Introduction: Our knowledge of normal human colonic motility remains incomplete. Historically, this has been due to the relative inaccessibility of this organ for study, and the lack of standardisation of methods used to investigate it. Recent device development has provided us with advanced tools by which to assess colonic motility, namely pancolonic manometry, and the wireless motility capsule (WMC). Using traditional diagnostic tests, a subgroup of patients presenting with severe intractable symptoms, but without organic disease, are found to have slow transit constipation (STC). This is believed to be primarily due to colonic dysmotility, although colonic motor functions remain poorly understood in this group also. Aims: The principal aims of this thesis were to: (1) explore the effect of pancolonic manometric recording technique on colonic motility; (2) describe pancolonic motility in STC, compared to healthy control subjects; (3) using the wireless motility capsule (WMC), validate the precise location of the pH fall around the ileo-caecal junction as a landmark for measuring colonic motility; (4) obtain normative data for colonic motility (transit and contractility) and intraluminal pH in a large cohort of healthy volunteers using the WMC, and compare this to patients with STC. Methods: The following methods were used: (1) prolonged pancolonic manometry in healthy volunteers and patients with STC; (2) a dual scintigraphic technique, involving radioactive-labelling of the WMC in healthy volunteers; (3) wireless motility capsule studies of colonic motility in healthy volunteers and in patients with STC. Results: Colonic manometric recording technique (bowel preparation or not, and different catheter types) significantly influences some characteristics of propagating sequence (PS) activity, including frequency, amplitude, polarity, relationship between consecutive PSs, and circadian rhythm. Patients with STC display dysregulated colonic motor function represented by disorganised spatiotemporal patterning and loss of 'regional linkage' among PSs. The fall in pH measured by the WMC was confirmed to be either in the caecum, ascending colon, or as the capsule moved from the caecum to the ascending colon. Using the WMC, the upper limit of normal colonic transit time (CTT) was found to be 51 h; however, CTT is not a continuous variable and exhibits peaks every 24 h. CTT is significantly prolonged in females and affected by the study protocol employed. In patients with STC, colonic contractility (motility index) is increased in comparison with healthy controls, and intraluminal pH is more acidic in the proximal colon, and more alkaline in the distal colon. Conclusions: The method of pancolonic manometry requires standardisation. However, novel metrics derived from prolonged pancolonic recordings have improved our understanding of the physiology of colonic motor function in health, and also pathophysiology in constipation. The WMC provides an alternative, less invasive method to investigate colonic motility; this technique also requires standardisation, but early results in patients with STC complement those from manometry, and also reveal alterations in intraluminal pH that may be of pathophysiological significance.

This thesis focuses on the characterization of rhythmic activity in the colon of healthy subjects and patients diagnosed with refractory constipation; this activity is mediated by pacemaker cells in the gastrointestinal system, the Interstitial cells of Cajal (ICC). The myogenic activity described are the cyclic motor patterns (CMP) and haustral activity; characterization of these motor patterns in healthy subjects provided control values for the subsequent comparison in patients. Frequency analysis of CMP revealed a novel high-frequency activity (7-15cpm) unrelated to the breathing artefact. Three categories of cyclic motor patterns were observed: (1) CMP following mass peristaltic events (HAPW); (2) those that occur in isolation of other colonic motor patterns (HAPW) in the colon; and (3) low-frequency (2-6cpm), prominently retrograde rhythmic activity in the rectum. CMP were scarcely present in majority of the patients; however, elevated retrograde CMP in the distal colon and rectum in some patients plays a role in retarding flow of colonic content. A detailed characterization of haustral activity (comprised of 2 boundaries and the activity within a haustrum) is reported for the first time using high-resolution colonic manometry. Furthermore, we find that over expression of haustral boundary activity in patients serves as a disproportionate hindrance in colonic transit. An in-depth methodology is developed for the identification and subsequent analysis of haustral activity and CMP; this provides transparency in the data acquisition and analysis. Lastly, a sphincter at the rectosigmoid junction, sphincter of O’Beirne is presented in a patient case report. The persistent presence and paradoxical contractions of this sphincter served to impede flow colonic content, an important factor contributing to the pathophysiology of severe refractory constipation. / Thesis / Master of Science (MSc) / Colonic manometry tests and measures strength and coordination of colonic muscles contractions. This tool was used to understand the rhythmic colonic motor patterns and their contribution to motility in healthy subjects and patients with constipation. Rhythmic activity in the gut is mediated by pacemaker cells, Interstitial cells of Cajal (ICC). We present a detailed characterization of ICC-mediated rhythmic activity that (1) occurs in the small pouches making up the colon (haustra) and (2) is greater than 5cm along the length of the colon (cyclic motor patterns-CMP).CMP possess high-frequency activity (7-15cpm), in addition to activity observed in the low-frequency range (2-6cpm). Activity in the haustra, or haustral activity, is comprised of 2 boundaries with activity within these bounds (intra-haustral activity); the overexpression in patients serves to retard flow of colonic content. Sphincter of O’Beirne is the last haustral boundary at the rectosigmoid junction; its persistent presence was characterized in a patient with refractory constipation.

Introduction: Functional motility disorders of the colon are poorly defined. Hence, patients with chronic colonic motor dysfunction are treated or undergo surgery without proper diagnosis. Most colonic motility assessment centers around the largest propagating motor pattern in the colon- the High Amplitude Propagating Pressure Wave (HAPW). However, there is no consensus regarding a definition of this important motor pattern. Additionally, no consideration is given to other aspects of colonic motility such as colo-ano-rectal coordination and control by the autonomic nervous system (ANS). The aim of this thesis was to improve understanding of HAPWs and other features of colonic motility in health and constipation, understand how autonomic dysfunction is related to observations in patients, and evaluate the effect of neuromodulation of the ANS. Methods: Motility was assessed in healthy volunteers and patients using water-perfused High Resolution Colonic Manometry (HRCM). To assess the association between ANS and colonic motor activity Heart Rate Variability (HRV) was measured in patients. Spatiotemporal maps were created using HRCM to analyse and quantify colonic motor activity following baseline, and interventions which included proximal balloon distention, meal, and rectal bisacodyl. Low-Level Light Therapy (LLLT) was also applied during HRCM as a method of neuromodulation, to observe its effect on colonic motility. Results: Normal HAPWs are those which have an amplitude of more than 50 mmHg and belong to one of 3 categories: proximally originating, proximal continuing, and transverse/descending. The best intervention sequence to generate these during HRCM assessment is baseline, proximal balloon distention, meal, rectal bisacodyl. Based on their responses to these interventions and the type of HAPWs present, patients could be classified into strong responder, weak responder and non-responder groups. Overall, patients in the strong responder group were most similar to healthy volunteers both with regard to motility and ANS control. Conversely, the weak and non-responders had showed decreased or no motility with decreased parasympathetic input and occasionally sympathetic inhibition. Additionally, other features of motility such as the sphincter of O'Beirne, and lack of colo-ano-rectal coordination were found to lead to constipation even in presence of normal HAPWs. LLLT shows promise in initiating colonic motor activity through neuromodulation of the sacral defecation center. Conclusions: HAPWs can be defined into one of three categories and used to categorize patients based on their HAPW response to different interventions. However, other aspects of colonic motility such as the colo-ano-rectal coordination and autonomic nervous system control of colonic motility should be taken into consideration in diagnosis of constipation, as they can point towards more non-invasive treatment methods such as neuromodulation using LLLT. / Thesis / Master of Science in Medical Sciences (MSMS)

Orientador: José Ricardo de Arruda Miranda / Resumo: Inflammatory bowel disease (IBD) is an idiopathic gastrintestinal tract disease that affects a large part of the world population and has its symptoms related to changes in colon motility. However, the evolution of these changes is not completely understood, and may be related to symptoms that appear in stages when the disease is apparently controlled. The objective of this work was to perform a long-term evaluation of the mechanical and electrical aspects of colonic contractility during the model of inflammation induced by trinitrobenzene sulfonic acid (TNBS) in rats. This work applied an efficient and low invasive methodology associating mechanical, electrical, chemical and histological information. The contractility and inflammatory parameters were acquired in the same animal at six different times: before induction of TNBS (control) and at 2, 5, 8, 11 and 14 days thereafter. The mechanical activities were acquired by Alternating Current Biosusceptometry (ACB) and subdivided in Rhythmic Propagation Ripples (RPR) and Rhythmic Propulsive Motor Complex (RPMC). We recorded the electrical activity by electromyography (EMG) and evaluated the inflammation processes determining the myeloperoxidase activity (MPO) in the feces. Additionally, we compared the thickness of colon layers throughout the inflammation by histopathological analyzes. Our results showed transient changes in MPO activity levels and frequency of RPMC contraction, while RPR and electrical activity underwent perma... (Resumo completo, clicar acesso eletrônico abaixo) / Doutor