Could Stress Contribute to Pain-Related Fear in Chronic Pain?

Learning to predict pain based on internal or external cues constitutes a fundamental and highly adaptive process aimed at self-protection. Pain-related fear is an essential component of this response, which is formed by associative and instrumental learning processes. In chronic pain, pain-related fear may become maladaptive, drive avoidance behaviors and contribute to symptom chronicity. Pavlovian fear conditioning has proven fruitful to elucidate associative learning and extinction involving aversive stimuli, including pain, but studies in chronic pain remain scarce. Stress demonstrably exerts differential effects on emotional learning and memory processes, but this has not been transferred to pain-related fear. Within this perspective, we propose that stress could contribute to impaired pain-related associative learning and extinction processes and call for interdisciplinary research. Specifically, we suggest to test the hypotheses that (1) extinction-related phenomena inducing a re-activation of maladaptive pain-related fear (e.g., reinstatement, renewal) likely occur in everyday life of chronic pain patients and may alter pain processing, impair perceptual discrimination and favour overgeneralization; (2) acute stress prior to or during acquisition of pain-related fear may facilitate the formation and/or consolidation of pain-related fear memories, (3) stress during or after extinction may impair extinction efficacy resulting in greater reinstatement or context-dependent renewal of pain-related fear; and (4) these effects could be amplified by chronic stress due to early adversity and/or psychiatric comorbidity such as depression or anxiety in patients with chronic pain

Role of brain imaging in disorders of brain-gut interaction: a Rome Working Team Report.

Imaging of the living human brain is a powerful tool to probe the interactions between brain, gut and microbiome in health and in disorders of brain-gut interactions, in particular IBS. While altered signals from the viscera contribute to clinical symptoms, the brain integrates these interoceptive signals with emotional, cognitive and memory related inputs in a non-linear fashion to produce symptoms. Tremendous progress has occurred in the development of new imaging techniques that look at structural, functional and metabolic properties of brain regions and networks. Standardisation in image acquisition and advances in computational approaches has made it possible to study large data sets of imaging studies, identify network properties and integrate them with non-imaging data. These approaches are beginning to generate brain signatures in IBS that share some features with those obtained in other often overlapping chronic pain disorders such as urological pelvic pain syndromes and vulvodynia, suggesting shared mechanisms. Despite this progress, the identification of preclinical vulnerability factors and outcome predictors has been slow. To overcome current obstacles, the creation of consortia and the generation of standardised multisite repositories for brain imaging and metadata from multisite studies are required

Alterations in prefrontal-limbic functional activation and connectivity in chronic stress-induced visceral hyperalgesia.

Repeated water avoidance stress (WAS) induces sustained visceral hyperalgesia (VH) in rats measured as enhanced visceromotor response to colorectal distension (CRD). This model incorporates two characteristic features of human irritable bowel syndrome (IBS), VH and a prominent role of stress in the onset and exacerbation of IBS symptoms. Little is known regarding central mechanisms underlying the stress-induced VH. Here, we applied an autoradiographic perfusion method to map regional and network-level neural correlates of VH. Adult male rats were exposed to WAS or sham treatment for 1 hour/day for 10 days. The visceromotor response was measured before and after the treatment. Cerebral blood flow (CBF) mapping was performed by intravenous injection of radiotracer ([(14)C]-iodoantipyrine) while the rat was receiving a 60-mmHg CRD or no distension. Regional CBF-related tissue radioactivity was quantified in autoradiographic images of brain slices and analyzed in 3-dimensionally reconstructed brains with statistical parametric mapping. Compared to sham rats, stressed rats showed VH in association with greater CRD-evoked activation in the insular cortex, amygdala, and hypothalamus, but reduced activation in the prelimbic area (PrL) of prefrontal cortex. We constrained results of seed correlation analysis by known structural connectivity of the PrL to generate structurally linked functional connectivity (SLFC) of the PrL. Dramatic differences in the SLFC of PrL were noted between stressed and sham rats under distension. In particular, sham rats showed negative correlation between the PrL and amygdala, which was absent in stressed rats. The altered pattern of functional brain activation is in general agreement with that observed in IBS patients in human brain imaging studies, providing further support for the face and construct validity of the WAS model for IBS. The absence of prefrontal cortex-amygdala anticorrelation in stressed rats is consistent with the notion that impaired corticolimbic modulation acts as a central mechanism underlying stress-induced VH

The relationship between irritable bowel syndrome and psychiatric disorders: from molecular changes to clinical manifestations

Irritable bowel syndrome (IBS) is a functional syndrome characterized by chronic abdominal pain accompanied by altered bowel habits. Although generally considered a functional disorder, there is now substantial evidence that IBS is associated with a poor quality of life and significant negative impact on work and social domains. Neuroimaging studies documented changes in the prefrontal cortex, ventro-lateral and posterior parietal cortex and thalami, and implicate alteration of brain circuits involved in attention, emotion and pain modulation. Emerging data reveals the interaction between psychiatric disorders including generalized anxiety disorder, panic disorder, major depressive disorder, bipolar disorder, and schizophrenia and IBS, which suggests that this association should not be ignored when developing strategies for screening and treatment. Psychological, social and genetic factors appear to be important in the development of IBS symptomatology through several mechanisms: alteration of HPA axis modulation, enhanced perception of visceral stimuli or psychological vulnerability. Elucidating the molecular mechanisms of IBS with or without psychiatric comorbidities is crucial for elucidating the pathophysiology and for the identification of new therapeutical targets in IBS

Breaking down the barriers: fMRI applications in pain, analgesia and analgesics

This review summarizes functional magnetic resonance imaging (fMRI) findings that have informed our current understanding of pain, analgesia and related phenomena, and discusses the potential role of fMRI in improved therapeutic approaches to pain. It is divided into 3 main sections: (1) fMRI studies of acute and chronic pain. Physiological studies of pain have found numerous regions of the brain to be involved in the interpretation of the 'pain experience'; studies in chronic pain conditions have identified a significant CNS component; and fMRI studies of surrogate models of chronic pain are also being used to further this understanding. (2) fMRI studies of endogenous pain processing including placebo, empathy, attention or cognitive modulation of pain. (3) The use of fMRI to evaluate the effects of analgesics on brain function in acute and chronic pain. fMRI has already provided novel insights into the neurobiology of pain. These insights should significantly advance therapeutic approaches to chronic pain

Neurophysiological, psychological and immunological evaluation of Irritable Bowel Syndrome

Irritable Bowel Syndrome (IBS) is a common gastroenterological disorder characterised by recurrent abdominal pain and a change in bowel habit. Diagnosis is made with reference to clinical symptomatology and the exclusion of other competing disorders. As such there is no reliable biomarker in the clinical field to prove or disprove the diagnosis. This has obvious implications for the treatment of the syndrome. Recent research has targeted the immunology of IBS to see if changes in cytokine expression support the concept of a chronic low-level inflammatory state. IBS has a strong association with psychological comorbidity. Visceral hypersensitivity is also a hallmark of the disease. This study was constructed to compare the psychological profiles of patients with IBS against a control group; to use cortical evoked potentials to observe the cortical representation of an electrical rectal stimulus to see if changes in amplitude or latency might be suggestive of enhanced afferent nerve transmission; and to use cytokine analysis of stimulated and un-stimulated peripheral blood mononuclear cells to study the inflammatory response

Human psychophysiological responses to visceral and somatic pain – the development of integrated, reproducible human pain phenotypes

PhDBackground Pain is the ubiquitous human experience, yet displays considerable inter- and intraindividual variability in health and disease. Many factors have been proposed to account for these differences. Pain activates a complex stress response, multiply determined through genetic, psychological, physiological and neuroanatomical factors. Chronic pain is a central defining characteristic of functional gastrointestinal disorders. They represent a major challenge for modern healthcare. An integrated understanding of the pathophysiology of these disorders remains to be elucidated. Aims To investigate human psychophysiological responses to visceral and somatic pain in health and disease, in order to develop multidimensional and reproducible pain phenotypes. Methods Study 1, in healthy volunteers, investigated personality traits, hypothalamic pituitary adrenal axes and selective novel non-invasive measures of autonomic tone in response to visceral and somatic pain. Study 2 examined the salience of genetic polymorphisms of the serotonin transporter. Study 3 evaluated the reproducibility of these responses after a period of one year. Study 4 utilised the methods of studies 1 and 2 in a case control study of patients with functional chest pain. Key Results Studies 1, 2 and 3 – Two pain phenotypes, or clusters, were found – cluster 1 (39%) had higher neuroticism scores, with higher sympathetic and hypothalamic pituitary adrenal axis tone at rest, and a predominant parasympathetic response to pain in the presence of the short allele of the serotonin transporter. Cluster 2 (61%) displayed the converse profile in the absence of the short allele. These responses were stable at an interval of one year. Study 4 – similar phenotypes were observed in patients with functional chest pain, although the Cluster 1 phenotype was overrepresented in patients in comparison to the controls (71% vs. 29%). Conclusions and Inferences This series of studies provides evidence for the existence of two reproducible human pain phenotypes in health, which have clinical salience in patients with functional chest pain. By phenotyping pain responses, subject homogeneity in future studies may be improved. Furthermore, such phenotyping techniques may open new therapeutic avenues by facilitating the selective targeting of nociceptive aberrancies, particularly in functional gastrointestinal disorders