Individuals with irritable bowel syndrome (IBS) may experience abdominal pain as a result of pain signals in the bowel and how these signals are processed in the brain. Studies using brain imaging (pictures) have shown that IBS patients with more pain diagnoses (i.e. fibromyalgia, migraines, etc.) have greater activity in the regions of the brain responsible for the emotional and thought processing of pain signals. This could possibly make bowel sensations and bowel difficulties feel abnormal or more noticeable, in turn causing more severe IBS symptoms. The purpose of this protocol is to explore the role of pain diagnoses and their affect on brain activity in IBS patients. The investigators will also examine the use of a medication, desipramine, which is known to affect these brain regions, in IBS patients.
Background Irritable bowel syndrome (IBS) is a common abdominal pain disorder diagnosed by symptom-based criteria (Rome III). Since there is no objective measure available to establish a formal diagnosis, IBS likely encompasses a biologically heterogeneous group of patients with distinct pathophysiology. To date, studies evaluating the mechanistic basis of IBS largely have focused on bowel-specific factors. More recently, differences in brain activation patterns in response to painful visceral stimuli (rectal balloon distention) have been identified in IBS subjects compared to healthy controls. These differences often are observed within the homeostatic afferent processing network (HAPN), regions of the brain responsible for the descending inhibition of pain signals, as well as the affective and emotional response to pain. However, IBS brain activation patterns are inconsistent across IBS studies. One likely explanation for this variation in brain activations is the role of psychiatric co-morbidity often present in IBS. No study to-date has considered whether unique patterns of cerebral activation during visceral stimulation exist among subgroups of IBS patients. In our current work, we are exploring the role of multiple co-morbid unexplained pain syndromes, hereafter referred to as 'somatization', and its relevance to IBS subjects' brain responses to pain. We anticipate that IBS patients with somatization (IBS-S+) have aberrant descending inhibitory neurocircuitry, facilitating more intense pain experiences across a spectrum of ascending pain signals (both visceral and somatic). Somatization can be readily detected using standardized instruments and medical histories, and when present in IBS subjects clinically portends more severe bowel symptoms, and poorer responses to proven bowel-specific IBS therapies. Greater insight into the relevance of somatization and mood symptoms to HAPN brain networks thus is not only critical to our understanding of the pathophysiology of IBS, but also may reveal additional clinical targets for the management of these disorders. Hypotheses and Aims The overarching hypothesis of this proposal is that abnormal homeostatic afferent processing network (HAPN) responses to visceral stimulation have mechanistic relevance to a subset of patients with IBS. It is further hypothesized that abnormalities HAPN responses to afferent pain signals in IBS subjects with comorbid somatization (IBS-S+) result in: (1) more generalized pain experiences (both visceral and somatic), and (2) more severe IBS and somatic pain symptom experiences. Using functional magnetic resonance imaging (fMRI), our preliminary findings have revealed abnormal activation of HAPN brain regions following visceral stimulation in IBS subjects compared to healthy controls. Our pilot data also demonstrated a distinct pattern of abnormal HAPN activations in response to visceral stimulation in IBS subjects with comorbid somatization (IBS-S+) compared to those without somatization (IBS-S-). These findings suggest that clinical differences between IBS-S+ and IBS-S- subjects may result from aberrant HAPN responses to visceral sensory input. The purpose of this proposal is to further investigate the mechanistic importance of the brain's homeostatic afferent processing network in the presence of overlapping somatization and mood disorders to symptom experiences in IBS. This goal will be realized through the pursuit of the following Specific Aims: Specific Aim 1. To validate homeostatic afferent processing network (HAPN) activation patterns with noxious visceral stimulation in IBS subjects, and determine their relationship to visceral pain symptom experiences. Hypothesis 1: IBS subjects collectively will demonstrate a pattern of abnormal HAPN activation in response to noxious visceral stimulation Hypothesis 1b: Abnormal HAPN brain activations overall will correlate with greater subjective pain ratings of noxious visceral stimulation in IBS subjects Specific Aim 2. To evaluate the influence of somatization on HAPN activations with noxious visceral and somatic stimulation in IBS subjects, and determine their relationship to pain symptom experiences. Hypothesis 2: IBS subjects with comorbid somatization (IBS-S+) will demonstrate abnormal HAPN activation in response to both noxious visceral and somatic stimuli, when compared to IBS subjects with no somatization (IBS-S-). Specific Aim 3: To determine the influence of despiramine on abnormal HAPN brain activations in IBS-S+ and IBS-S- subjects. Hypothesis 3: Desipramine will normalize HAPN activations in both IBS-S+ and IBS-S-, with greater effects in the IBS-S+ cohort.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
18
Desipramine 25 mg/day administered in the evening. Dosing may be increased dependent upon side-effects and clinical response to a maximum of 100 mg/day. Absent significant side-effects, all patients are increased at the one week visit to 50 mg/day at bedtime if they have not achieved a report of "Adequate relief". Thereafter, up to week 4, the daily desipramine dose may be increased weekly by 25 mg up to the 100 mg/d maximum.
Washington University School of Medicine
St Louis, Missouri, United States
MRI Blood Oxygen Level Dependent (BOLD) Activation CONTRASTS (in Prespecified Regions of Interest (ROI) in VOXELS
CONTRASTS (comparisons of study group BOLD activations vs rest) are the outcome of interest. Voxel-wise comparisons (ANOVAs) were performed to determine differences in activations between groups within these regions. First level analyses of rectal balloon distensions experienced by subjects were modeled as box car functions then convolved with the canonical hemodynamic response function (HRF). For the second level analyses, differences in brain activation while experiencing both high and low painful rectal balloon distensions between IBS patients with High somatization vs Low somatization were examined with two-sample t-tests utilizing contrast images generated from the first level analysis. Unconventionally, these inferential statistics are regarded as the primary outcome in the study. Accordingly individual group level BOLD values where not recorded or evaluated separately in the cohorts. These data are not available, and cannot be reported "per Arm".
Time frame: 1 month
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.