TMS in Inflammatory Bowel Disease

Higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60. Compared to sham-rTMS, active-iTBS rTMS is anticipated to show Higher rates of clinical remission (score ≤12 on the MADRS) and Higher rates of clinical response (≥50% reduction in MADRS scores)

Young Mania Rating Scale (YMRS) will be used to assess changes in mood from baseline to Week 4. The YMRS total score ranges from 0 to 60 where higher scores indicate more severe mania, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in manic symptoms. Total score ≤12 indicates remission (13-19=minimal symptoms; 20-25=mild mania, 26-37=moderate mania, 38-60=severe mania)

The Short Inflammatory Bowel Disease Questionnaire (short IBDQ) will be used to measure symptoms of persons with inflammatory bowel disease. The minimum score for Short IBDQ is 10 points, indicating very poor quality of life, while the maximum score is 70 points, indicating an optimal quality of life.

The EuroQol-5 Dimension-5 Level (EQ-5D-5L) is a self-assessed, health related, quality of life questionnaire. The scale measures quality of life on a 5-component scale including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension in the EQ-5D-5L has five response levels: no problems (Level 1); slight; moderate; severe; and extreme problems (Level 5). There are 3,125 possible health states defined by combining one level from each dimension, ranging from 11111 (full health) to 55555 (worst health).

The General Anxiety Disorder 7-item scale (GAD-7) is a tool for self reported measure of patient anxiety. Scores range from 0 (no anxiety) to 35 (severe anxiety) with scores of 5, 10, and 15 are taken as the cut-off points for mild, moderate and severe anxiety, respectively.

The Patient Health Questionaire-9 (PHQ-9) is a 9-item questionnaire which objectifies degree of depression severity. Scores range from 0-4 = no depression, 5-9 = mild depression, 10-14 = moderate depression, 15-19= moderately severe depression, 20-27 = severe depression.

The Quick Inventory of Depressive Symptomatology (QIDS) rates depression symptoms via self-assessment.Severity of depression can be judged based on the total score.

1-5 = No depression 6-10 = Mild depression 11-15 = Moderate depression 16-20 = Severe depression 21-27 = Very severe depression

The Patient-Reported Outcomes Measurement Information System (PROMIS) is a flexible set of tools designed to measure self-reported physical, mental and social health and wellbeing. The PROMIS-29, a generic health-related quality of life survey, assesses 7 domains (depression; anxiety; physical function; pain interference; fatigue; sleep disturbance; and ability to participate in social roles and activities) with 4 questions. The questions are ranked on a 5-point Likert Scale. There is also one 11-point rating scale for pain intensity

The Patient-Reported Outcomes Measurement Information System (PROMIS) is a flexible set of tools designed to measure self-reported physical, mental and social health and wellbeing. The PROMIS-V10 is a brief questionnaire that asks patients 5 questions regarding belly pain during the past week. Each question is ranked on a 5-point Likert Scale, with 1 representing no symptoms and 5 representing maximal symptoms. Summation of the points gives a total score.

The Multidimensional Assessment of Interoceptive Awareness (MAIA) is a 32-item state-trait questionnaire to measure multiple dimensions of interoception by self-report. Individuals rate items based on a 6 point Likert scale from 0-5 with '0' indicating 'Never' and '5' indicating 'Always'. Higher total scores and subscale scores indicate higher levels of positive awareness.

The Pain Catastrophizing scale is one of the most widely used instruments for measuring catastrophic thinking related to pain. People are asked to indicate the degree to which they have thoughts and feelings when they are experiencing pain using the 0 (not at all) to 4 (all the time) scale. A total score is yielded (ranging from 0-52), along with three subscale scores assessing rumination, magnification and helplessness.

The Pittsburgh Sleep Quality Index (PSQI) contains 19 self-rated questions to measure sleep quality. The 19 self-rated items are combined to form component scores, each of with has a range of 0 (no difficulty) to 3 (severe difficulty) points. A global score of all components range from 0 (no difficulty in all areas) - 21 (severe difficulty in all areas)

The Fatigue Severity Scale (FSS) is a 9-item scale which measures the severity of fatigue and its effect on a person's activities and lifestyle.

Cognitive function will be assessed using the THINC-it brief cognitive assessment tool. THINC-it includes 4 objective cognitive tests (adapted from choice reaction time, 1-back working memory task, symbol digit coding, and Trails-B) and a subjective cognitive questionnaire (PDQ-5). Results indicate cognitive performance compared to healthy age-, sex- and education-matched individuals.

The investigators will assess fecal microbial diversity and the relative abundance of bacterial and fungal taxa using phyloseq along with additional R-based computational tools. Principal Component Analysis (PCoAs) will be conducted on both a variance stabilization transformed and rarefied OTU matrices and then statistically confirmed by a PERMANOVA. The Shannon and Chao1 alpha-diversity indices will be calculated using phyloseq and statistically confirmed by Mann-Whitney (GraphPad Prism software, version 5c). The R packages DESeq2 and MaAsLin will used to calculate differentially abundant microbial taxa. Correlation analysis between taxa and metadata will performed using the by bicor method in R package 'microbiome'.

In addition to the specific microbiome analysis, composite measures using supervised (partial least squares discriminant analysis- PLS-DA) and unsupervised PCoA data reduction techniques will be explored in order to determine the most discriminatory combination of microbiome parameters. Receiver operator characteristics and permutation testing will be used to quantify discrimination performance and statistical significance, and leave-one-out-cross-validation will be used to estimate discrimination performance.

The investigators aim to attempt to identify microbial biodiversity measures that best predict general anxiety, depression and pain scores and neuroimaging findings.

All samples will be amplified by polymerase chain reaction (PCR) in triplicate using 37-nucleotide barcoded primer pairs flanking the V4 region of the 16S gene and the ITS2 gene. Pooled PCR amplicons will be sequenced across the hyper-variable regions. Sequences will be pre-processed, denoised, and quality filtered by size using DADA229. Representative sequences will be clustered into operational taxonomic units (OTUs) and classified against the Greengenes Database30 according to 97% similarity.

Using the sequencing data, the investigators will identify the microbial features (taxa and diversity measurements) that associate with general anxiety and depression and pain scores and neuroimaging findings using methods from community ecology.

Death Implicit Association Test (D-IAT) is a behavioral test that measures the strength of automatic (implicit) associations between concepts in people's minds relying on latency measures in a simple sorting task. The strength of an association between concepts of "death" and "ones self" is measured by the standardized mean difference score of the 'hypothesis-inconsistent' pairings and 'hypothesis-consistent' pairings

Change in task and resting state functional connectivity as determined by an fMRI. A whole-brain resting-state fMRI scan to determine the strength of functional connections between brain regions (inferred from degree of temporal synchrony, called connectivity) as well as the magnitude of spontaneous neuronal activity within brain regions (T2*-weighted gradient-echo echo planar imaging, 3 mm3 resolution, 2-sec temporal resolution; 8min).

Change in brain metabolites in regions of interest.

Change in volume measurements in brain regions of interest. A whole-brain anatomical scan at 1 mm3 resolution to permit precise volume measurements of brain regions (3D T1-weighted; 5 min)

Change in structural integrity of white matter tracts. A whole-brain diffusion tensor imaging (DTI ) scan to permit quantitative measurements of structural integrity within known white matter tracts (30 gradient directions, b1 = 1000, b2 = 2000 s/mm2, 2 mm3 resolution; 9 min).

Change in inflammation in brain regions of interest. A whole-brain quantitative susceptibility mapping (QSM) scan to infer the degree of inflammation within brain regions (T2*-weighted gradient-echo susceptibility weighted imaging, 8 echoes, 1 mm3 resolution; 5 min)