James K. Ruffle

Molecular neurobiology of addiction: what’s all the (Δ)FosB about?

Abstract The transcription factor ΔFosB is upregulated in numerous brain regions following repeated drug exposure. This induction is likely to, at least in part, be responsible for the mechanisms underlying addiction, a disorder in which the regulation of gene expression is thought to be essential. In this review, we describe and discuss the proposed role of ΔFosB as well as the implications of recent findings. The expression of ΔFosB displays variability dependent on the administered substance, showing region-specificity for different drug stimuli. This transcription factor is understood to act via interaction with Jun family proteins and the formation of activator protein-1 (AP-1) complexes. Once AP-1 complexes are formed, a multitude of molecular pathways are initiated, causing genetic, molecular and structural alterations. Many of these molecular changes identified are now directly linked to the physiological and behavioral changes observed following chronic drug exposure. In addition, ΔFosB induction is being considered as a biomarker for the evaluation of potential therapeutic interventions for addiction.

Cannabinoid hyperemesis syndrome: an important differential diagnosis of persistent unexplained vomiting.

Introduction Chronic nausea and vomiting have a detrimental impact on quality of life. When standard diagnostic investigations fail to provide a definitive diagnosis, patients are often attributed as having a functional gastrointestinal disorder such as cyclic vomiting syndrome. Cannabinoid hyperemesis syndrome (CHS) is a relatively recently described entity presenting with symptoms similar to cyclic vomiting syndrome. Methods We carried out a retrospective cohort study of all patients attending a tertiary neurogastroenterology and secondary care gastroenterology clinic from 2013 to 2015. Data were obtained by review of clinical notes, letters and electronic patient records. Results We identified 10 cases of CHS (five men, mean age 27 years, range 19–51), who hitherto had been labelled with a variety of alternative diagnoses. All patients had symptoms that were episodic and refractory to medical therapy. Patients had experienced symptoms for a mean of 19.3±11.09 months before diagnosis. The median length of cannabinoid use was 42 months (interquartile range: 15–81.8). Eight patients (80%) had a history of compulsive hot water bathing (hydrophilia). The patients had a median follow-up of 9.5 months (range 1–20), during which symptoms recurred in three patients who returned to regular cannabis use. Conclusion CHS is an underappreciated cause of recurrent nausea and vomiting and is frequently misdiagnosed. Healthcare providers should have a low index of suspicion for diagnosing CHS and the clinical history in such patients should routinely include direct questioning on cannabis use. The prognosis is very good upon cessation of cannabis intake.

The Role of Esophageal Hypersensitivity in Functional Esophageal Disorders

The Rome IV diagnostic criteria delineates 5 functional esophageal disorders which include functional chest pain, functional heartburn, reflux hypersensitivity, globus, and functional dysphagia. These are a heterogenous group of disorders which, despite having characteristic symptom profiles attributable to esophageal pathology, fail to demonstrate any structural, motility or inflammatory abnormalities on standard clinical testing. These disorders are associated with a marked reduction in patient quality of life, not least considerable healthcare resources. Furthermore, the pathophysiology of these disorders is incompletely understood. In this narrative review we provide the reader with an introductory primer to the structure and function of esophageal perception, including nociception that forms the basis of the putative mechanisms that may give rise to symptoms in functional esophageal disorders. We also discuss the provocative techniques and outcome measures by which esophageal hypersensitivity can be established.

Morphology of subcortical brain nuclei is associated with autonomic function in healthy humans

The autonomic nervous system (ANS) is a brain body interface which serves to maintain homeostasis by influencing a plethora of physiological processes, including metabolism, cardiorespiratory regulation and nociception. Accumulating evidence suggests that ANS function is disturbed in numerous prevalent clinical disorders, including irritable bowel syndrome and fibromyalgia. While the brain is a central hub for regulating autonomic function, the association between resting autonomic activity and subcortical morphology has not been comprehensively studied and thus was our aim. In 27 healthy subjects [14 male and 13 female; mean age 30 years (range 22–53 years)], we quantified resting ANS function using validated indices of cardiac sympathetic index (CSI) and parasympathetic cardiac vagal tone (CVT). High resolution structural magnetic resonance imaging scans were acquired, and differences in subcortical nuclei shape, that is, ‘deformation’, contingent on resting ANS activity were investigated. CSI positively correlated with outward deformation of the brainstem, right nucleus accumbens, right amygdala and bilateral pallidum (all thresholded to corrected P < 0.05). In contrast, parasympathetic CVT negatively correlated with inward deformation of the right amygdala and pallidum (all thresholded to corrected P < 0.05). Left and right putamen volume positively correlated with CVT (r = 0.62, P = 0.0047 and r = 0.59, P = 0.008, respectively), as did the brainstem (r = 0.46, P = 0.049). These data provide novel evidence that resting autonomic state is associated with differences in the shape and volume of subcortical nuclei. Thus, subcortical morphological brain differences in various disorders may partly be attributable to perturbation in autonomic function. Further work is warranted to investigate these findings in clinical populations. Hum Brain Mapp 39:381–392, 2018.

490 Studies of the Psychophysiological Markers and the Brain Processing of Nausea in Healthy Humans Using a Novel Virtual Reality Video

Hydrogen sulfide(H2S), mainly produced endogenously by two enzymes, cystathionine γlyase(CSE) and cystathionine β-synthase(CBS), is a messenger molecule in the central nervous system, in the GI tract and in sympathetic prevertebral ganglia. Our previous study found, in mouse superior mesenteric ganglion(SMG), that exogenous H2S acts selectively on splanchnic nerve terminals to potentiate fast excitatory post synaptic potentials (F-EPSPs). In this study, we investigated the distribution of CSE and CBS and the role of endogenously produced H2S on central sympathetic input. Methods: The SMG, splanchnic nerve trunks and colonic nerve trunk were dissected from adult SJL/J mice. Immunostaining was performed with antibodies for CSE and CBS and for vesicular acetylcholine transporter(VAChT) to identify cholinergic nerve terminals. Microelectrodes were used for intracellular recordings. Results: CSE immunoreactivity(IR) was found in neurons and glia cells and did not co-localize with VAChT-IR. CBS-IR was found only in glia cells. To determine whether the F-EPSPs could be potentiated by endogenously released H2S, we tested the effect of inhibiting H2S breakdown with stigmatellin, a specific sulfide quinone reductase inhibitor, on F-EPSPs. Stigmatellin(1μM) significantly(P<0.05) increased the amplitude and the area of F-EPSPs evoked by splanchnic nerve stimulation(21.0±4.8mV and 441±107ms●mV with stigmatellin vs. 18.4±5.3mV and 338±108ms●mV before stigmatellin, n=4) but had no significant effect on F-EPSPs evoked by colonic nerve stimulation. In contrast, the CSE inhibitor, dl-propargylglycine(PAG, 1mM), significantly(P<0.05) decreased the amplitude and the area of F-EPSPs evoked by splanchnic nerve stimulation(23.7±3.9mV and 824±288ms●mV with PAG vs. 27.0±4.1mV and 1230±414ms●mV before PAG, n=6), but had no effect on F-EPSPs evoked by colonic nerve stimulation. Surprisingly, the CBS inhibitor, aminooxyacetic acid(AOAA, 0.5mM), increased the amplitude and the area of F-EPSPs evoked by splanchnic nerve stimulation(23.6±12.1mV and 651±455ms●mV with AOAA vs. 20.2±10.9mV and 438±318ms●mV before AOAA, n=4, P<0.05) and increased the amplitude and the area of F-EPSPs evoked by colonic nerve stimulation(36.2±8.2mV and 1609±468ms●mV with AOAA vs. 28.9±8.1mV and 1084±402ms●mV before AOAA, n=6, P<0.05). Bicuculline(20μM), a specific GABA-A receptor inhibitor, blocked the potentiating effect of AOAA suggesting that the AOAA induced potentiation of F-EPSPs was due to the inhibition of GABA transaminase-induced accumulation of GABA. Conclusion: We conclude that endogenously produced H2S in the mouse SMG modulates fast cholinergic synaptic input in a pathwayspecific manner. H2S modulates fast cholinergic synaptic input from central splanchnic nerve terminals but has no affect on input from peripheral cholinergic input. (Funded by NIH DK17238)

Pronociceptive effects mediated by adenosinergic A2A activity at the nucleus accumbens, but what about the autonomic nervous system?

Letter to Editor: We read with interest the recent article by Sardi et al., which raises many thought-provoking points that advance our understanding of the neurobiology of pain. In particular, the authors have elegantly demonstrated in a rodent model that rapid eye movement sleep deprivation (REM-SD) has a pronociceptive effect, likely due to increased adenosinergic A2A activity (with decrease in dopaminergic D2 activity) in the nucleus accumbens (NAc). Taken together with the authors’ previous study, the findings add weight to the possibility that REM-SD disrupts central endogenous pain modulation, thereby implicating NAc adenosinergic A2A activity. Nevertheless, we wish to propose an additional hypothesis for the results presented, as a means to provoke further discussion and stimulate research, which may help to establish novel antinociceptive therapies. Specifically, we suggest a role of the autonomic nervous system (ANS) in pronociception and question whether the presented results could be explained by a pain-induced insult to autonomic homeostasis. It has been appreciated for some time that the ANS has a role in nociceptive modulation. Recently, there has been an exponential increase in studies investigating the interplay between the ANS and pain. The ANS broadly comprises the sympathetic nervous system (SNS) and parasympathetic nervous system (PNS), to which the SNS and PNS are considered to be pronociceptive and antinociceptive, respectively. Moreover, the PNS is proposed to have antinociceptive activity due to vagus nerve-mediated activation of key brain areas implicated in descending analgesia. This has, in many ways, formed the basis of a concurrent academic interest in the modulation of pain by vagal nerve stimulation. We suggest that the SNS may be implicated in the pronociceptive adenosinergic A2A activity in the NAc. To explain, we have recently shown that structural deformation in the shape of the NAc is associated strongly with resting autonomic tone, in particular, the activity of the SNS, quantified by cardiac sympathetic index. Second, adenosinergic A2A receptors have been previously shown to facilitate sympathetic excitation, and there is a strong association of receptor activity with reflex cardiac sympathoexcitation. A previous sleep study has additionally concluded that the adenosinergic A2A receptors are implicated in autonomic regulation during REM sleep. Clinically, increased sympathetic tone is observed in disorders associated with disrupted REM sleep such as posttraumatic stress disorder, whereby both sympathetic tone and REM-SD are reduced with successful behavioural therapy. In summary, current data suggest the following: (1) REM-SD is pronociceptive by disruption of endogenous pain modulation, by means of NAc adenosinergic A2A activity ; (2) adenosinergic A2A activity facilitates sympathetic excitation; (3) adenosinergic A2A activity aids autonomic homeostasis in REM sleep, and increased sympathetic tone occurs should REM sleep be disrupted; (4) NAc morphology is linearly associated with sympathetic tone, and (5) sympathetic tone is pronociceptive. Thus, we reason that the intriguing findings presented by Sardi et al. may therefore reflect an SNS-driven effect of pronociception (by disrupting endogenous modulation), implicating the NAc. We hope that this hybridisation of previous findings may further stimulate research questions investigating the interplay between sleep, the ANS, and pain, with view to further deepening our current understanding of the autonomic neuromodulation of pain.

Delineation between different components of chronic pain using dimension reduction - an ASL fMRI study in hand osteoarthritis

Traditional psychometric measures aimed at characterizing the pain experience often show considerable overlap, due to interlinked affective and modulatory processes under central nervous system control. Neuroimaging studies have been employed to investigate this complexity of pain processing, in an attempt to provide a quantifiable, adjunctive description of pain perception. In this exploratory study, we examine psychometric and neuroimaging data from 38 patients with painful osteoarthritis of the carpometacarpal joint. We had two aims: first, to utilize principal component analysis (PCA) as a dimension reduction strategy across multiple self‐reported endpoints of pain, cognitive and affective functioning; second, to investigate the relationship between identified dimensions and regional cerebral blood flow (rCBF) as an indirect measure of brain activity underpinning their ongoing pain experiences.

Pharmacological and other treatment modalities for esophageal pain.

Treatment of esophageal pain remains a major challenge for the clinician. Although many patients have heartburn and may respond to proton pump inhibitors, there in an unmet need for other treatment modalities in patients where there are no obvious pathological findings. Although analgesics are the mainstay in esophageal pain treatment, many patients are nonresponders to these drugs. The current concise review focuses on other systems affecting pain processing, where better understanding may serve as a framework for therapy. These are the parasympathetic nervous system, exercise, and personality profiles. Finally, treatment with analgesics for functional chest pain remains a challenge, and an overview of treatment with antidepressive drugs is provided.

Irritable bowel syndrome

Irritable bowel syndrome (IBS) is a prevalent disorder affecting around 12% of the population and is present worldwide. It constitutes approximately 40% of consultations in secondary care gastroenterology clinics. Given the prevalence of the disease, it exerts a significant societal burden, through increased health care costs, and personal burden, through a reduced quality of life. The aetiology of IBS is multifactorial and incompletely understood. In a similar manner the management of IBS is also multifactorial and encompasses the establishment of a therapeutic relationship, exclusion of other organic causes and the delineation of predominant bowel habit. Specific pharmacotherapy is directed towards symptomatic management. This review provides a focused summary of the epidemiology, clinical features, differential diagnosis and management of IBS.

OC-066 Influence Of Extraversion On Brain Activity At Baseline, Pain Anticipation And Visceral Pain Processing

Introduction Eysenck proposed ‘trait theory’ of personality, where the dimensions extraversion (degree of optimism and sociability) and neuroticism (degree of anxiety and fear) encompass numerous individual qualities. Whilst the influence of neuroticism on the brain processing of pain is well studied, the role of extraversion in pain processing remains to be investigated and thus this was the aim of our study using functional magnetic resonance imaging (fMRI). Methods 33 healthy volunteers participated in the study, all of whom consented in writing (17 male; mean age 29, range 20–53, all right handed). Extraversion was measured using the Eysenck Personality Questionnaire. fMRI data was acquired using a 3T GE MRI scanner during rest, anticipation of pain, and painful distal oesophageal balloon distention. During fMRI, 480 T2* weighted images per slice (40 × 3 mm slices, 0.3 interslice gap, TE 30 ms, TR 2500 ms, flip angle 80°, matrix size 642, sum of images per scan = 19,200) were captured to illustrate blood oxygen level dependent (BOLD) contrast during the different experimental events. The effects of extraversion on fMRI response during these events were subsequently determined using ANOVA brain activation mapping analyses within XBAM, a statistical package of image processing and statistical inference. Results There was a diversity of extraversion scores (range 6–22), which did not influence pain threshold or rating. High extraversion was associated with significantly greater activity in the left cuneus (Brodmann Area (BA) 18) during rest (p < 0.001) and the right insula (BA13) during both anticipation (p < 0.0002) and pain (p < 0.0008). Low extraversion was associated with significantly greater brain activity in numerous regions during pain anticipation, including the bilateral precuneus (BA31), bilateral lingual gyrus (BA18) and the right inferior temporal gyrus (p < 0.0001). Conclusion Our results suggest that the brain processing of pain is influenced by the personality dimension of extraversion and therefore like other personality dimensions such as neuroticism, extraversion should be controlled for in brain imaging studies of pain in health and disease. Disclosure of Interest None Declared.