iTBS-DCS in Fibromyalgia

PROMIS® (Patient-Reported Outcomes Measurement Information System®) is a set of person-centered measures that evaluates and monitors physical, mental, and social health in adults and children. PROMIS-29 is a 29 item questionnaire that assesses 7 domains: physical function, anxiety, depression, fatigue, sleep disturbance, satisfaction with participation in social roles, pain interference, and a 0-10 pain intensity scale.

Domain 1 assesses physical function through 4 questions scored from 1-5, with lower scores indicating greater impairment. Suggested interpretation of total scores below:

15- 20 = Acceptable/ mild 7 - 15 = Moderate concern 4 - 6 = Significant concern

PROMIS® (Patient-Reported Outcomes Measurement Information System®) is a set of person-centered measures that evaluates and monitors physical, mental, and social health in adults and children. PROMIS-29 is a 29 item questionnaire that assesses 7 domains: physical function, anxiety, depression, fatigue, sleep disturbance, satisfaction with participation in social roles, pain interference, and a 0-10 pain intensity scale.

Domain 2 assesses anxiety through 4 questions scored from 1-5, with higher scores indicating greater levels of anxiety. Suggested interpretation of total scores below:

4-10 = Acceptable/ mild 11-15 = Moderate concern 16-20 = Significant concern

PROMIS® (Patient-Reported Outcomes Measurement Information System®) is a set of person-centered measures that evaluates and monitors physical, mental, and social health in adults and children. PROMIS-29 is a 29 item questionnaire that assesses 7 domains: physical function, anxiety, depression, fatigue, sleep disturbance, satisfaction with participation in social roles, pain interference, and a 0-10 pain intensity scale.

Domain 3 assesses depression through 4 questions scored from 1-5, with higher scores indicating increased depressive symptoms. Suggested interpretation of total scores below:

4-10 = Acceptable/ mild 11-16 = Moderate concern 17-20 = Significant concern

PROMIS® (Patient-Reported Outcomes Measurement Information System®) is a set of person-centered measures that evaluates and monitors physical, mental, and social health in adults and children. PROMIS-29 is a 29 item questionnaire that assesses 7 domains: physical function, anxiety, depression, fatigue, sleep disturbance, satisfaction with participation in social roles, pain interference, and a 0-10 pain intensity scale.

Domain 4 assesses Fatigue through 4 questions scored from 1-5, with higher scores indicating greater fatigue. Suggested interpretation of total scores below:

4-13 = Acceptable/ mild 14-18 = Moderate concern 19-20 = Significant concern

PROMIS® (Patient-Reported Outcomes Measurement Information System®) is a set of person-centered measures that evaluates and monitors physical, mental, and social health in adults and children. PROMIS-29 is a 29 item questionnaire that assesses 7 domains: physical function, anxiety, depression, fatigue, sleep disturbance, satisfaction with participation in social roles, pain interference, and a 0-10 pain intensity scale.

Domain 5 assesses sleep quality through 4 questions scored from 1-5, with higher scores indicating greater sleep disturbances. Suggested interpretation of total scores below:

4-15 = Acceptable/ mild 16-19 = Moderate concern 20 = Significant concern

PROMIS® (Patient-Reported Outcomes Measurement Information System®) is a set of person-centered measures that evaluates and monitors physical, mental, and social health in adults and children. PROMIS-29 is a 29 item questionnaire that assesses 7 domains: physical function, anxiety, depression, fatigue, sleep disturbance, satisfaction with participation in social roles, pain interference, and a 0-10 pain intensity scale.

Domain 6 assesses ability to participate in social roles/activities through 4 questions scored from 1-5, with lower scores indicating greater impairment. Suggested interpretation of total scores below:

10- 20 = Acceptable/ mild 5 - 9 = Moderate concern 4 = Significant concern

PROMIS® (Patient-Reported Outcomes Measurement Information System®) is a set of person-centered measures that evaluates and monitors physical, mental, and social health in adults and children. PROMIS-29 is a 29 item questionnaire that assesses 7 domains: physical function, anxiety, depression, fatigue, sleep disturbance, satisfaction with participation in social roles, pain interference, and a 0-10 pain intensity scale.

Domain 7 assesses pain interference through 4 questions scored from 1-5, with higher scores indicating higher pain interference. Suggested interpretation of total scores below:

4 -11 = Acceptable/ mild 12-18 = Moderate concern 19-20 = Significant concern

PROMIS® (Patient-Reported Outcomes Measurement Information System®) is a set of person-centered measures that evaluates and monitors physical, mental, and social health in adults and children. PROMIS-29 is a 29 item questionnaire that assesses 7 domains: physical function, anxiety, depression, fatigue, sleep disturbance, satisfaction with participation in social roles, pain interference, and a 0-10 pain intensity scale.

The Pain intensity scale asks individuals to rate their pain on a scale from 0 to 10, where 0 is no pain and 10 is the worst possible pain.

The Short-Form McGill Pain Questionnaire (SF-MPQ) is a self-reported measurement of pain consisting of 15 descriptive items and two overall pain scales. The descriptive items are rated on an intensity scale as 0 = none, 1 = mild, 2 = moderate and 3 = severe. The scale for present pain intensity is rated from 0 (no pain) to 5 (excruciating pain) and a average pain intensity is rated on a 10-point visual analogue scale (VAS), with 0 representing no pain and 10 representing the worst possible pain.

The measure is calculated by summing the point values for responses to 15 questions and the two scales, with totals ranging from 0 (no pain) to 60 (worst possible pain).

painDETECT is a nine-item questionnaire that consists of seven sensory symptom items for pain that are graded from 0= never to 5= strongly, one temporal item on pain-course pattern graded -1 to +1, and one spatial item on pain radiation graded 0 for no radiation or +2 for radiating pain. A total score that ranges from -1 to 38 can be calculated from the nine items, with higher scores indicating higher levels of pain.

The Central Sensitization Inventory (CSI) is a self-report outcome measure designed to identify patients who have symptoms that may be related to central sensitivity syndromes such as fibromyalgia, neck injury, temporomandibular joint disorder or migraine/tension headaches. The CSI may be used to determine severity of chronic centralized pain. The CSI consists of 25 questions and may be self-administered. Each question may be answered as follows: Never(0points), Rarely(1point), Sometimes(2points), Often(3points), or Always(4points). Total points reflect the severity of the central sensitization pain.

Following is a break down of score ranges and the intensity of central sensitization pain they represent.

Subclinical: 0 to 29 Mild: 30 to 39 Moderate: 40 to 49 Severe: 50 to 59 Extreme: 60 to 100

The polysymptomatic distress scale (PDS) provides an overall measure of pain extent and symptom distress, and is considered a measure of fibromyalgia severity. The scale total ranges from 0 to 31, with higher scores indicating greater severity.

Change in severity of depressive symptoms as measured by the MADRS, a clinician-rated instrument. The MADRS is a ten-item diagnostic questionnaire used to measure the severity of depressive episodes. The overall score ranges from 0 - 60. Cutoff points are 0-6 = normal, 7-9 = mild depression, 20-34 = moderate depression, >34 = severe depression.

Clinical remission of depressive symptoms will be measured by the Montgomery-Asberg Depression Rating Scale (MADRS); a clinician-rated instrument. The MADRS is a ten-item diagnostic questionnaire used to measure the severity of depressive episodes. The overall score ranges from 0 - 60. A score of </= 10 on the MADRS indicates clinical remission.

Clinical depression response will be measured by the Montgomery-Asberg Depression Rating Scale (MADRS); a clinician-rated instrument. The MADRS is a ten-item diagnostic questionnaire used to measure the severity of depressive episodes. The overall score ranges from 0 - 60. A reduction of >/= 50% in the MADRS score indicates clinical response.

The CGI-Severity scale is clinician rated from 1-7 representing 'Not at all ill' to 'Severely ill'.

The CGI-Improvement scale is a clinician rated 1-7, representing the range between 'Very much improved' and 'Very much worse' from the baseline visit.

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

Anxiety symptoms will be assessed using the 7 item Generalized Anxiety Disorder (GAD-7) questionnaire. The GAD-7 measures self-reported feelings of anxiety within the last 2 weeks. Scores range from 0-21. Scores of 5, 10, and 15 represent cut points for mild, moderate, and severe anxiety, respectively.

The Hospital Anxiety and Depression Scale (HADS) is a self-rating scale developed to assess psychological distress in non-psychiatric patients. It consists of 14 items on a 4-point Likert scale (range 0-3). It is designed to measure anxiety and depression. The total score is the sum of the 14 items. A higher score indicates higher distress.

The Insomnia Severity Index (ISI) is a brief, 7 question instrument that was designed to assess the severity and symptoms of insomnia. The seven answers are added up to get a total score, with higher scores indicating greater severity of insomnia.

Total score categories:

0-7 = No clinically significant insomnia 8-14 = Subthreshold insomnia 15-21 = Clinical insomnia (moderate severity) 22-28 = Clinical insomnia (severe)

A Visual Analog Scale (VAS) will ask participants how good or bad their overall health is today. This scale is numbered from 0 to 100. 100 indicates the best health they can imagine. 0 indicates the worst health they can imagine.

The WHOQOL-BREF is a self-reported questionnaire which assesses individual's perception of their quality of life across 4 domains; physical health, psychological, social relationships and environment. Domains scores are calculated to range from 0-20 and scaled in a positive direction (ie. higher scores denote higher quality of life).

The Chalder Fatigue Questionnaire is an 11-item questionnaire measuring the severity of physical and mental fatigue. Each question uses a 4-point Likert scale with higher values representing greater symptoms. The respondent's global score can range from 0 (no symptoms) to 33 (most symptomatic). The global score can be further split into two dimensions-physical fatigue (measured by items 1-7) and psychological fatigue (measured by items 8-11).

The Pain Catastrophizing Questionnaire (PCQ) is a 13-item instrument for measuring catastrophic thinking related to pain. People are asked to indicate the degree to which they have catastrophizing thoughts and feelings when they are experiencing pain on 5-point Likert scales, from (0) note at all to (4) all the time.

A total score is yielded (ranging from 0-52), with higher scores indicating higher levels of catastrophizing. The total score can further be split into three subscale scores, assessing rumination (sum of items 8, 9, 10 and 11. Range of 0-16), magnification (sum of items 6, 7, and 13. Range of 0-12), and helplessness (sum of items 1, 2, 3, 4, 5, and 12. Range of 0-24).

Total scores of above 30 indicates clinically relevant level of catastrophizing.

The Big Five Inventory (BFI) is a self-report inventory designed to measure the Big Five dimensions of personality: extroversion, agreeableness, openness, conscientiousness, and neuroticism. The test consists of 44 items that you must rate on how true they are about you on a five point scale where 1=Disagree, 3=Neutral and 5=Agree.

Participants will be asked to list all medications they have used in the last week to manage pain, including prescription and over the counter treatments.

The Cognitive Failures Questionnaire (CFQ) is used to assess the frequency with which people experienced cognitive failures, such as absent-mindedness, in everyday life -- slips and errors of perception, memory, and motor functioning.

Individuals are asked to rate how often they experience different cognitive failures from "never "(0) to "very often" (4). The sum of the ratings of the 25 individual items yields a score from 0-100, with higher scores indicating more cognitive failures.

The Multidimensional Inventory of Subjective Cognitive Impairment is a 10-item instrument to evaluate subjective cognitive function in patients with fibromyalgia. Each item consists of a statement regarding cognitive abilities in the past week and responders are asked to agree with each statement on a 5-point Likert scale, from 1 (not at all/never) to 5 (very much/always).

Scoring: 4 negatively-worded items (item 7 - 10) from the MISCI are reverse scored. Items are summed to receive a total score ranging from 10 to 50, with higher total scores indicative of better subjective cognitive functioning.

Cognitive function will be assessed using the THINC-integrated tool (THINC-it) brief cognitive assessment tool. THINC-it includes a summation of four objective cognitive tests and a subjective cognitive questionnaire.

The cognitive questionnaire is called the Perceived Deficits Questionnaire - 5 item scale (PDQ-5). The questionnaire assesses self perceived cognition by asking questions about attention/concentration, retrospective memory, prospective memory, and planning/organization. Each item is rated on a 5-point scale ranging from 0 (never) to 5 (almost always). Higher scores indicate greater perceived deficits in cognition.

Total results from the THINC-it assessment indicate cognitive performance compared to healthy age-, sex- and education-matched individuals. Change between the two arms will be assessed.

Cognitive function will be assessed using the THINC-it brief cognitive assessment tool. THINC-it includes a summation of four objective cognitive tests and a subjective cognitive questionnaire.

The first objective cognitive test is called "spotter" and measures choice reaction time by calculating the total time that elapses between the presentation of a stimulus and the occurrence of a response in a task that requires a participant to make one of two different responses depending on which stimuli is presented. Less time between presentation of stimulus and occurrence of a response can be used as an indicator for better reaction time.

Total results from the THINC-it assessment indicate cognitive performance compared to healthy age-, sex- and education-matched individuals. Change between the two arms will be assessed.

Cognitive function will be assessed using the THINC-it brief cognitive assessment tool. THINC-it includes a summation of four objective cognitive tests and a subjective cognitive questionnaire.

The second objective cognitive test is called "Symbol Check" and is an n-back test. N-back tests measure working memory by presenting the subject with a sequence of stimuli, and the task consists of selecting the stimuli that was presented n steps earlier in the sequence. The greater amount of correct responses can be used as an indicator of better working memory.

Total results from the THINC-it assessment indicate cognitive performance compared to healthy age-, sex- and education-matched individuals. Change between the two arms will be assessed.

Cognitive function will be assessed using the THINC-it brief cognitive assessment tool. THINC-it includes a summation of four objective cognitive tests and a subjective cognitive questionnaire.

The third objective cognitive test is called "CodeBreaker" and is a Digit Symbol Substitution Test (DSST). DSST involves a key consisting of the numbers 1-6, each paired with a unique symbol. Below the key are a series of the numbers 1-6 in random order and repeated several times. Subjects must select the corresponding symbol as fast as possible. The number of correct symbols within the allowed time is measured, with higher number of correct symbols indicating greater cognitive function.

Total results from the THINC-it assessment indicate cognitive performance compared to healthy age-, sex- and education-matched individuals. Change between the two arms will be assessed.

Cognitive function will be assessed using the THINC-it brief cognitive assessment tool. THINC-it includes a summation of four objective cognitive tests and a subjective cognitive questionnaire.

The fourth objective cognitive test is called "Trails" and is a version of the Trail Making Test part B (TMT-B). The subject is presented with numbers and letters in circles placed in random array on the screen. The subject must draw a line from one circle to the next in ascending order; however, s/he must alternate the circles with numbers in them and circles with letters in them (ie, 1-A-2-B-3-C etc). The TMT is a timed test and the goal is to complete the tests accurately and as quickly as possible. Less time to accurately complete the trial indicates greater cognitive function.

Total results from the THINC-it assessment indicate cognitive performance compared to healthy age-, sex- and education-matched individuals. Change between the two arms will be assessed.

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

Participants will provide blood samples to characterize inflammatory profiles. Human Cytokine Proinflammatory Focused 15-Plex Discovery Assay® Array (HDF15) will be used for quantification of proinflammatory cytokines in human blood plasma samples.

Change in resting state functional connectivity as determined by an fMRI.

Baseline differences in functional activity and connectivity as determined by a fMRI acquisition between healthy controls and patients with fibromyalgia

Change in brain metabolites in regions of interest.

Baseline differences in metabolites in regions of interest between healthy controls and patients with fibromyalgia

Baseline differences in neuromelanin between healthy control and patients with fibromyalgia as measured by MRI

Sensory perception will be assessed using a quantitative sensory testing battery. This will quantify multiple aspects of pain, including pain pressure thresholds using algometry. The pain pressure threshold is the point at which a non-painful pressure stimulus turns into a painful pressure sensation. Algometry will be administered at the trapezius and insertion point of the quadriceps. Subjects will be asked to indicate when the stimulus feels painful, which will terminate the application. The pressure will be measured as a range of 0 kPa-1,100 kPa. Higher values indicate higher pain threshold. This will be repeated 3 times at each site.

Metrics from each of these tests will be compared between groups and overtime using ANCOVA models.

In a separate set of analyses, the treatment end scores will be compared to healthy, matched control sample to determine treatment effects in relation to health. These will involve ANOVA or chi-square tests and Fisher's exact test where required

Temporal summation will be used to measure central sensitization. Participants will be asked to rate the sensation of a weighted punctate probe (Range:0 "no pain" - 100 "worst pain imaginable") to a single stimulus and to a train of stimuli (10 identical stimuli repeated every second for 10 seconds). Central sensitization can be quantified by subtracting the rating of the single stimuli from the rating of the train of stimuli. Values greater than 0 indicate central sensitization, negative values will indicate a lack of central sensitization. This will be repeated 2 times (probes at force of 256mN and 512mN) at the non-dominant middle finger and patella.

Metrics from each of these tests will be compared between groups and overtime using ANCOVA models.

The treatment end scores will be compared to healthy, matched control sample to determine treatment effects in relation to health. These will involve ANOVA or chi-square tests and Fisher's exact test where required

Sensory perception will be assessed using a quantitative sensory testing battery. This will quantify multiple aspects of pain, including cold-pressor conditioning to measure conditioned pain modulation, in which a hand is immersed in a 4-8°C water bath during pressure threshold testing of the opposite trapezius and compared to the baseline pain pressure threshold. The amount of pressure will be measured as a range of 0 kPa-1,100 kPa. Higher values indicate higher pain threshold. The time that the hand is in the water is approximately 30 seconds. This is repeated 3 times, with at least 2 minute breaks between each trial

Metrics from each of these tests will be compared between groups and overtime using ANCOVA models.

In a separate set of analyses, the treatment end scores will be compared to healthy, age-matched control sample to determine treatment effects in relation to health. These will involve ANOVA or chi-square tests and Fisher's exact test where required

Sensory perception will be assessed using a quantitative sensory testing battery. This will quantify multiple aspects of pain, cold pressor tolerance testing, in which a hand is placed in a 4-8°C water bath for 5 minutes, with numerical rating of level of discomfort every 30 seconds (Rating: 0 "no pain" - 100 "worst pain imaginable"). Participants may withdraw hand prior to 5 minutes if this becomes painful (rather than noxious).

Time in cold water bath will also be indicative of cold pressor tolerance (more time indicating more cold tolerance).

Metrics from each of these tests will be compared between groups and overtime using ANCOVA models.

In a separate set of analyses, the treatment end scores will be compared to healthy, age-matched control sample to determine treatment effects in relation to health. These will involve ANOVA or chi-square tests and Fisher's exact test where required