The purpose of this study is to understand how a drug called Linaclotide improves bowel function and abdominal pain in patients with Irritable Bowel Syndrome with Constipation (IBS-C) as well as to examine whether Linaclotide alters communication between the brain and pelvic-floor region.

Linaclotide has been shown to improve abdominal pain and bowel symptoms in IBS-C, and is approved by the FDA for the treatment of this condition. However, how exactly this drug works to relieve abdominal pain and discomfort in humans is not clearly known. Studies in animal models suggest that patients with IBS-C have hypersensitivity in the gut.

Consequently, in IBS-C patients, there is rapid and excessive conduction of signals both from the brain and central nervous system region towards the pelvic-floor (anorectal axis) and the reverse direction. The investigators hypothesize that treatment with Linaclotide may improve/normalize these signals and thereby improve bowel symptoms.

Investigators will test this theory using a new, noninvasive (and established) method of studying this communication pathway between the brain and gut.

modulate these mechanisms and thereby improve visceral pain.

Investigators propose three specific aims:

1. Examine the hyperexcitability of the afferent-pelvic floor brain axis in 60 patients with IBS by measuring the cortical evoked potentials (CEP) and sensory thresholds after electrical stimulation of the rectum and anus before and after administration of linaclotide or placebo for a period of 10 weeks.
2. Study the efferent brain pelvic floor axis by stimulating the cortex with transcranial magnetic stimulation and record the anal and rectal motor evoked potentials (MEP) in 60 IBS-C patients.
3. Determine the locus for neuronal modulation i.e are the neuroenteric changes due to central or peripheral neuronal sensitization or both, by evoking anal and rectal MEPs after selectively stimulating the lumbar and sacral nerves bilaterally, and by comparing segmental with transcranial-induced MEPs.

Inclusion Criteria:

• During the previous year, all patients must have recurrent abdominal discomfort or pain for at least 3 days per month in the last 3 months associated with two or more of the following symptoms (36): i) improvement with defecation; ii) onset associated with a change in frequency of stool; and/or iii) onset associated with a change in form (appearance) of stool.
• No evidence for structural diseases- (excluded by colonoscopy, sigmoidoscopy or barium enema). Patients over 50 will not be eligible to enroll unless they have had a colonoscopy, sigmoidoscopy or barium enema within ten years prior to screening. Individuals under the age of 50 would only be required to undergo one of such diagnostic procedures if they present with alarm symptoms such as rectal bleeding, unexplained weight loss or anemia). There is no plan undergo such procedures as part of this research protocol. Therefore, individuals requiring such a procedure will be referred back to their treating physician (due to reaching age 50 and requiring a general screening of colon check or any age, due to alarm symptoms) and will not be enrolled in the study.
• No evidence of metabolic problems (to be excluded by laboratory testing; a comprehensive blood count and metabolic panel are required to be within six months of screening visit. If none are available on the patient's electronic records or records provided by an external provider, we will have them complete blood testing to exclude clinically significant metabolic abnormalities). The P.I. will decide if any values that fall out of range represent clinical significance or not.
• Women of childbearing potential must agree to a urine pregnancy test at screening and to avoid pregnancy throughout the study.
• On a prospective symptom/stool diary patients reported i) presence of abdominal pain/discomfort for at least 2 days per week; ii) hard or lumpy stools >25% and loose or watery stools in < 25% of bowel movements (IBS-C); (iii) loose or watery stools in >25% of bowel movements and hard stools <25% of Bowel Movements(IBS-D); >25% of hard or loose stools within one week (IBS-M)

Exclusion Criteria:

• Patients with laxative abuse, anorexia nervosa, and bulimia;
• Patients taking opioids (e.g. codeine or morphine), antispasmodics (dicyclomine or hyoscyamine), or muscle relaxants (e.g. cyclobenzaprine). If a patient is taking any of these drugs or supplements, and the P.I. determines that they may be able to safely come off of their medication, the patient may be eligible to re-screen, pending a two week minimum washout before enrollment;
• Patients with active episodic major depression will not be enrolled and will be referred for treatment, if necessary. Patients with a history of depression and have achieved stable remission are eligible.
• Patients with comorbid illnesses, severe cardiac disease, chronic renal failure or previous gastrointestinal surgery except cholecystectomy and appendectomy;
• Patients with neurologic diseases (e.g. head injuries, epilepsy, multiple sclerosis, strokes, spinal cord injuries) or brain disorders prone to causing seizures;
• Patients experiencing impaired cognizance (mini mental score of < 15) and/or legally blind;
• Women who are pregnant or likely to conceive (women with potential for pregnancy must use contraceptive measures to be included);
• Patients with ulcerative and Crohns colitis;
• Patients with rectal prolapse, anal fissure, anal surgery or inflamed hemorrhoids. Patients found to have any of these conditions are not eligible for enrollment due to the potential discomfort of probe placement. If a patient who is excluded due to anal fissure or inflamed hemorrhoids achieves full remission after the initial screening, they may be eligible for rescreening.