Hypnosis and Irritable Bowel Syndrome Head or Gut? Nashville 2010

1. Hypnosis and Irritable Bowel Syndrome Head or Gut? Nashville 2010

2. This lecture will review, explain and define the condition known as Irritable Bowel Syndrome. I will review all pertinent literature where IBS and hypnosis interface. I will discuss the fMRI data and possible mechanism of action of hypnosis in IBS. Time permitting will facilitate a group discussion on the implementation of hypnosis for the treatment of IBS in the participant’s practices at a practical level. Upon completion of the program, you should be able to: • Explain and define Irritable Bowel Syndrome using the current Rome criteria • Understand current Hypnosis research in IBS including fMRI data • Extrapolate to other hypnotically treated diseases a possible mechanism by which hypnosis may work

3. IBS is a diagnosis of exclusion! Irritable bowel syndrome, is classified as a "functional" disorder. A functional disorder refers to a disorder or disease where the primary abnormality is an altered physiological function rather than an identifiable structural or biochemical cause. Thus proper testing for other GI diseases should be undertaken before the presumption of IBS is made.

4. IBS Common disorder in which bowel habits are altered in association with abdominal pain or discomfort

5. IBS • 12 percent among adults in the United States and a similar prevalence worldwide

6. IBS • By definition, no mechanical, biochemical, or overt inflammatory condition explains the symptoms.

7. IBS • Diarrhea is a symptom that often leads to medical consultation • Frequent trips to the bathroom alters lifestyle • Anxiety • Decreased quality of life.

8. IBS • Constipation type has • Bloating • Discomfort • Altered body image

9. IBS Differential Diagnosis Microscopic colitis Celiac disease Giardiasis Lactose malabsortion Tropical sprue Small bowel overgrowth syndrome Bile salt malabsorption Colon cancer

10. IBS Incidence increases during adolescence Peaks in the third and fourth decades Rare onset after 50 Women have a (2:1 ratio) High frequency of psychosocial stress

11. IBS • Psychosocial stress appears to predict both the use of health care and the persistence of symptoms

12. Manning Criteria other V Distinguish IBS from organic disease are as follows: Onset of pain associated with more frequent bowel movements Onset of pain associated with looser bowel movements Pain relieved by defecation Visible abdominal bloating Subjective sensation of incomplete evacuation more than 25% of the time Mucorrhea more than 25% of the time

13. Rome Consensus panel created first in Rome. It has been updated twice and so now we use: “Rome III” Rome Criteria designed to provide a standardized diagnosis for research and clinical practice.

15. The Rome III Criteria May 23, 2006, Rome III was officially launched • C. Functional Bowel Disorders • C1. Irritable Bowel Syndrome • Diagnostic criterion* • Recurrent abdominal pain or discomfort** at least 3 days/month in the last • 3 months associated with two or more of the following: • 1. Improvement with defecation • 2. Onset associated with a change in frequency of stool • 3. Onset associated with a change in form (appearance) of stool • *Criterion fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis • ** “Discomfort” means an uncomfortable sensation not described as pain. • In pathophysiology research and clinical trials, a pain/discomfort frequency of at least 2 days a week during screening evaluation is recommended for subject eligibility.

16. D. Functional Abdominal Pain Syndrome D. Functional Abdominal Pain Syndrome Diagnostic criteria* Must include all of the following: 1. Continuous or nearly continuous abdominal pain 2. No or only occasional relationship of pain with physiological events (e.g., eating, defecation, or menses) 3. Some loss of daily functioning 4. The pain is not feigned (e.g., malingering) 5. Insufficient symptoms to meet criteria for another functional gastrointestinal disorder that would explain the pain * Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis

17. IBS Pathophysiology • The cause of irritable bowel syndrome is unknown

18. IBS Pathophysiology • Associated pathophysiology includes altered gastrointestinal motility and increased gut sensitivity

19. Pathophysiology • An increased small-bowel and colonic contractions temporally associated with abdominal pain. • A heightened sensitivity to visceral distention, particularly that which is perceived as noxious. • The interplay between motor and sensory dysfunction appears to explain the symptoms of irritable bowel syndrome.

20. Altered GI motility? • The myoelectric activity of the normal colon has background slow waves with superimposed spike potentials. • IBS has variations in slow-wave frequency and a blunted, late-peaking, postprandial response of spike potentials. Patients who are prone to diarrhea demonstrate this disparity to a greater degree than patients who are prone to constipation. • Hypothesize a generalized smooth muscle hyperresponsiveness. • There have been reports of increased urinary symptoms, including frequency, urgency, nocturia, and hyperresponsiveness to methacholine challenge.

21. Visceral hyperalgesia? • Enhanced perception of normal motility and visceral pain characterizes IBS. Rectosigmoid and small bowel balloon inflation produces pain at lower volumes in patients than in controls. • Hypersensitivity appears with rapid but not gradual distention. • Patients who are affected describe widened dermatomal distributions of referred pain. • Sensitization of the intestinal afferent nociceptive pathways that synapse in the dorsal horn of the spinal cord provides a unifying mechanism.

22. Post Infectious? Postinfective IBS has been reported after shigella, salmonella and campylobacter infections but does not appear specific to any particular organism. Between 6-17% of patients with IBS report that their symptoms began with an episode of gut inflammation related to gastroenteritis. The literature provides several lines of evidence that the colonic bacterial ecology is altered in IBS, and there mucosal inflammation characterized by cellular infiltration, and functional studies in mucosa and circulating blood consistent with some inflammation; for example, increased mast cell and T lymphocyte numbers, and increased IL-1b mRNA in mucosa, reduced IL-10/IL-12 ratio in blood, increased circulating IL-6, IL-8, tumor necrosis factor A. The environment of nociceptor terminals in the gut of IBS patients is likely to be altered, suggesting a role for peripheral sensitisation.

23. Psychological factors Two thirds of IBS patients referred to secondary care show some form of psychological distress, most commonly anxiety. Some patients are reluctant to expose their feelings, whereas normal anxiety about unexplained symptoms may be mistakenly judged as abnormal. Hostility may be apparent, particularly in patients who feel dissatisfied with previous consultations with doctors, whom they felt expressed little sympathy. It is vital that any ongoing severe stress, especially of a domestic nature, is identified, as it has been shown this impairs the response to treatment. Multiple unexplained physical symptoms are common in IBS and can be a manifestation of somatisation disorder.

24. Psychopathology? • Associations between psychiatric disturbances and IBS pathogenesis are not clearly defined. • Patients with psychological disturbances relate more frequent and debilitating illness than control populations. • Patients who seek medical care have a higher incidence of panic disorder, major depression, anxiety disorder, and hypochondriasis than control populations. • An Axis I disorder coincides with the onset of GI symptoms in as many as 77% of patients. • A higher prevalence of physical and sexual abuse has been demonstrated in patients with IBS. • Whether psychopathology incites development of IBS or vice versa remains unclear.

25. INCREASED VISCERAL SENSITIVITY IS NOT SUFFICIENT TO EXPLAIN PAIN REPORTS OF IBS IBS patients with a history of sexual or physical abuse report greater pain but have higher visceral sensation thresholds. Patients with more severe IBS are distinguished from those with milder IBS by having greater psychological distress and disturbances yet with no differences in visceral sensation thresholds. These data highlight the importance of central pain processing in amplifying the perception of visceral signals. {The pain is in the central processor (ie the ACC) and not in the gut.}

26. Central neurohormonal mechanisms? Abnormal glutamate activation of N-methyl-D-aspartate (NMDA) receptors, activation of nitric oxide synthetase, activation of neurokinin receptors, and induction of calcitonin gene-related peptide have been observed. The hypothalamic-pituitary axis may be intimately involved in the origin. Motility disturbances correspond to an increase in hypothalamic corticotropin-releasing factor (CRF) production in response to stress. CRF antagonists eliminate these changes.

27. microscopic inflammation? Recently, microscopic inflammation has been documented in some patients. This concept is groundbreaking in that IBS had previously been considered to have no demonstrable pathologic alterations. Risk factors for developing post-infectious IBS include: female gender longer duration of illness the type of pathogen involved an absence of vomiting during the infectious illness young age

28. microscopic inflammation? Laproscopic full-thickness jejunal biopsy samples revealed infiltration of lymphocytes into the myenteric plexus and intraepithelial lymphocytes in a subset of patients. Neuronal degeneration of the myenteric plexus was also present in some patients. Patients with postinfectious IBS may have increased numbers of colonic mucosal lymphocytes and enteroendocrine cells. Enteroendocrine cells in postinfectious IBS appear to secrete high levels of serotonin, increasing colonic secretion and possibly leading to diarrhea.

29. Genetics? IBS clearly aggregates within families. First degree relatives of IBS patients are twice as likely to have IBS as the relatives of the IBS patient’s spouse. Studies cannot distinguish the influence of genetic and shared environmental factors. Associations between various candidate genes and IBS have been studied. Polymorphisms of the serotonin transporter 5-HTT, an adrenergic receptor, interleukin (IL)-10, and tumour necrosis factor a (TNFa) genes have been associated with some forms of IBS.

30. Villani Genetic Risk Factors for Post-Infectious Irritable Bowel Syndrome Following a Waterborne Outbreak of Gastroenteritis Gastroenterology (2009), doi:10.1053/j.gastro.2009.12.049. In May 2000, more than 2300 residents of Walkerton Ontario developed gastroenteritis from microbial contamination of the municipal water supply with 36% developed IBS. This allowed for a unique longitudinal study including genetic susceptibility to post-infectious (PI)-IBS. This is the first study to assess potential genetic determinants of PI-IBS. Genes that encode proteins involved in epithelial cell barrier function and the innate immune response to enteric bacteria are associated with the development of IBS following acute gastroenteritis. The TLR9, IL6, and CDH1 variants all persisted as independent risk factors for PI-IBS when controlling for previously identified clinical risk factors. Villani, A.C., Lemire, M., Thabane, M., Belisle, A., Geneau, G., Garg, A.X., Clark, W.F., Moayyedi, P., Collins, S.M., Franchimont, D., Marshall, J.K. Genetic Risk Factors for Post-Infectious Irritable Bowel Syndrome Following a Waterborne Outbreak of Gastroenteritis Gastroenterology (2009), doi:10.1053/j.gastro.2009.12.049.

31. Neuroimmune mechanisms It is possible that stress, by activating mast cells, may contribute to persistently increased gut permeability and hence to immune activation. This stress effect has been demonstrated in numerous animal models. Regardless of bowel habit subtype, IBS patients may show evidence of an ongoing immune activation at the gut epithelium level. A genetic tendency to under-produce IL-10 might pre-dispose to this immune activation. An abnormally small number of high IL-10 producing genotypes has been reported in IBS.

32. The right genetics coupled with an infectious agent produces an interleukin filled neuro-immune cascading response that up-regulates sensitization in the jejuneal neural plexus leading to a hard wired behavior?

33. THE CNS IS ‘‘WIRED’’ TO MODULATE VISCERAL AFFERENT PAINFUL SIGNALS AND RESPONSES TO STRESS.

34. The ‘‘gate control’’ pain system allows for bidirectional signals between the gut and brain. It begins with visceral signals ascending to the CNS via the dorsal horn of the spinal cord.

35. From the spinal cord up to the thalamus, and then laterally to the somatosensory cortex and medially to the Limbic system and cingulate cortex.

36. Amplification of these signals can occur at the level of the mucosa via sensitization from inflammation or injury, at the dorsal horn (central sensitization), or higher at midbrain structures. In addition, corticofugal pathways from the emotional motor system via the periaqueductal gray and nucleus raphe magnus descend to the dorsal horn where they can amplify or suppress afferent signals coming up from the gut.

37. Animal studies have shown that stimulation of the periaqueductal grey matter in the midbrain inhibits behavioural responses to noxious stimulation sent up from the spinal neurons. The periaqueductal grey matter receives direct inputs from the hypothalamus and the limbic cortex and controls spinal nociceptive transmission through descending pathways.

39. Brain –Gut connection Brain Imagery fMRI

40. GUT 2005;54;569-573 doi:10.1136/gut.2004.058446

41. Figure 1 Structure of the cingulate cortex. The anterior region of the mid cingulate cortex (MCC, shown in green) is a subregion called the anterior mid cingulate cortex of the ACC (aMCC); it has a variety of other names including the caudal ACC, the dorsal ACC (dACC), or cognitive division of theACC (ACC-CD). pACC, anterior perigenual ACC; rACC, rostral ACC.

42. Rainville Rainville and his associates showed that strategically worded suggestions can dissociate the two components of pain, selectively altering one but not the other. The two components of pain have different biological substrates: sensory pain in the primary somatosensory cortex, and suffering in the anterior cingulate cortex. (Rainville, Duncan, Price, Carrier, & Bushnell, 1997).

43. Schulz-Stubner Clinical Hypnosis Modulates Functional Magnetic Resonance Imaging Signal Intensities and Pain Perception in a Thermal Stimulation Paradigm Regional Anesthesia and Pain Medicine, 2004 Based of the findings of increased BOLD signals in the left hemispheric ACC and the basal ganglia with less activation of the classic pain network while under hypnosis; the left ACC and basal ganglia might play a role in increasing inhibitory signals, which in turn may lead to a loss of signal from painful thermal stimuli in the more proximal sensory cortex. This is still speculative given the limitations of the study design. Schulz-Stubner S, Krings T, Meister IG, Rex S, Thron A, Rossaint R. Clinical Hypnosis Modulates Functional Magnetic Resonance Imaging Signal Intensities and Pain Perception in a Thermal Stimulation Paradigm Regional Anesthesia and Pain Medicine, Vol 29, No 6 (November-December, 2004: pp 549-556

44. Derbyshire Cerebral activation during hypnotically induced and imagined pain. Neuroimage 2004 ….In contrast with imagined pain, fMRI revealed significant changes during this hypnotically induced pain experience within the thalamus and anterior cingulate (ACC), insula, prefrontal, and parietal cortices. These findings compare well with the activation patterns during pain from nociceptive sources and provide the first direct experimental evidence in humans linking specific neural activity with the immediate generation of a pain experience. Derbyshire, Stuart W G. Whalley, Matthew G. Stenger, V Andrew. Oakley, David A. Cerebral activation during hypnotically induced and imagined pain.Neuroimage. 23(1):392-401, Sept. 2004

45. Mohr The anterior cingulate cortex contains distinct areas dissociating external from self-administered painful stimulation: a parametric fMRIstudy. Pain 2005 The anterior cingulate cortex (ACC) has a pivotal role in human pain processing by integrating sensory, executive, attentional, emotional, and motivational components of pain. Mohr, C. Binkofski, F. Erdmann, C. Buchel, C. Helmchen, C. The anterior cingulate cortex contains distinct areas dissociating external from self-administered painful stimulation: a parametric fMRIstudy. Pain. 114(3):347-57, 2005 Apr.

47. Amir Raz Phd Hypnotic suggestion reduces conflict in the human brain Amir Raz†, Jin Fan‡, and Michael I. Posner Sackler Institute for Developmental Psychobiology, Weill Medical College of Cornell University, New York, NY 10021 Contributed by Michael I. Posner, April 13, 2005 Functional MRI data revealed that under posthypnotic suggestion, both ACC and visual areas presented reduced activity in highly hypnotizable persons compared with either no-suggestion or less-hypnotizable controls.

48. Stroop In the Stroop task, experienced readers are asked to name the ink color of a colored word. In responding to the ink color of an incompatible color word (eg, the word BLUE displayed in red ink), subjects are usually much slower and less accurate than in identifying the ink color of a control item (eg, XXXX or SHIP printed in red). This is called the Stroop Interference Effect (SIE), and it is one of the most robust and well-studied phenomena in attention research. Reading words is considered to be automatic; a proficient reader cannot withhold accessing a word's meaning, despite explicit instructions to attend only to the ink color. Therefore it is the "gold standard" of automated performance.

49. Stroop A simple strategy-free posthypnotic suggestion to circumvent reading within a classical Stroop design using 32 proficient readers of English naive to the Stroop task, recruited from a medical students at Cornell University. Sixteen hypnosis subjects scoring in the highly suggestible range and 16 control subjects scoring in the less-suggestible range on the SHSS-C were recruited.

50. Stroop Suggestion Very soon you will be playing the computer game. When I clap my hands, meaningless symbols will appear in the middle of the screen. They will feel like characters of a foreign language that you do not know, and you will not attempt to attribute any meaning to them. This gibberish will be printed in one of 4 ink colors: red, blue, green or yellow. Although you will only be able to attend to the symbols' ink color, you will look straight at the scrambled signs and crisply see all of them. Your job is to quickly and accurately depress the key that corresponds to the ink color shown. You will find that you can play this game easily and effortlessly.