the most common approaches for signal decomposition are blind source-separation algorithms such as independent component analysis and second-order blind identification. Drewes et al. have successfully used signal decomposition with independent component analysis to study EPs and sequential brain activation and cross talk between brain centers following electrical stimulation of the esophagus in healthy controls.29 Recently, multichannel matching pursuit was introduced, which decomposes the EP data into a sum of waveforms (usually termed atoms), each of them being defined in time, frequency, and space. Analysis on these atoms is superior to inverse modeling on instantaneous EP data and other signal decomposition methods.30 This has been used in modeling of the analgesic response to esophageal pain as well as in diabetic neuropathy. For a short review, the reader is referred to Ref. 35. In conclusion, the stability and temporal resolution of the EPs and source modeling validates their use in patient studies, and may pave the road for a better understanding of how esophageal pain is processed in the brain.
ever, it has become evident that pain control in man includes several levels of pain modulation. Diffuse noxious inhibitory control One of the unique inhibitory mechanisms is the phenomenon termed DNIC. Neurons within the dorsal horn of the spinal cord are strongly inhibited in response to a conditioning noxious tonic stimulus applied on a heterotopic location. Hence, DNIC reduces the pain perception from a primary stimulus, and can be induced experimentally by heterotopic tonic pain stimuli outside the receptive field of the primary stimulus.36,37 In other words, DNIC underlies the phrase “pain inhibits pain.” DNIC influences only convergent neurons: other cell types located in the dorsal horn, such as specific nociceptive neurons in lamina I and II, are not affected by this type of control.38 The inhibition is extremely potent, affects all the activities of the convergent neurons, and persists, sometimes for several minutes, after the removal of the conditioning stimulus. DNIC results from the physiological activation of brain structures putatively involved in descending inhibition.
Christina Brock, Jens Brøndum Frøkjær, and Asbjørn Mohr Drewes [email protected]
Measurement of descending inhibition in animals The classical knowledge of DNIC derives from animal studies where direct nerve recordings can be obtained before, during, and after the heterotopic stimulation. From these experiments it is known that lesions of the following structures did not modify DNIC: the periaqueductal gray, the cuneiform nucleus, the parabrachial area, the locus coeruleus/subcoeruleus, or the rostral ventromedial medulla (RVM) including the raphe magnus, the gigantocellularis, and the paragigantocellularis nuclei. By contrast, lesions of the dorsal raphe nucleus (DRN) in the caudal medulla strongly reduced DNIC.39,40 Thus, it has been proposed that DRN is exclusively inhibitory.41 However, other studies have proposed that DRN is also involved in descending facilitation.42 The classical animal studies examining DNIC show inhibition of spinal dorsal horn neurons following noxious heterotopic stimuli.43,44
The pain experience originating from the esophagus is multifaceted and complex. The perception is continuously modulated by inhibitory and facilitatory mechanisms. Most research on descending pain control originates in animal experiments, where the involved mechanisms are clearly described. How-
Measurements of descending inhibition in humans In humans, the reticular systems in the brain stem, and probably in the spinoreticular tracts, are also believed to be key neuronal links in the loop subserving DNIC.45 Neurons within the DRN are multiceptive
6. How can descending inhibition be measured in animal and human studies?
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neurons that have the whole body as receptive field, and the descending projections involved in DNIC terminate in the dorsal horn at all levels of the spinal cord.46 The involvement of supraspinal structures is supported by a study that showed that psychological parameters can shape the DNIC response, as it has been shown that expectation of hyperalgesia completely blocks the DNIC effect.47 An experimental study showed decreased pain-detection threshold to esophageal electrical stimulation after chemical perfusion of the distal esophagus with hydrochloride acid and capsaicin. This may likely be caused by DNIC induction following the chemical perfusion.48 Another means of assessing DNIC could involve a test stimulus applied to the esophagus while a conditioning stimulus is applied (e.g., by immersing the hand or foot into cooled water either at a fixed temperature or individually adjusted to tolerance threshold). Disinhibition The term disinhibition describes an impairment of the human descending pain control involving either inhibitory or facilitatory mechanisms or both. Disinhibition has been proposed to potentially underlie the pathogenesis in chronic somatic and visceral pain.49 Only limited information exists regarding disinhibition in painful esophageal and GI diseases, but some evidence has been shown in patients suffering from chronic pancreatitis and irritable bowel syndrome. Conclusion A thorough investigation of esophageal pain should ideally not only focus on the ascending transmission and activation, but look at the interplay between ascending and descending mechanisms. New experimental protocols, which include descending control mechanisms, may be a promising approach to understand the brain dynamics in response to esophageal organic and functional pain. Conflicts of interest The authors declare no conflicts of interest. References 1. Drewes, A.M., H. Gregersen & L. Arendt-Nielsen. 2003. Experimental pain in gastroenterology. A reappraisal of human studies. Scand. J. Gastroenterol. 38: 1115–1130.
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