Evaluating the Antidepressant Efficacy of Transcranial Magnetic Stimulation (TMS) in Patients With Inflammatory Bowel Disease (IBD) and Effects on IBD-related Symptoms.

Brief Summary

Detailed Description

Background and rationale: Comorbid maladaptive behaviors and pain are highly prevalent in patients with IBD and are often under-treated. These comorbidities lack effective therapies and thus complicate medical management, adversely impact patient outcome and health, and increase the resource burden on the healthcare system. Development of effective treatment delivery is therefore vital. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive form of brain stimulation in which an electric pulse generator placed at the scalp produces a rapidly changing magnetic field at biologically relevant frequencies to induce a stimulating electrical current at targeted sites in the brain. rTMS has demonstrated diagnostic and therapeutic potential for a number of conditions, including Alzheimer's disease, autism, bipolar disorder, epilepsy, chronic pain, major depressive disorder, Parkinson's disease, post-traumatic stress disorder (PTSD), schizophrenia (negative symptoms), obsessive-compulsive disorder (OCD), and for the cessation of smoking. To date, however, rTMS has not been used to treat the mental health issues and symptoms observed in persons with IBD. The investigators will develop rTMS interventions for IBD to target comorbid maladaptive behaviors and pain using evidence-based knowledge of TMS effectiveness for other chronic medical conditions. Research Question: Compared to sham, does twice daily intermittent theta-burst stimulation rTMS delivered to the left dorsolateral prefrontal cortex for two weeks (20 sessions) improve comorbid maladaptive behavior (heightened interoceptive awareness, sleep, fatigue, catastrophizing, anxiety and depression), reduce pain and improve quality of life in persons with inflammatory bowel disease (IBD)? Further, will TMS benefits be associated with changes in gut microbiome and normalization of IBD-associated changes in brain structure and/or function as measured by magnetic resonance imaging (MRI)? Methods: Forty male and female IBD (Chron's Disease (CD) and Ulcerative Colitis (UC)) patients with co-morbid anxiety and depression will be recruited for this study. Patients will be randomized 1:1 to TMS or sham TMS according to a computer-generated randomization list from eligible patients identified from the cohort study. Randomization will be stratified by type of IBD (UC versus CD). Patients will be randomized 1:1 to 2 weeks of twice-daily active or sham TMS. The investigators will utilize intermittent theta-burst stimulation (iTBS 600 pulses per session delivered as triplets at 50Hz repeated at 5Hz at 80% resting motor threshold) delivered to the left dorsolateral prefrontal cortex (DLPFC) using a MagPro X100 stimulator and a COOL-B70 (active) or MCF-P-B70 (placebo) coil. Participants will receive 20 treatments over two weeks. All participants allocated to the double-blind phase will be offered 2 weeks of open-label twice-daily iTBS to the left DLPFC if they do not achieve 50% reduction in QIDS-SR score during the double-blind phase. Baseline characterization will include demographic information, self-reported measures of comorbid maladaptive behaviors and pain, neurocognitive tests, analysis of IBD symptoms, microbiome analysis Participants will undergo an MRI of the brain prior to receiving treatment for localization of the DLPFC, as well as characterization of volumetric imaging, white matter imaging, resting state activity and inflammation imaging. A second MRI will be repeated characterizing these same parameters after the conclusion of the sham-controlled treatment (week 2). Stool, blood and urine samples will be collected at baseline, after the conclusion of the sham-controlled treatment (week 2) and 4 weeks follow up (week 6). These will be used for assessment of fecal calprotectin, fecal bacterial and fungal microbiome, inflammatory markers and metabolomic analysis. Brief, computerized neurocognitive tests will be administered at baseline, after TMS treatment (week 2) and 4 week follow up (week 6)

Primary Outcomes

Secondary Outcomes

• Change in IBD symptoms with active iTBS rTMS compared to sham rTMS(Measured at baseline, halfway through rTMS treatment (week 1), end of rTMS treatment (week 2) and 4 weeks post treatment (week 6))
• Change in self reported physical, mental and social health and well-being in persons with IBD with active iTBS rTMS compared to sham rTMS(Measured at baseline, halfway through rTMS treatment (week 1), end of rTMS treatment (week 2) and 4 weeks post treatment (week 6))
• Stool samples- Individual microbial analysis(Stool will be collected at baseline, at the conclusion of the 2 week double-blind phase, and at 4 weeks post treatment (week 6))
• Magnetic Resonance (MR) spectroscopy(Subjects will undergo MRI at 0 (baseline) and at the completion of the blinded phase (week 2))
• Change in self reported anxiety symptoms in persons with IBD with active iTBS rTMS compared to sham rTMS(Measured at baseline, halfway through rTMS treatment (week 1), end of rTMS treatment (week 2) and 4 weeks post treatment (week 6))
• Change in self reported symptoms of gastrointestinal pain in persons with IBD with active iTBS rTMS compared to sham rTMS(Measured at baseline, halfway through rTMS treatment (week 1), end of rTMS treatment (week 2) and 4 weeks post treatment (week 6))
• Change in quality of sleep with active iTBS rTMS compared to sham rTMS in persons with IBD.(Measured at baseline, halfway through rTMS treatment (week 1), end of rTMS treatment (week 2) and 4 weeks post treatment (week 6))
• Change in self reported fatigue in persons with IBD with active iTBS rTMS compared to sham rTMS(Measured at baseline, halfway through rTMS treatment (week 1), end of rTMS treatment (week 2) and 4 weeks post treatment (week 6))
• Magnetic Resonance Imaging (MRI)- White matter imaging(Subjects will undergo MRI at 0 (baseline) and at the completion of the blinded phase (week 2))
• Change in depressive symptoms as measured by Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to week-2 (post rTMS treatment) with iTBS-rTMS as compared to sham treatment group(Measured at baseline, halfway through rTMS treatment (week 1), end of rTMS treatment (week 2) and 4 weeks post treatment (week 6))
• Change in mood from baseline to week 2 (post rTMS treatment) with iTBS-rTMS as compared to sham treatment group(Measured at baseline, halfway through rTMS treatment (week 1), end of rTMS treatment (week 2) and 4 weeks post treatment (week 6))
• Change in self reported depressive symptoms in persons with IBD with active iTBS rTMS compared to sham rTMS as measured by the Patient Health Questionaire.(Measured at baseline, halfway through rTMS treatment (week 1), end of rTMS treatment (week 2) and 4 weeks post treatment (week 6))
• Change in interoceptive awareness with active iTBS rTMS compared to sham rTMS in persons with IBD.(Measured at baseline, halfway through rTMS treatment (week 1), end of rTMS treatment (week 2) and 4 weeks post treatment (week 6))
• Change in cognitive function with active iTBS rTMS compared to sham rTMS in persons with IBD.(tests will also be administered at baseline and at the conclusion of the 2 week double-blind phase, and at 4 weeks post treatment (week 6))
• Functional Magnetic Resonance Imaging (fMRI)(Subjects will undergo MRI at 0 (baseline) and at the completion of the blinded phase (week 2))
• Magnetic Resonance Imaging (MRI)- Volumetric imaging.(Subjects will undergo MRI at 0 (baseline) and at the completion of the blinded phase (week 2))
• Change in quality of life in persons with IBD with active iTBS rTMS compared to sham rTMS(Measured at baseline, halfway through rTMS treatment (week 1), end of rTMS treatment (week 2) and 4 weeks post treatment (week 6))
• Change in self reported depressive symptoms in persons with IBD with active iTBS rTMS compared to sham rTMS as measured by the Quick Inventory of Depressive Symptomatology(Measured at baseline, halfway through rTMS treatment (week 1), end of rTMS treatment (week 2) and 4 weeks post treatment (week 6))
• Stool samples- Microbial community measurements(Stool will be collected at baseline, at the conclusion of the 2 week double-blind phase, and at 4 weeks post treatment (week 6))
• Magnetic Resonance Imaging (MRI)- Inflammation imaging.(Subjects will undergo MRI at 0 (baseline) and at the completion of the blinded phase (week 2))
• Change in catastrophizing thoughts and feelings in persons with IBD with active iTBS rTMS compared to sham rTMS(Measured at baseline, halfway through rTMS treatment (week 1), end of rTMS treatment (week 2) and 4 weeks post treatment (week 6))
• 16S and ITS2 rRNA gene sequencing.(Stool, urine, and blood samples will be collected at baseline, at the conclusion of the 2 week double-blind phase, and at 4 weeks post treatment (week 6))
• Implicit Suicidal Thoughts(tests will also be administered at baseline, at the conclusion of the 2 week double-blind phase, and at 4 weeks post treatment (week 6))