Huynh Giao Ly

Efficacy of Mirtazapine in Patients With Functional Dyspepsia and Weight Loss

BACKGROUND & AIMS A subset of patients with functional dyspepsia (FD) present with early satiation and weight loss, for which there are no established therapeutic options. We investigated the efficacy of mirtazapine (an antidepressant and antagonist of the histamine receptor H1, the α2 adrenergic receptor, and the serotonin receptors 5-HT2C and 5-HT-3) in patients with FD and weight loss. METHODS We conducted a randomized, placebo-controlled pilot trial that studied 34 patients with FD (29 women; mean age, 35.9 ± 2.3 years) with weight loss >10% of original body weight (mean loss, 12.4 ± 2.3 kg) without depression or anxiety. After a run-in period, patients were randomly assigned to groups given placebo (n = 17) or mirtazapine 15 mg each day for 8 weeks (n = 17) in a double-blind manner. Subjects were evaluated during a 2-week baseline and 8-week treatment for dyspepsia symptom severity, quality of life (on the basis of the Nepean Dyspepsia Index), and gastrointestinal-specific anxiety; they were given a nutrient challenge test and weighed. Data were analyzed by using linear mixed models, followed by planned contrasts with adaptive step-down Bonferroni multiple testing correction. RESULTS Two patients in each group dropped out. At weeks 4 and 8, mirtazapine significantly reduced mean dyspepsia symptom severity scores compared with week 0 (P = .003 and P = .017, respectively); there was no significant reduction in the placebo group (P > .37 for weeks 4 and 8). The difference in change from week 0 between mirtazapine and placebo showed a trend with a large effect size at week 4 (P = .059) that was not significant at week 8 (P = .55). However, improvements from week 0 to weeks 4 and 8 were significantly larger in the mirtazapine group than placebo group for early satiation, quality of life, gastrointestinal-specific anxiety, weight, and nutrient tolerance (mostly with large effect sizes). CONCLUSIONS In a randomized, placebo-controlled trial, mirtazapine significantly improved early satiation, quality of life, gastrointestinal-specific anxiety, nutrient tolerance, and weight loss in patients with FD. ClinicalTrials.gov number: NCT01240096.

Increased Cerebral Cannabinoid-1 Receptor Availability Is a Stable Feature of Functional Dyspepsia: A [18F]MK-9470 PET Study

Background: Functional dyspepsia (FD) is a prevalent functional gastrointestinal disorder (FGID) defined by chronic epigastric symptoms in the absence of organic abnormalities likely to explain them. Comorbidity with mood and anxiety disorders as well as with other FGIDs and functional somatic syndrome (FSS) is high. FD is characterized by abnormal regional cerebral activity in cognitive/affective pain modulatory circuits, but it is unknown which neurotransmitter systems are involved. The authors aimed to assess and compare in vivo cerebral cannabinoid-1 (CB1) receptor availability between FD patients and age-, gender- and BMI-matched healthy controls (HC). Methods: Twelve FD patients and 12 matched HC were investigated using positron emission tomography (PET) with the CB1 receptor radioligand [18F]MK-9470. Nine of the patients received a second PET scan after a naturalistic follow-up period of 36 ± 9.6 months (range: 25.2-50.4 months). Results: FD patients had significantly higher CB1 receptor availability in the cerebral regions involved in (visceral) nociception (brainstem, insula, anterior cingulate cortex) as well as in the homeostatic and hedonic regulation of food intake [hypothalamus, (ventral) striatum] (p < 0.05 corrected for multiple testing, region of interest analysis), which persisted after a follow-up period of 36 ± 9.6 months. Conclusions: Although these findings need replication in larger samples, they suggest that the abnormal brain activity in several of these regions, previously demonstrated in FD, may be due to a sustained endocannabinoid system dysfunction, identifying it as a potential novel target for treatment and warranting further studies to elucidate whether it is also a feature of other FGIDs or FSSs.

Influence of Interoceptive Fear Learning on Visceral Perception.

Objectives Interoceptive fear learning and generalization have been hypothesized to play a key role in unexplained abdominal and esophageal pain in patients with functional gastrointestinal disorders. However, there is no experimental evidence demonstrating that fear learning and generalization to visceral sensations can be established in humans and alter visceral perception. Methods In a novel fear learning–generalization paradigm, an innocuous esophageal balloon distension served as conditioned stimulus (CS), and distensions at three different pressure levels around the pain detection threshold were used as generalization stimuli. During fear learning, the CS was paired with a painful electrical stimulus (unconditioned stimulus) in the conditioning group (n = 30), whereas in the control group (n = 30), the unconditioned stimulus was delivered alone. Before and after fear learning, visceral perception thresholds for first sensation, discomfort, and pain and visceral discrimination sensitivity were assessed. Results Fear learning was established in the conditioning group only (potentiated eye-blink startle to the CS (t(464.06) = 3.17, p = .002), and fear generalization to other stimulus intensities was observed (t(469.12) = 2.97, p = .003; t(464.29) = 4.17, p < .001). The thresholds for first sensation habituated in the control group, whereas it remained constant in the conditioning group (F(1,43) = 9.77, p = .003). Conclusions These data show that fear learning using visceral stimuli induces fear generalization and influences visceral perception. These findings support the idea that in functional gastrointestinal disorder, fear learning and generalization can foster gastrointestinal-specific anxiety and contribute to visceral hypersensitivity.

Differential Activation in Amygdala and Plasma Noradrenaline during Colorectal Distention by Administration of Corticotropin-Releasing Hormone between Healthy Individuals and Patients with Irritable Bowel Syndrome.

Irritable bowel syndrome (IBS) often comorbids mood and anxiety disorders. Corticotropin-releasing hormone (CRH) is a major mediator of the stress response in the brain-gut axis, but it is not clear how CRH agonists change human brain responses to interoceptive stimuli. We tested the hypothesis that brain activation in response to colorectal distention is enhanced after CRH injection in IBS patients compared to healthy controls. Brain H215O- positron emission tomography (PET) was performed in 16 male IBS patients and 16 age-matched male controls during baseline, no distention, mild and intense distention of the colorectum using barostat bag inflation. Either CRH (2 μg/kg) or saline (1:1) was then injected intravenously and the same distention protocol was repeated. Plasma adrenocorticotropic hormone (ACTH), serum cortisol and plasma noradrenaline levels were measured at each stimulation. At baseline, CRH without colorectal distention induced more activation in the right amygdala in IBS patients than in controls. During intense distention after CRH injection, controls showed significantly greater activation than IBS patients in the right amygdala. Plasma ACTH and serum cortisol secretion showed a significant interaction between drug (CRH, saline) and distention. Plasma noradrenaline at baseline significantly increased after CRH injection compared to before injection in IBS. Further, plasma noradrenaline showed a significant group (IBS, controls) by drug by distention interaction. Exogenous CRH differentially sensitizes brain regions of the emotional-arousal circuitry within the visceral pain matrix to colorectal distention and synergetic activation of noradrenergic function in IBS patients and healthy individuals.

Generalizable representations of pain, cognitive control, and negative emotion in medial frontal cortex

The medial frontal cortex, including anterior midcingulate cortex, has been linked to multiple psychological domains, including cognitive control, pain, and emotion. However, it is unclear whether this region encodes representations of these domains that are generalizable across studies and subdomains. Additionally, if there are generalizable representations, do they reflect a single underlying process shared across domains or multiple domain-specific processes? We decomposed multivariate patterns of functional MRI activity from 270 participants across 18 studies into study-specific, subdomain-specific, and domain-specific components and identified latent multivariate representations that generalized across subdomains but were specific to each domain. Pain representations were localized to anterior midcingulate cortex, negative emotion representations to ventromedial prefrontal cortex, and cognitive control representations to portions of the dorsal midcingulate. These findings provide evidence for medial frontal cortex representations that generalize across studies and subdomains but are specific to distinct psychological domains rather than reducible to a single underlying process.Assessing person-level human brain maps across 18 fMRI studies, the authors identify separable representations of pain, cognitive control, and negative emotion in the medial frontal cortex that generalize across different studies and tasks.

Lack of endogenous opioid release during sustained visceral pain: a [11C]carfentanil PET study.

Summary Sustained visceral pain does not induce endogenous opioid release in the brain, contrary to a somatic pain stimulus with similar characteristics used in previous studies. Abstract Opioidergic neurotransmission in the central nervous system is involved in somatic pain, but its role in visceral pain remains unknown. We aimed to quantify endogenous opioid release in the brain during sustained painful gastric distension. Therefore, 2 dynamic [11C]carfentanil positron emission tomography scans were performed in 20 healthy subjects during 2 conditions: sustained (20 minutes) painful proximal gastric balloon distension at predetermined individual discomfort threshold (PAIN) and no distension (NO PAIN), in counterbalanced order. Pain levels were assessed during scanning using visual analogue scales and after scanning using the McGill Pain Questionnaire. Emotional state was rated after scanning using the Positive and Negative Affect Schedule. Distribution volume ratios in 21 volumes of interest in the pain matrix were used to quantify endogenous opioid release. During the PAIN compared to the NO PAIN condition, volunteers reported a significantly higher increase in negative affect (5.50 ± 1.29 versus 0.10 ± 1.08, P = .0147) as well as higher pain ratings (sensory: 74.05 ± 9.23 versus 1.50 ± 0.95, P < .0001; affective: 91.42 ± 8.13 versus 4.33 ± 6.56, P < .0001). No difference in endogenous opioid release was demonstrated in any of the volumes of interest. Thus, contrary to its somatic counterpart, no opioid release is detected in the brain during sustained visceral pain, despite similar pain intensities. Endogenous opioids may play a less important role in visceral compared to somatic pain.

Altered brain and gut responses to corticotropin-releasing hormone (CRH) in patients with irritable bowel syndrome

Stress is a known trigger of irritable bowel syndrome (IBS) and exacerbates its gastrointestinal symptoms. However, underlying the physiological mechanism remains unknown. Here, we investigated hypothalamic–pituitary–adrenal (HPA) axis, colonic motility, and autonomic responses to corticotropin-releasing hormone (CRH) administration as well as brain activity alterations in IBS. The study included 28 IBS patients and 34 age and sex-matched healthy control subjects. IBS patients demonstrated greater adrenocorticotropic hormone (ACTH) responses to CRH than control subjects. Male IBS patients had greater increases in colonic motility than male HCs after CRH. Female IBS patients showed altered sympathovagal balance and lower basal parasympathetic tone relative to female control subjects. Brain responses to rectal distention were measured in the same subjects using functional magnetic resonance imaging, and their associations with individual ACTH responses to CRH were tested. A negative association between ACTH response to CRH and activity in the pregenual anterior cingulate cortex (pACC) during rectal distention was identified in controls but not in IBS patients. Impaired top-down inhibitory input from the pregenual ACC to the HPA axis may lead to altered neuroendocrine and gastrointestinal responses to CRH. Centrally acting treatments may dampen the stress induced physical symptoms in IBS.

Brain responses to uncertainty about upcoming rectal discomfort in quiescent Crohn's disease – a fMRI study

Patients with Crohns disease (CD) in remission are exposed to chronic psychological distress, due to the constant risk of relapse. This permanent situation of anticipation and uncertainty can lead to anxiety, which may, in turn, trigger relapse. We aimed to investigate the effects of uncertainty on behavioral and brain responses to anticipation of visceral discomfort in quiescent CD patients.

161 Mirtazapine Improves Early Satiation, Nutrient Intake, Weight Recovery and Quality of Life in Functional Dyspepsia With Weight Loss: A Double-Blind, Randomized, Placebo-Controlled Pilot Study

Background: A population of multipotent stem cells capable of differentiating into neurons and glia has been isolated from adult intestine in humans and rodents. While they may provide a pool of stem cells for neurogenesis in the enteric nervous system (ENS), such a function has been difficult to demonstrate in vivo. Here we introduce a novel approach to study neurogenesis in the ENS using an ex vivo system. Methods: Using organotypic cultures of longitudinal muscle and myenteric plexus (LMMP) from Wnt1-cre;tdTomato (tdT) we performed EdU uptake assays at different time points and EdU incubations. To evaluate stem cell properties, LMMP treated with EdU was digested and flow cytometry performed with antibodies to nestin, CD49b, p75, and GFAP. We also performed a clonogenic sphereforming assay in which single cells were seeded into microwells to assess sphere forming capacity and retention of EdU signal. To evaluate for neurogenesis, LMMP treated with EdU was analyzed by flow cytometry and immunofluorescence with antibodies to neuronal and glial markers including Tuj, PGP9.5, nNOS, VIP, GFAP, and S100B. Protein expression for PTEN, pPTEN, Akt, and pAkt was analyzed by western blot and RT-PCR. Finally, organotypic cultures were treated with inhibitors BpV(phen) and LY294002, and EdU uptake assays were performed. Results: Culturing LMMP with EdU for 48h resulted in EdU uptake in 78% of neural crest cells (tdT+), indicating that the enteric nervous system has tremendous replicative capacity. Administering pulses of EdU at different time points, we found that proliferation occurred after an initial lag phase that lasted slightly over 24h. While undetectable at baseline and 24h, EdU uptake reached nearly 45% of tdT+ cells by 72h (p ,.001). Flow cytometry revealed that .90% of EdU+ neural crest cells expressed enteric neural stem cell markers nestin, CD49b, p75 and GFAP. Tracking single cells we found that EdU+ cells are capable of forming secondary NLBs suggestive of stem cell-like properties. Under differentiating conditions (withdrawal of growth factors), EdU uptake was detected in cells expressing Tuj, PGP9.5, nNOS, VIP, GFAP and S100B. This was supported with flow cytometry where .50% of cells positive for neuronal markers Tuj or PGP9.5 demonstrated EdU uptake (also seen for glial markers GFAP and S100B). Proliferation appears to be dependent on the PTEN/PI3K/Akt pathway with inhibition of PTEN (50% decrease in PTEN expression and 80-fold increase in pPTEN:PTEN (inactivation)) corresponding to activation of Akt (4-fold increase in pAkt:Akt) by 24h. Treatment of LMMP with PI3K inhibitor, LY294002, caused over 95% reduction (p,.01) and PTEN inhibitor, BpV(phen), caused 3fold increase (p,.001) in EdU uptake. Conclusion: This data suggest that the ENS is capable of neurogenesis in a PTEN dependent manner.

Differential brain responses to gradual intragastric nutrient infusion and gastric balloon distension: A role for gut peptides?

Background: Rapid gastric balloon distension to discomfort threshold activates the “pain neuromatrix” and deactivates exteroceptive sensory and “default mode network” regions. However, little is known about brain mechanisms underlying tolerance of meal‐induced gastric distension. We aimed to directly compare brain responses to gradual balloon distension and intragastric nutrient infusion and to explore the role of differential gut peptide release in these responses. Materials and methods: Brain responses to balloon‐ and nutrient‐induced distension (to individually titrated pain or maximal satiation threshold) were measured in 15 healthy volunteers using H215O‐PET on 2 separate days in counterbalanced order. The effects of increasing gastric distension and plasma levels of ghrelin and peptide YY3–36 (PYY3–36) on neural activity were assessed. Results: Balloon distension progressively activated pain‐responsive regions and deactivated exteroceptive sensory and “default mode network” areas. During nutrient infusion, “pain neuromatrix” regions and the orbitofrontal cortex were progressively deactivated, while the midbrain was activated. Plasma levels of PYY3–36 and ghrelin increased and decreased, respectively, during nutrient infusion only; decreasing ghrelin levels correlated with increasing midbrain activity. Conclusion: Different brain responses to gastric balloon distension and intragastric nutrient infusion are associated with nutrient‐induced gut‐brain signals, particularly to the midbrain, where these signals may interfere with both descending pain modulatory and mesolimbic reward processes. Deactivation of the “pain neuromatrix” during nutrient infusion may constitute the neurophysiological mechanism underlying the tolerance of normal meal volumes in health without induction of (painful) symptoms. Nutrient‐induced deactivation of the orbitofrontal cortex may represent a key interoceptive meal termination signal.