Background

We all have experienced it at least once – visceral pain, arising from the internal organs of the thorax, abdomen or pelvis (viscera = intestines). The gastrointestinal tract is innervated by the vegetative nervous system making visceral pain experiences substantially different from pain in somatically innervated organs like the skin or muscles. It is often described as dull and diffuse, is more difficult to localise and is perceived as more unpleasant and more threatening than somatic pain (Boeckxstaens et al., 2016). These perceptual differences are due to both anatomic and physiological, as well as central nervous characteristics of visceral pain processing. The complex interplay of these peripheral and neural mechanisms can best be described by the concept of a bidirectional brain-gut axis (figure 1).

Visceral organs like the intestines are not equipped with specific pain receptors (nociceptors), but have organ specific low- and high threshold receptor systems, which are activated by e.g. stretching. Usually, we are not aware of physiological gastrointestinal functions, except feelings of satiety or bowel movement. Only activation of high-threshold receptors, for example by intense distensions, leads to the conscious perception of signals from the gastrointestinal tract, including pain. Visceral signals are transmitted to the spinal cord via nerve fibres of the vegetative nervous system. Here, initiation of reflex systems takes place, which, together with the nervous system of the gastrointestinal tract – the enteric nervous system – regulate physiological functions (e.g. gut motility) of the visceral organs. Even though the majority of signals do not get transmitted to the cerebrum and are therefore not consciously perceived, part of this information from the body periphery is registered in the brain stem. Painful visceral stimuli on the other hand are transmitted to higher, pain processing brain areas independent of the affected organ. Moreover, in contrast to somatic stimuli, visceral pain stimuli are not mapped in the primary, but the evolutionary older, secondary somatosensory cortex and the insular cortex. Various communication pathways within the vegetative nervous system, the hormone system, as well as the immune system, allow a tight connection of the brain stem and the cerebrum with the enteric nervous system. The complex array of biological and psychological factors affecting gastrointestinal function can best be described in a biopsychosocial disease model, which is considered to underlie the pathophysiology of chronic visceral pain.

Fig. 1

Schematic illustration of the bidirectional communication pathways along the brain-gut axis and its central biological and psychological modulators. CRH = corticotropin releasing hormone. This figure was created using the Motifolio PPT Drawing Toolkits (www.motifolio.com).

Chronic visceral pain

Chronic visceral pain is the cardinal symptom of functional gastrointestinal disorders (FGID). To date, no distinct organic cause can be identified for these disorders, which are considered exemplary for a dysfunctional brain-gut interaction. With prevalence rates of about 11%, irritable bowel syndrome (IBS), characterized by recurrent abdominal pain and disturbed bowel habits, is the most commonly diagnosed FGID, followed by functional dyspepsia (FD), a disease dominated by upper abdominal pain (Enck et al., 2016). Women are affected considerably more often than men, suggesting sex-related factors. FGID substantially limit the quality of life of patients and are associated with severe socioeconomic consequences. A large overlap with psychiatric disorders, particularly anxiety disorders and depression, suggests that psychological factors play an important role in the etiology and pathophysiology of FGID (Van Oudenhove et al., 2016). Despite a variety of available therapy options including pharmacological, psychotherapeutic or alternative medicine approaches, they often fail to maintain long-term reduction or alleviation of symptoms. This is also due to the fact that the cause and underlying mechanisms of FGID are still poorly understood, illustrating urgently needed further research (Layer et al., 2011).

Interdisciplinary research approaches investigating the brain-gut axis and its disorders at the interface of psychology, neurogastroenterology and the neurosciences are currently considered best suited to address the complex interplay of biological, psychological and social factors (Tanaka et al., 2011; figure 1). Early studies reporting changes in gastrointestinal motility and sensitivity in response to emotional stress in FGID have laid the foundation for current approaches, which address peripheral and central mechanisms and their interactions. Crucial pathophysiological concepts include allodynia and hyperalgesia, which also play a central role in somatic pain research. Allodynia describes a hypersensitivity, leading to pain sensations evoked by non-harmful and non-painful stimuli, whereas hyperalgesia is characterised by a low pain threshold, resulting in more pronounced reactions to painful stimuli (Elsenbruch, 2011; Mayer et al., 2015a). More recent studies further focus on the role of changes in attentional processing. The term hypervigilance describes increased attention towards physical signals and processes (Elsenbruch and Enck, 2016). In chronic visceral pain, this selective focus on signals from the gastrointestinal tract is often associated with a negatively biased interpretation involving catastrophising thoughts. Thus, gastrointestinal perceptions are more likely experienced as a potential symptom of disease, negatively evaluated and produce emotional memories. The influence of these centrally-mediated, psychological factors and their interactions on the pathophysiology of FGID represent a key focus of current interdisciplinary, psychobiological research on visceral pain.

Stress and psychological factors

Chronic stress and symptoms of anxiety or depression are often observed in patients suffering from FGID. They affect both, the severity of gastrointestinal symptoms as well as the patients` quality of life (Van Oudenhove et al., 2016). Animal models provide substantial insights into mechanisms underlying the influence of acute and chronic stress on functions of the brain-gut axis. They document various stress-induced changes in gastrointestinal functions such as delayed gastric emptying and accelerated intestinal transit, increased acid secretion and impaired mucosal perfusion (Taché et al., 2017), some of which could also be observed in humans (Boeckxstaens et al. 2016). These effects are essentially mediated by components of the stress axis, in particular by corticotropin releasing hormone (CRH, Taché et al., 2017). Moreover, new research approaches demonstrate a complex interaction of stress (-mediators) and the microbial milieu of the gut (microbiota) (Mayer et al., 2014; Moloney et al., 2016). For example, a recent study documents that faecal transplantation from IBS patients into germ-free rats can induce visceral hypersensitivity in the animals (Crouzet et al., 2013).

If and to what extent findings on stress derived from animal studies can be transferred to humans remains to be elucidated. It is not possible to conduct experimental studies on chronic stress in humans, however, longitudinal studies provide important evidence on cause-and-effect-relationships between chronic psychological stress and chronic pain. In these studies, increased anxiety symptoms and reduced quality of life in participants without gastrointestinal complaints could be identified as risk factors for the development of FGID later in life (Ford et al., 2008; Koloski et al., 2012). Further, prospective studies on post-infectious IBS induced by an acute intestinal infection reveal chronic stress and depression as risk factors for a chronification (Spiller and Garsed, 2009). However, a current prospective study suggests that emotional disturbances can both, precede the manifestation of chronic visceral pain or occur subsequently to the disease (Koloski et al., 2016). Thus, a complex interplay between psychological changes and gastrointestinal symptoms in terms of a vicious cycle are likely to underlie the pathophysiology of FGID.

Brain imaging

Brain imaging techniques such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) put the brain as a “central hub” of the brain-gut axis into the focus of research on visceral pain in both health and disease. They allow the investigation of brain responses during the processing of experimentally induced pain stimuli and provide important insights into neurobiological mechanisms underlying the integration of sensory, cognitive and emotional dimensions of pain.

Patients suffering from IBS show increased neural activation in response to rectal distensions particularly in brain regions associated with emotional arousal, cognitive control as well as endogenous pain modulation compared to healthy controls (Mayer et al., 2015b). While controls show activation primarily in brain regions related to pain inhibition, increased responses of the thalamus, insula and the anterior cingulate cortex in IBS has been consistently reported. Stronger involvement of these brain regions as part of a salience network emphasizes the importance of dysfunctional attentional processes in terms of visceral hypervigilance (Mayer et al., 2015b). Acute stress or negative emotions alter neural activation patterns both in healthy volunteers and IBS patients (Elsenbruch et al., 2010a; Phillips et al., 2003), underscoring the key role of psychological factors. Changes in central pain processing in IBS have further been shown to be associated with anxiety symptoms and depression (Elsenbruch et al., 2010b). Interestingly, IBS patients exhibit altered brain activation also during pain anticipation (Mayer et al., 2015b). Such anticipatory responses mainly in brain areas linked to attention and emotional processing, reflect pain-related fear resulting from associative learning processes (Icenhour et al., 2015b, Labus et al., 2013), which influence the processing of visceral stimuli even in healthy humans (Icenhour et al., 2017). Finally, studies on placebo effects in the context of visceral pain highlight the relevance of pain-related expectations. For example, the administration of an inert substance (a placebo) in combination with positive expectations of pain relief results in an actual reduction of perceived pain – a placebo-analgesia. This effect is paralleled by a significant reduction of pain-induced brain activation in a complex network of brain areas, which are involved in sensory, emotional, motivational and cognitive aspects of pain modulation. However, placebo effects and their underlying neurobiological mechanisms are still poorly understood in patients suffering from chronic visceral pain– a research gap which, with respect to the clinical potential of placebo mechanisms, should be closed soon (Elsenbruch and Enck, 2015).

Patients with FGID also show alterations in spontaneous brain activation under resting conditions, as documented by an increasing number of resting-state fMRI studies. Disturbances in resting-state neural activation and functional connectivity, which illustrates the interaction between neural systems, are most consistently observed in the default mode network, which is associated with self-related processing, including the monitoring of bodily and emotional states. Furthermore, alterations of the salience, the emotional arousal and the sensorimotor networks have been described (Lee et al., 2016; Mayer et al., 2015b), particularly involving brain regions which show stimulus-induced functional changes. These findings lend further support for a key role of disturbed processes of attention and emotional regulation in the context of chronic visceral pain.

Voxel-based morphometry (VBM) or diffusion tensor imaging (DTI) allow a non-invasive investigation of brain structure and tracts connecting specific brain areas. Patients with FGID show substantial alterations also in these structural measures particularly in brain regions involved in sensory processing, integration and modulation, such as the somatosensory cortex, thalamus and basal ganglia and in prefrontal areas, which play a central role in regulatory processes. Further, significant changes in the salience network have been described, consistent with findings from functional imaging. Interestingly, observed differences between patients and healthy controls appear to be mainly attributable to psychopathological symptoms rather than disease duration or symptom severity (Mayer et al., 2015b). Even though existing data suggests morphological changes in the brain in chronic visceral pain, they do not allow conclusions on whether structural alterations are a cause or occur as a consequence of chronic pain. Thus, longitudinal studies are required in order to derive causal associations between changes in the central nervous system and chronic visceral pain.

Sex-related differences in imaging studies on visceral pain

Functional brain imaging studies provide evidence of sex differences in the context of visceral pain processing, both in healthy humans and in patients suffering from chronic visceral pain. Compared to men, healthy women as well as female patients demonstrate increased pain-induced activation of brain areas associated with emotional pain processing and modulation (Icenhour et al., 2015a), supporting the key role of emotional factors also in sex-related differences in the processing and modulation of acute visceral pain. Given higher prevalence rates in women also for psychological disturbances such as anxiety disorders and depression, emotional factors could, as psychological stressors, be considered sex-specific risk factors, facilitating the development and chronification of visceral pain in women. Ultimately, a complex interplay involving the abovementioned psychological and neurobiological mechanisms is most likely to underlie sex differences in visceral pain. Especially female sex hormones seem to have a crucial impact on visceral sensitivity and pain perception (Icenhour et al., 2015a). However, the relevance of sex hormones in neural processing of visceral pain remains incompletely understood.

Conclusion

The complex interactions between biological, psychological and social factors underlying the subjective experience of visceral pain require interdisciplinary research approaches bridging psychophysiology, neurogastroenterology and the neurosciences. A deeper understanding of the brain-gut axis and its mechanisms on biological, psychological and ultimately also social levels is essential in order to implement successful therapeutic concepts for the treatment of chronic visceral pain.