<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02969707</url>
  </required_header>
  <id_info>
    <org_study_id>38138</org_study_id>
    <secondary_id>1R33AT009305-01</secondary_id>
    <nct_id>NCT02969707</nct_id>
  </id_info>
  <brief_title>Use of Repetitive Transcranial Magnetic Stimulation to Augment Hypnotic Analgesia</brief_title>
  <official_title>Use of Repetitive Transcranial Magnetic Stimulation to Augment Hypnotic Analgesia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Stanford University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institutes of Health (NIH)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Center for Complementary and Integrative Health (NCCIH)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Stanford University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The investigators plan to use functional neuroimaging (fMRI) to understand the brain systems&#xD;
      affected when hypnosis and hypnotic analgesia are augmented with repetitive transcranial&#xD;
      magnetic stimulation (rTMS), a form of non-invasive brain stimulation to 100 people with&#xD;
      fibromyalgia, a chronic pain condition. The investigators will measure the effect of&#xD;
      rTMS-augmentation on the brain networks underlying hypnotizability, as well as the effect of&#xD;
      rTMS-augmentation on hypnotic analgesia networks. The investigators hope to demonstrate that&#xD;
      a combination of these psychological and neuromodulatory treatments will be more effective&#xD;
      than hypnosis alone, thereby enhancing the depth of hypnosis, range of hypnosis and the&#xD;
      efficacy of hypnotic analgesia and hopefully creating a new treatment modality for&#xD;
      individuals suffering from pain syndromes such as fibromyalgia pain.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Overall Study Design. The investigators propose to develop a combinatory approach where an&#xD;
      integrative technique (hypnosis) is augmented with a neurotechnology (repetitive transcranial&#xD;
      magnetic stimulation). This application seeks to utilize the previously established&#xD;
      brain-based mechanisms of both hypnosis and repetitive transcranial magnetic stimulation as&#xD;
      biomarkers to assess the potential synergistic mechanism of this combinatory approach. 100&#xD;
      low-moderately hypnotizable subjects with fibromyalgia will be identified. The subjects'&#xD;
      response to rTMS-augmentation of hypnosis will be measured. The volunteers will be randomized&#xD;
      to active or sham rTMS. Two scan sessions will be performed for each subject, with the first&#xD;
      scan session investigating the effect of rTMS-augmentation on hypnosis and hypnotizability&#xD;
      (120 min scan session) and the second scan session focused on the effect of rTMS-augmented&#xD;
      hypnotic analgesia (120 min scan session).&#xD;
&#xD;
      The study will require that participants participate in an in-person screening visit, a&#xD;
      screening MRI scan and 2 MRI scan sessions that include the TMS and hypnosis.&#xD;
&#xD;
      Experimental design. Before each MRI scan session, participants will undergo a preparation&#xD;
      session, where hypnotizability and either psychological testing or experimental pain training&#xD;
      will be conducted. Volunteer subjects will then participate in 2 MRI scan sessions on two&#xD;
      separate days, each lasting approximately 120 mins.&#xD;
&#xD;
      Hypnosis induction procedures. Hypnosis will be induced while the subject is in the scanner&#xD;
      though the use of headphones and a pre-recorded induction script. Hypnotic instructions will&#xD;
      be standardized, and will involve a simple induction instruction used in our prior research&#xD;
      on the brain signature of the hypnotic state and in clinical care. The ability to enter and&#xD;
      maintain the hypnotic state through such an induction mechanism in the fMRI environment has&#xD;
      been previously demonstrated.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 24, 2017</start_date>
  <completion_date type="Actual">December 21, 2019</completion_date>
  <primary_completion_date type="Actual">December 21, 2019</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>Double blind sham vs. real rTMS; data analysts blind to group assignment; subjects debriefed on their guess about sham vs. real - no better than chance</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>The Change in Functional Connectivity (FC) Between the Left Dorsolateral Prefrontal Cortex (L-DLPFC) and the Dorsal Anterior Cingulate Cortex (dACC)</measure>
    <time_frame>Baseline and at 15-20 min post-TMS (up to 30 min)</time_frame>
    <description>Functional MRI (fMRI) measures changes in oxygenated blood in the brain; at rest these levels fluctuate over time. These fluctuations can be similar between different brain regions. FC is the similarity in fluctuations of these fMRI signals and suggests how strongly two regions communicate with each other. We measured how inhibitory continuous theta-burst stimulation (cTBS) over L-DLPFC changes FC between L-DLPFC and dACC. This was done by estimating z-transformed correlation coefficients (CC) for each voxel (-1 to 1) between the L-DLPFC and dACC pre and post cTBS intervention. Negative FC was assigned to voxels with a weight &lt; 0, positive FC to voxels with weight&gt; 0. Total FC includes positive and negative voxels. The change in FC is regarded as the change in the sum of these weighted voxels from pre to post cTBS for total, positive and negative FC, respectively. Greater sums of voxels correspond to more significant levels of coordinated activity (positive, negative, or total).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>The Change in the Neural Network Underlying Hypnotic Intensity</measure>
    <time_frame>Baseline and 2 hours</time_frame>
    <description>Blood oxygen level dependent (BOLD) signal and interleaved TMS-BOLD analyses will be used to determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC on modulating the neural network that underlies hypnotic intensity.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Hypnotic Induction Profile Score</measure>
    <time_frame>Baseline and Immediately post rTMS (up to 30 min)</time_frame>
    <description>The investigators used the Hypnotic Induction Profile (HIP) to determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC on enhancing hypnotizability.&#xD;
HIP scores range from 0 to 10 (low to high hypnotizability).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in The Hypnosis Intensity Scale</measure>
    <time_frame>Baseline and immediately post rTMS (up to 2 hrs)</time_frame>
    <description>The investigators used the Hypnotic Intensity Scale (HIS) to determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC on enhancing hypnotic intensity.&#xD;
HIS scores range from 0 to 10 (low to high hypnotic intensity).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The Change in Functional Connectivity (FC) Within The Neural Network Underlying Conflict Regulation.</measure>
    <time_frame>Baseline and at 15-20 min post-TMS (up to 30 min)</time_frame>
    <description>We examined the effect of active, inhibitory cTBS over L-DLPFC on functional connectivity (FC) in key nodes in the neural network underlying the conflict regulation system. FC between each voxel in the L-DLPFC and the entire dACC was established by estimating z-transformed correlation coefficients (CC) for each voxel (-1 to 1) pre and post cTBS intervention. This paradigm was also used for voxels in the Default Mode Network (DMN) (Schaefer, 2018; Yeo, 2011) to the entire right inferior frontal gyrus (rIFG). Negative FC was assigned to voxels with a weight &lt; 0, positive FC to voxels with weight &gt; 0. Total FC includes positive and negative voxels. The change in FC is regarded as the change in the sum of these weighted voxels from pre to post cTBS for total, positive and negative FC, respectively. Greater sums of voxels correspond to more significant levels of coordinated activity (positive, negative, or total).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The Change in Stroop Performance</measure>
    <time_frame>Baseline and at 15-20 min post-TMS (up to 30 min)</time_frame>
    <description>Stroop effect is measured by the response time of a participant during the stroop task. Increases in response time indicate increased stroop effect (SE) and vice versa.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Stroop Task</measure>
    <time_frame>Baseline and at 15-20 min post-TMS (up to 30 min)</time_frame>
    <description>Active, inhibitory cTBS effect over L-DLPFC on the neural network that underlies the hypnotic Stroop modulation effect was determined by first estimating the average of connectivity weights for all parcel pairs linking Ventral Attentional Network (VAN) to the DMN. Parcels are determined by extracting mean resting state BOLD time-series for each region of the Schaefer 100 parcellation. A correlation matrix between all parcels is created and FC weights for each pair are established by estimating z-transformed correlation coefficients (CC) (-1 to 1). Each parcel pair is then assigned to one of the 7 resting state networks defined by Yeo et al., (2011). Negative FC is defined for parcel pairs with a weight &lt; 0, positive FC pairs with weight &gt; 0 and total FC includes all pairs. FC is thus the average value between parcel pairs in the DMN and VAN pre/post TMS. Greater sums of weighted pairs correspond to more significant levels of coordinated activity (positive, negative, or total).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Linear Relationship Between the Change in FC of the VAN to the DMN and the Change in Stroop Performance (Correlation Coefficient) With no Hypnosis Intervention.</measure>
    <time_frame>Baseline and at 15-20 min post-TMS (up to 1 hr)</time_frame>
    <description>Spearman's correlation was used to determine the linear relationship between the response time taken to answer incongruent Stroop task blocks (a measure of Stroop performance) and the change the resting-state network FC between the VAN and the DMN when no hypnosis intervention was implemented.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Linear Relationship Between the Change in FC of the VAN to the DMN and the Change in Stroop Performance (Correlation Coefficient) With Hypnosis Intervention.</measure>
    <time_frame>Baseline and at 15-20 min post-TMS (up to 1 hr)</time_frame>
    <description>Spearman's correlation was used to determine the linear relationship between the response time taken to answer incongruent Stroop task blocks (a measure of Stroop performance) and the change the resting-state network FC between the VAN and the DMN when the hypnosis intervention was implemented.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Linear Relationship Between the Change in FC of the VAN to the DMN and the Change in Stroop Interference (Correlation Coefficient) With no Hypnosis Intervention.</measure>
    <time_frame>Baseline and at 15-20 min post-TMS (up to 1 hr)</time_frame>
    <description>Spearman's correlation was used to determine the linear relationship between the Stroop interference and the change the resting-state network FC between the VAN and the DMN when no hypnosis intervention was implemented.&#xD;
In psychology, the Stroop effect is the delay in reaction time between congruent and incongruent stimuli.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Linear Relationship Between the Change in FC of the VAN to the DMN and the Change in Stroop Interference (Correlation Coefficient) With Hypnosis Intervention.</measure>
    <time_frame>Baseline and at 15-20 min post-TMS (up to 1 hr)</time_frame>
    <description>Spearman's correlation was used to determine the linear relationship between the Stroop interference and the change the resting-state network FC between the VAN and the DMN when the hypnosis intervention was implemented.&#xD;
In psychology, the Stroop effect is the delay in reaction time between congruent and incongruent stimuli.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in the Numeric Pain Rating Scale</measure>
    <time_frame>Baseline and immediately post-rTMS (up to 30 minutes)</time_frame>
    <description>To determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC on modulating the neural network that underlies hypnotic analgesia (HA).&#xD;
Numeric Pain Rating Scale scores range from 0 to 10 (low to high pain intensity).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Sense of Agency Rating Scale (SOARS)</measure>
    <time_frame>Baseline and immediately post-rTMS (up to 30 min)</time_frame>
    <description>The investigators used the Sense of Agency Rating Scale (SOARS) to determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC on altering the subjective sense of agency during hypnotizability.&#xD;
SOARS scores are calculated for Involuntariness and Effortlessness, each range from 0 to 35 (low to high).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Metabolic Alterations in Fibromyalgia (FMS) Defined by Excitatory / Inhibitory Ratio</measure>
    <time_frame>Baseline Scan (up to 15 min)</time_frame>
    <description>E/I ratio is defined as the logarithm of the concentration of Glx (excitatory neurotransmitter metabolite complex) /GABA+ (inhibitory neurotransmitter metabolite complex) relative to either water or creatine peak signal and it is a unitless measure ranging from -1 to 1. Logarithmic transformations are used to account for non-normal distributions of metabolite concentrations across participants and ratios &gt; 0 are thought to be excitatory neurotransmitter dominant while ratios &lt;0 are thought to be inhibition dominant.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Alterations in Pain Perception in Fibromyalgia</measure>
    <time_frame>Baseline visit (up to 30 min)</time_frame>
    <description>To characterize clinical pain measures, which are defined as thermal pain threshold and thermal pain tolerance. Thermal pain threshold is determined as the temperature of a thermode determined as painful (degrees Celsius) by a participant. Thermal pain tolerance extends this to the point at which discontinuation is necessary (degrees Celsius).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Linear Regression of Thermal Pain Threshold to Logarithm of E/I Ratio as it Relates to Water in Fibromyalgia (Coefficient of Determination)</measure>
    <time_frame>Baseline visit (up to 45 min)</time_frame>
    <description>Linear regression was used to evaluate the scalar relationship between E/I ratio as it relates to water and Thermal Pain Threshold with E/I as the independent variable and Thermal Pain Threshold as the dependent variable.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Linear Regression of Thermal Pain Tolerance to Logarithm of E/I Ratio as it Relates to Water in Fibromyalgia (Coefficient of Determination)</measure>
    <time_frame>Baseline visit (up to 45 min)</time_frame>
    <description>Linear regression was used to evaluate the scalar relationship between E/I ratio as it relates to water and Thermal Pain Tolerance with E/I as the independent variable and Thermal Pain Tolerance as the dependent variable.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Linear Regression of Thermal Pain Threshold to Logarithm of E/I Ratio as it Relates to Creatine in Fibromyalgia (Coefficient of Determination)</measure>
    <time_frame>Baseline visit (up to 45 min)</time_frame>
    <description>Linear regression was used to evaluate the scalar relationship between E/I ratio as it relates to creatine and Thermal Pain Threshold with E/I as the independent variable and Thermal Pain Threshold as the dependent variable.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Linear Regression of Thermal Pain Tolerance to Logarithm of E/I Ratio as it Relates to Creatine in Fibromyalgia (Coefficient of Determination)</measure>
    <time_frame>Baseline visit (up to 45 min)</time_frame>
    <description>Linear regression was used to evaluate the scalar relationship between E/I ratio as it relates to creatine and Thermal Pain Tolerance with E/I as the independent variable and Thermal Pain Tolerance as the dependent variable.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Metabolic Changes in L-DLPFC Pre- and Post-rTMS</measure>
    <time_frame>Baseline Scan and at 15-20 min post-TMS (up to 30 min)</time_frame>
    <description>To determine the relationship between the metabolic alterations pre and post-rTMS. Metabolic changes as measured by MEGA-PRESS spectroscopy were assessed by quantification of excitatory (Glx) and inhibitory (GABA+) neurotransmitter complexes. The E/I ratio is defined as the logarithm of the concentration of Glx/GABA+relative to either the reference water or creatine signal and it is a unitless measure ranging from -1 to 1. Logarithmic transformations are used to account for non-normal distributions of metabolite concentrations across participants and ratios &gt; 0 are thought to be excitatory neurotransmitter dominant while ratios &lt;0 are thought to be inhibition dominant.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">101</enrollment>
  <condition>Fibromyalgia</condition>
  <arm_group>
    <arm_group_label>Active rTMS</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The active group will receive repetitive Transcranial Magnetic Stimulation</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sham rTMS</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>The sham repetitive Transcranial Magnetic Stimulation group will have the stimulation blocked.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>MagPro TMS system (MagVenture, Denmark)</intervention_name>
    <description>The investigators will perform two applications of 40s of continuous theta-burst stimulation (cTBS) form of rTMS at 80% resting motor threshold (previously determined), with a 15 minute intersession interval. The standardized treatment location for the left DLPFC will be determined by Localite Neuronavigation and targeted at the posterior middle frontal gyrus. The baseline structural scan obtained during the scan 1 will be utilized for this localization process. rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark). sham rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark).sham rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark).</description>
    <arm_group_label>Active rTMS</arm_group_label>
    <arm_group_label>Sham rTMS</arm_group_label>
    <other_name>rTMS will be delivered using the MagPro TMS system (MagVenture, Denmark).</other_name>
  </intervention>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Hypnosis</intervention_name>
    <description>Hypnotizability will be measured using the Hypnotic Induction Profile before and after administration of real vs. sham rTMS. Hypnotizability will be measured using the Hypnotic Induction Profile before and after administration of real vs. sham rTMS. Hypnosis will be employed to influence Stroop performance (conflict detection) and for pain management. The hypnotic instructions for this will be pre-recorded and played during fMRI.</description>
    <arm_group_label>Active rTMS</arm_group_label>
    <arm_group_label>Sham rTMS</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Fulfill 2010 Fibromyalgia Diagnostic Criteria&#xD;
&#xD;
          -  Age 18 - 70&#xD;
&#xD;
          -  Right-handed&#xD;
&#xD;
          -  Agree to and able to have two fMRI scans as well as rTMS sessions&#xD;
&#xD;
          -  Willingness to suspend use of analgesic drugs or cough suppressants for 24 hours prior&#xD;
             to the scans&#xD;
&#xD;
          -  Willingness to suspend us of antidepressant drugs for 2 weeks prior to the scans (6&#xD;
             weeks for fluoxetine)&#xD;
&#xD;
          -  Proficiency in English sufficient to complete questionnaires/follow instructions&#xD;
             during fMRI assessments&#xD;
&#xD;
          -  US Citizen or resident able to receive payment legally&#xD;
&#xD;
          -  Low-Moderate Hypnotizability in the Hypnotic Induction Profile (score of 0-8)&#xD;
&#xD;
          -  Normal color vision&#xD;
&#xD;
          -  Women of childbearing potential must agree to use adequate contraception prior to&#xD;
             study entry and continue this for the duration of the study&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  A medical condition that would contraindicate the use of rTMS&#xD;
&#xD;
          -  Any condition that would contraindicate MRI (like ferromagnetic metal in the body)&#xD;
&#xD;
          -  Pregnancy or breast feeding&#xD;
&#xD;
          -  Any significant neurologic disease, including dementia, multi-infarct dementia,&#xD;
             Parkinson's or Huntington's disease, brain tumor, progressive supranuclear palsy,&#xD;
             seizure disorder, subdural hematoma, multiple sclerosis, history of significant head&#xD;
             trauma&#xD;
&#xD;
          -  Current antidepressant use (must be washed out for two weeks prior to starting&#xD;
             protocol)&#xD;
&#xD;
          -  Inability to stop taking medication contraindicated with treatment&#xD;
&#xD;
          -  High Hypnotizability in the Hypnotic Induction Profile (score &gt;8)&#xD;
&#xD;
          -  Any significant psychiatric disorder as identified on the Mini Mental State Exam&#xD;
             (Dysthymia not an exclusion criteria)&#xD;
&#xD;
          -  Color blindness&#xD;
&#xD;
          -  Any significant psychiatric disorder as identified on the Mini International&#xD;
             Neuropsychiatric Interview&#xD;
&#xD;
          -  Previous exposure to rTMS&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Nolan Williams, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Stanford University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Stanford University</name>
      <address>
        <city>Palo Alto</city>
        <state>California</state>
        <zip>94305</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
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  </reference>
  <reference>
    <citation>Goldsworthy MR, Pitcher JB, Ridding MC. Neuroplastic modulation of inhibitory motor cortical networks by spaced theta burst stimulation protocols. Brain Stimul. 2013 May;6(3):340-5. doi: 10.1016/j.brs.2012.06.005. Epub 2012 Jul 5.</citation>
    <PMID>22835528</PMID>
  </reference>
  <reference>
    <citation>Goldsworthy MR, Pitcher JB, Ridding MC. Spaced Noninvasive Brain Stimulation: Prospects for Inducing Long-Lasting Human Cortical Plasticity. Neurorehabil Neural Repair. 2015 Sep;29(8):714-21. doi: 10.1177/1545968314562649. Epub 2014 Dec 11.</citation>
    <PMID>25505220</PMID>
  </reference>
  <reference>
    <citation>Hoeft F, Gabrieli JD, Whitfield-Gabrieli S, Haas BW, Bammer R, Menon V, Spiegel D. Functional brain basis of hypnotizability. Arch Gen Psychiatry. 2012 Oct;69(10):1064-72. doi: 10.1001/archgenpsychiatry.2011.2190. Erratum In: JAMA Psychiatry. 2013 Jan;70(1):97.</citation>
    <PMID>23026956</PMID>
  </reference>
  <verification_date>August 2021</verification_date>
  <study_first_submitted>November 16, 2016</study_first_submitted>
  <study_first_submitted_qc>November 18, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 21, 2016</study_first_posted>
  <results_first_submitted>June 20, 2021</results_first_submitted>
  <results_first_submitted_qc>August 4, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">August 30, 2021</results_first_posted>
  <disposition_first_submitted>December 15, 2020</disposition_first_submitted>
  <disposition_first_submitted_qc>August 4, 2021</disposition_first_submitted_qc>
  <disposition_first_posted type="Actual">August 30, 2021</disposition_first_posted>
  <last_update_submitted>August 4, 2021</last_update_submitted>
  <last_update_submitted_qc>August 4, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">August 30, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Stanford University</investigator_affiliation>
    <investigator_full_name>David Spiegel</investigator_full_name>
    <investigator_title>Willson Professor and Associate Chair of Psychiatry &amp; Behavioral Sciences, Director of the Center on Stress and Health, and Medical Director of the Center for Integrative Medicine at Stanford University School of Medicine</investigator_title>
  </responsible_party>
  <keyword>repetitive Transcranial Magnetic Stimulation</keyword>
  <keyword>functional MRI</keyword>
  <keyword>Fibromyalgia</keyword>
  <keyword>Hypnosis</keyword>
  <keyword>Pain Assessment</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Fibromyalgia</mesh_term>
    <mesh_term>Myofascial Pain Syndromes</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>February 14, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/07/NCT02969707/Prot_SAP_001.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>May 28, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/07/NCT02969707/ICF_002.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Active rTMS</title>
          <description>The active group received active repetitive Transcranial Magnetic Stimulation&#xD;
Active repetitive Transcranial Magnetic Stimulation: The investigators performed two applications of 40s of continuous theta-burst stimulation (cTBS) form of rTMS at 80% resting motor threshold (previously determined), with a 15 minute intersession interval. The standardized treatment location for the left dorsolateral prefrontal cortex (DLPFC) was determined by Localite Neuronavigation and targeted at the posterior middle frontal gyrus. The baseline structural scan obtained during the scan 1 was utilized for this localization process. rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).</description>
        </group>
        <group group_id="P2">
          <title>Sham rTMS</title>
          <description>The sham repetitive Transcranial Magnetic Stimulation group had the stimulation blocked.&#xD;
Sham repetitive Transcranial Magnetic Stimulation: This was identical to active rTMS except the stimulation was blocked. Both active and sham repetitive Transcranial Magnetic Stimulation received simulation from a specially designed coil which is capable of delivering either active rTMS or sham rTMS in a manner, which is randomized by the system itself and therefore blinded to the treater. Sham rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="49"/>
                <participants group_id="P2" count="52"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="41"/>
                <participants group_id="P2" count="44"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="8"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Active rTMS</title>
          <description>The active group received active repetitive Transcranial Magnetic Stimulation&#xD;
Active repetitive Transcranial Magnetic Stimulation: The investigators performed two applications of 40s of continuous theta-burst stimulation (cTBS) form of rTMS at 80% resting motor threshold (previously determined), with a 15 minute intersession interval. The standardized treatment location for the left DLPFC was determined by Localite Neuronavigation and targeted at the posterior middle frontal gyrus. The baseline structural scan obtained during the scan 1 was utilized for this localization process. rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).</description>
        </group>
        <group group_id="B2">
          <title>Sham rTMS</title>
          <description>The sham repetitive Transcranial Magnetic Stimulation group had the stimulation blocked.&#xD;
Sham repetitive Transcranial Magnetic Stimulation: This was identical to active rTMS except the stimulation was blocked. Both active and sham repetitive Transcranial Magnetic Stimulation received simulation from a specially designed coil which is capable of delivering either active rTMS or sham rTMS in a manner, which is randomized by the system itself and therefore blinded to the treater. Sham rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="49"/>
            <count group_id="B2" value="52"/>
            <count group_id="B3" value="101"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="47"/>
                    <measurement group_id="B2" value="50"/>
                    <measurement group_id="B3" value="97"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="48.9" spread="12.8"/>
                    <measurement group_id="B2" value="50" spread="11.6"/>
                    <measurement group_id="B3" value="49.47" spread="12.15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="48"/>
                    <measurement group_id="B2" value="48"/>
                    <measurement group_id="B3" value="96"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="35"/>
                    <measurement group_id="B2" value="40"/>
                    <measurement group_id="B3" value="75"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="14"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="49"/>
                    <measurement group_id="B2" value="52"/>
                    <measurement group_id="B3" value="101"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>The Change in Functional Connectivity (FC) Between the Left Dorsolateral Prefrontal Cortex (L-DLPFC) and the Dorsal Anterior Cingulate Cortex (dACC)</title>
        <description>Functional MRI (fMRI) measures changes in oxygenated blood in the brain; at rest these levels fluctuate over time. These fluctuations can be similar between different brain regions. FC is the similarity in fluctuations of these fMRI signals and suggests how strongly two regions communicate with each other. We measured how inhibitory continuous theta-burst stimulation (cTBS) over L-DLPFC changes FC between L-DLPFC and dACC. This was done by estimating z-transformed correlation coefficients (CC) for each voxel (-1 to 1) between the L-DLPFC and dACC pre and post cTBS intervention. Negative FC was assigned to voxels with a weight &lt; 0, positive FC to voxels with weight&gt; 0. Total FC includes positive and negative voxels. The change in FC is regarded as the change in the sum of these weighted voxels from pre to post cTBS for total, positive and negative FC, respectively. Greater sums of voxels correspond to more significant levels of coordinated activity (positive, negative, or total).</description>
        <time_frame>Baseline and at 15-20 min post-TMS (up to 30 min)</time_frame>
        <population>Participants with resting-state scans for both pre and post-TMS conditions that passed QC and motion-based scan inclusion criteria; outlier data were excluded.</population>
        <group_list>
          <group group_id="O1">
            <title>Active rTMS</title>
            <description>The active group received active repetitive Transcranial Magnetic Stimulation&#xD;
Active repetitive Transcranial Magnetic Stimulation: The investigators performed two applications of 40s of continuous theta-burst stimulation (cTBS) form of rTMS at 80% resting motor threshold (previously determined), with a 15 minute intersession interval. The standardized treatment location for the left DLPFC was determined by Localite Neuronavigation and targeted at the posterior middle frontal gyrus. The baseline structural scan obtained during the scan 1 was utilized for this localization process. rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).utilized for this localization process. rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark).</description>
          </group>
          <group group_id="O2">
            <title>Sham rTMS</title>
            <description>The sham repetitive Transcranial Magnetic Stimulation group had the stimulation blocked.&#xD;
Sham repetitive Transcranial Magnetic Stimulation: This was identical to active rTMS except the stimulation was blocked. Both active and sham repetitive Transcranial Magnetic Stimulation received simulation from a specially designed coil which is capable of delivering either active rTMS or sham rTMS in a manner, which is randomized by the system itself and therefore blinded to the treater. Sham rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).</description>
          </group>
        </group_list>
        <measure>
          <title>The Change in Functional Connectivity (FC) Between the Left Dorsolateral Prefrontal Cortex (L-DLPFC) and the Dorsal Anterior Cingulate Cortex (dACC)</title>
          <description>Functional MRI (fMRI) measures changes in oxygenated blood in the brain; at rest these levels fluctuate over time. These fluctuations can be similar between different brain regions. FC is the similarity in fluctuations of these fMRI signals and suggests how strongly two regions communicate with each other. We measured how inhibitory continuous theta-burst stimulation (cTBS) over L-DLPFC changes FC between L-DLPFC and dACC. This was done by estimating z-transformed correlation coefficients (CC) for each voxel (-1 to 1) between the L-DLPFC and dACC pre and post cTBS intervention. Negative FC was assigned to voxels with a weight &lt; 0, positive FC to voxels with weight&gt; 0. Total FC includes positive and negative voxels. The change in FC is regarded as the change in the sum of these weighted voxels from pre to post cTBS for total, positive and negative FC, respectively. Greater sums of voxels correspond to more significant levels of coordinated activity (positive, negative, or total).</description>
          <population>Participants with resting-state scans for both pre and post-TMS conditions that passed QC and motion-based scan inclusion criteria; outlier data were excluded.</population>
          <units>Z-transformed CC</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="26"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Change in sum of positive z-transformed CC.</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="61.98" spread="21.63"/>
                    <measurement group_id="O2" value="4.16" spread="16.43"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change in sum of negative z-transformed CC.</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-21.41" spread="16.8"/>
                    <measurement group_id="O2" value="-13.22" spread="16.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change in sum of all z-transformed CC.</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="40.56" spread="32.34"/>
                    <measurement group_id="O2" value="-9.06" spread="28.25"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Examining the Change in sum of positive z-transformed CC.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.035</p_value>
            <method>t-test, 2 sided</method>
            <method_desc>2-sample t-test</method_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Examining the change in sum of all z-transformed CC.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.7</p_value>
            <p_value_desc>2-sample t-test</p_value_desc>
            <method>t-test, 2 sided</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Examining the change in sum of negative z-transformed CC.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>2-sample t-test</non_inferiority_desc>
            <p_value>0.11</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Examining the change in positive functional connectivity between the L-DLPFC and the dACC within the active group from pre to post TMS.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.008</p_value>
            <method>t-test, 2 sided</method>
            <method_desc>One sample(paired) t-test</method_desc>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>61.98</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>The Change in the Neural Network Underlying Hypnotic Intensity</title>
        <description>Blood oxygen level dependent (BOLD) signal and interleaved TMS-BOLD analyses will be used to determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC on modulating the neural network that underlies hypnotic intensity.</description>
        <time_frame>Baseline and 2 hours</time_frame>
        <population>During the study, data were not collected using interleaved TMS-BOLD, as originally planned.</population>
        <group_list>
          <group group_id="O1">
            <title>Active rTMS</title>
            <description>The active group received active repetitive Transcranial Magnetic Stimulation.&#xD;
Active repetitive Transcranial Magnetic Stimulation: The investigators performed two applications of 40s of continuous theta-burst stimulation (cTBS) form of rTMS at 80% resting motor threshold (previously determined), with a 15 minute intersession interval. The standardized treatment location for the left DLPFC was determined by Localite Neuronavigation and targeted at the posterior middle frontal gyrus. The baseline structural scan obtained during the scan 1 was utilized for this localization process. rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).</description>
          </group>
          <group group_id="O2">
            <title>Sham rTMS</title>
            <description>The sham repetitive Transcranial Magnetic Stimulation group had the stimulation blocked.&#xD;
Sham repetitive Transcranial Magnetic Stimulation: This was identical to active rTMS except the stimulation was blocked. Both active and sham repetitive Transcranial Magnetic Stimulation received simulation from a specially designed coil which is capable of delivering either active rTMS or sham rTMS in a manner, which is randomized by the system itself and therefore blinded to the treater. Sham rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).</description>
          </group>
        </group_list>
        <measure>
          <title>The Change in the Neural Network Underlying Hypnotic Intensity</title>
          <description>Blood oxygen level dependent (BOLD) signal and interleaved TMS-BOLD analyses will be used to determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC on modulating the neural network that underlies hypnotic intensity.</description>
          <population>During the study, data were not collected using interleaved TMS-BOLD, as originally planned.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Hypnotic Induction Profile Score</title>
        <description>The investigators used the Hypnotic Induction Profile (HIP) to determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC on enhancing hypnotizability.&#xD;
HIP scores range from 0 to 10 (low to high hypnotizability).</description>
        <time_frame>Baseline and Immediately post rTMS (up to 30 min)</time_frame>
        <population>Participants who completed the protocol are included in the analysis. Outliers were conservatively defined as having HIP change scores ≥ 3 standard deviations from the mean (a change of approximately 5 points or more of the 0-10 HIP scale).</population>
        <group_list>
          <group group_id="O1">
            <title>Active rTMS</title>
            <description>The active group received active repetitive Transcranial Magnetic Stimulation.&#xD;
Active repetitive Transcranial Magnetic Stimulation: The investigators performed two applications of 40s of continuous theta-burst stimulation (cTBS) form of rTMS at 80% resting motor threshold (previously determined), with a 15 minute intersession interval. The standardized treatment location for the left DLPFC was determined by Localite Neuronavigation and targeted at the posterior middle frontal gyrus. The baseline structural scan obtained during the scan 1 was utilized for this localization process. rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).</description>
          </group>
          <group group_id="O2">
            <title>Sham rTMS</title>
            <description>The sham repetitive Transcranial Magnetic Stimulation group had the stimulation blocked.&#xD;
Sham repetitive Transcranial Magnetic Stimulation: This was identical to active rTMS except the stimulation was blocked. Both active and sham repetitive Transcranial Magnetic Stimulation received simulation from a specially designed coil which is capable of delivering either active rTMS or sham rTMS in a manner, which is randomized by the system itself and therefore blinded to the treater. Sham rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Hypnotic Induction Profile Score</title>
          <description>The investigators used the Hypnotic Induction Profile (HIP) to determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC on enhancing hypnotizability.&#xD;
HIP scores range from 0 to 10 (low to high hypnotizability).</description>
          <population>Participants who completed the protocol are included in the analysis. Outliers were conservatively defined as having HIP change scores ≥ 3 standard deviations from the mean (a change of approximately 5 points or more of the 0-10 HIP scale).</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="40"/>
                <count group_id="O2" value="38"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value=".63" spread="1.18"/>
                    <measurement group_id="O2" value=".01" spread="1.02"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Pre- to post-rTMS change in HIP scores were calculated for both Active and Sham conditions. Two-tailed t-tests were used to evaluate the difference between the two conditions' change scores.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>We assessed the superiority of active over sham.</non_inferiority_desc>
            <p_value>=.016</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in The Hypnosis Intensity Scale</title>
        <description>The investigators used the Hypnotic Intensity Scale (HIS) to determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC on enhancing hypnotic intensity.&#xD;
HIS scores range from 0 to 10 (low to high hypnotic intensity).</description>
        <time_frame>Baseline and immediately post rTMS (up to 2 hrs)</time_frame>
        <population>Participants who completed the protocol and completed HIS ratings are included in the analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Active rTMS</title>
            <description>The active group received active repetitive Transcranial Magnetic Stimulation.&#xD;
Active repetitive Transcranial Magnetic Stimulation: The investigators performed two applications of 40s of continuous theta-burst stimulation (cTBS) form of rTMS at 80% resting motor threshold (previously determined), with a 15 minute intersession interval. The standardized treatment location for the left DLPFC was determined by Localite Neuronavigation and targeted at the posterior middle frontal gyrus. The baseline structural scan obtained during the scan 1 was utilized for this localization process. rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).</description>
          </group>
          <group group_id="O2">
            <title>Sham rTMS</title>
            <description>The sham repetitive Transcranial Magnetic Stimulation group had the stimulation blocked.&#xD;
Sham repetitive Transcranial Magnetic Stimulation: This was identical to active rTMS except the stimulation was blocked. Both active and sham repetitive Transcranial Magnetic Stimulation received simulation from a specially designed coil which is capable of delivering either active rTMS or sham rTMS in a manner, which is randomized by the system itself and therefore blinded to the treater. Sham rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).</description>
          </group>
        </group_list>
        <measure>
          <title>Change in The Hypnosis Intensity Scale</title>
          <description>The investigators used the Hypnotic Intensity Scale (HIS) to determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC on enhancing hypnotic intensity.&#xD;
HIS scores range from 0 to 10 (low to high hypnotic intensity).</description>
          <population>Participants who completed the protocol and completed HIS ratings are included in the analysis.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="40"/>
                <count group_id="O2" value="39"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value=".475" spread="2.242"/>
                    <measurement group_id="O2" value="-.128" spread="1.490"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Pre- to post-rTMS change in HIS scores were calculated for both Active and Sham conditions. Two-tailed t-tests were used to evaluate the difference between the two conditions' change scores.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>We assessed the superiority of active over sham.</non_inferiority_desc>
            <p_value>=.164</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>The Change in Functional Connectivity (FC) Within The Neural Network Underlying Conflict Regulation.</title>
        <description>We examined the effect of active, inhibitory cTBS over L-DLPFC on functional connectivity (FC) in key nodes in the neural network underlying the conflict regulation system. FC between each voxel in the L-DLPFC and the entire dACC was established by estimating z-transformed correlation coefficients (CC) for each voxel (-1 to 1) pre and post cTBS intervention. This paradigm was also used for voxels in the Default Mode Network (DMN) (Schaefer, 2018; Yeo, 2011) to the entire right inferior frontal gyrus (rIFG). Negative FC was assigned to voxels with a weight &lt; 0, positive FC to voxels with weight &gt; 0. Total FC includes positive and negative voxels. The change in FC is regarded as the change in the sum of these weighted voxels from pre to post cTBS for total, positive and negative FC, respectively. Greater sums of voxels correspond to more significant levels of coordinated activity (positive, negative, or total).</description>
        <time_frame>Baseline and at 15-20 min post-TMS (up to 30 min)</time_frame>
        <population>Population consisted of patients with fibromyalgia who underwent either active or sham cTBS either in combination with hypnosis or without it. Participants were excluded from the original sample for 1) fMRI imaging problems, 2) missing data. For the analyses below additional outliers were excluded on a test by test basis.</population>
        <group_list>
          <group group_id="O1">
            <title>Active rTMS</title>
            <description>The active group will receive repetitive Transcranial Magnetic Stimulation&#xD;
repetitive Transcranial Magnetic Stimulation: The investigators will perform two applications of 40s of continuous theta-burst stimulation (cTBS) form of rTMS at 80% resting motor threshold (previously determined), with a 15 minute intersession interval. The standardized treatment location for the left DLPFC will be determined by Localite Neuronavigation and targeted at the posterior middle frontal gyrus. The baseline structural scan obtained during the scan 1 will be utilized for this localization process. rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark).</description>
          </group>
          <group group_id="O2">
            <title>Sham rTMS</title>
            <description>The sham repetitive Transcranial Magnetic Stimulation group will have the stimulation blocked.&#xD;
Sham repetitive Transcranial Magnetic Stimulation: This will be identical to active rTMS except the stimulation will be blocked. Both active and sham repetitive Transcranial Magnetic Stimulation will receive simulation from a specially designed coil which is capable of delivering either active rTMS or sham rTMS in a manner, which is randomized by the system itself and therefore blinded to the treater. rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark).</description>
          </group>
        </group_list>
        <measure>
          <title>The Change in Functional Connectivity (FC) Within The Neural Network Underlying Conflict Regulation.</title>
          <description>We examined the effect of active, inhibitory cTBS over L-DLPFC on functional connectivity (FC) in key nodes in the neural network underlying the conflict regulation system. FC between each voxel in the L-DLPFC and the entire dACC was established by estimating z-transformed correlation coefficients (CC) for each voxel (-1 to 1) pre and post cTBS intervention. This paradigm was also used for voxels in the Default Mode Network (DMN) (Schaefer, 2018; Yeo, 2011) to the entire right inferior frontal gyrus (rIFG). Negative FC was assigned to voxels with a weight &lt; 0, positive FC to voxels with weight &gt; 0. Total FC includes positive and negative voxels. The change in FC is regarded as the change in the sum of these weighted voxels from pre to post cTBS for total, positive and negative FC, respectively. Greater sums of voxels correspond to more significant levels of coordinated activity (positive, negative, or total).</description>
          <population>Population consisted of patients with fibromyalgia who underwent either active or sham cTBS either in combination with hypnosis or without it. Participants were excluded from the original sample for 1) fMRI imaging problems, 2) missing data. For the analyses below additional outliers were excluded on a test by test basis.</population>
          <units>Z-transformed CC</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="25"/>
                <count group_id="O2" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Change in sum of all z-transformed CC in L-DLPFC.</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="23"/>
                    <count group_id="O2" value="23"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.01" spread="0.14"/>
                    <measurement group_id="O2" value="-0.003" spread="0.13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change in sum of positive z-transformed CC in L-DLPFC.</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="23"/>
                    <count group_id="O2" value="23"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="33.76" spread="136.5"/>
                    <measurement group_id="O2" value="6.39" spread="99.82"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change in sum of negative z-transformed CC in L-DLPFC.</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="23"/>
                    <count group_id="O2" value="23"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-20.36" spread="88.88"/>
                    <measurement group_id="O2" value="-10.11" spread="96.55"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change in sum of all z-transformed CC in DMN.</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="23"/>
                    <count group_id="O2" value="23"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.004" spread="0.05"/>
                    <measurement group_id="O2" value="-0.01" spread="0.05"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change in sum of positive z-transformed CC in DMN.</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="23"/>
                    <count group_id="O2" value="23"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-31.20" spread="137.73"/>
                    <measurement group_id="O2" value="21.12" spread="153.54"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change in sum of negative z-transformed CC in DMN.</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="23"/>
                    <count group_id="O2" value="23"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="51.35" spread="243.68"/>
                    <measurement group_id="O2" value="-67.65" spread="219.05"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>The Change in Stroop Performance</title>
        <description>Stroop effect is measured by the response time of a participant during the stroop task. Increases in response time indicate increased stroop effect (SE) and vice versa.</description>
        <time_frame>Baseline and at 15-20 min post-TMS (up to 30 min)</time_frame>
        <population>Population consisted of patients with fibromyalgia who underwent either active or sham cTBS either in combination with hypnosis or without it. Participants were excluded from the original sample for 1) poor Stroop task performance, 2) fMRI imaging problems, 3) missing data. For the analyses below additional outliers were excluded on a test by test basis.</population>
        <group_list>
          <group group_id="O1">
            <title>Active rTMS</title>
            <description>The active group will receive repetitive Transcranial Magnetic Stimulation&#xD;
repetitive Transcranial Magnetic Stimulation: The investigators will perform two applications of 40s of continuous theta-burst stimulation (cTBS) form of rTMS at 80% resting motor threshold (previously determined), with a 15 minute intersession interval. The standardized treatment location for the left DLPFC will be determined by Localite Neuronavigation and targeted at the posterior middle frontal gyrus. The baseline structural scan obtained during the scan 1 will be utilized for this localization process. rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark).</description>
          </group>
          <group group_id="O2">
            <title>Sham rTMS</title>
            <description>The sham repetitive Transcranial Magnetic Stimulation group will have the stimulation blocked.&#xD;
Sham repetitive Transcranial Magnetic Stimulation: This will be identical to active rTMS except the stimulation will be blocked. Both active and sham repetitive Transcranial Magnetic Stimulation will receive simulation from a specially designed coil which is capable of delivering either active rTMS or sham rTMS in a manner, which is randomized by the system itself and therefore blinded to the treater. rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark).</description>
          </group>
        </group_list>
        <measure>
          <title>The Change in Stroop Performance</title>
          <description>Stroop effect is measured by the response time of a participant during the stroop task. Increases in response time indicate increased stroop effect (SE) and vice versa.</description>
          <population>Population consisted of patients with fibromyalgia who underwent either active or sham cTBS either in combination with hypnosis or without it. Participants were excluded from the original sample for 1) poor Stroop task performance, 2) fMRI imaging problems, 3) missing data. For the analyses below additional outliers were excluded on a test by test basis.</population>
          <units>Seconds</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="23"/>
                <count group_id="O2" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Mean difference in change in Stroop effect (s) without hypnosis (TMS - no TMS) condition.</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="23"/>
                    <count group_id="O2" value="24"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.01" spread="0.1"/>
                    <measurement group_id="O2" value="-0.02" spread="0.082"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Mean difference in change in Stroop effect (s) with hypnosis (TMS - no TMS) condition.</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="23"/>
                    <count group_id="O2" value="23"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.04" spread="0.12"/>
                    <measurement group_id="O2" value="-0.009" spread=".10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Stroop Task</title>
        <description>Active, inhibitory cTBS effect over L-DLPFC on the neural network that underlies the hypnotic Stroop modulation effect was determined by first estimating the average of connectivity weights for all parcel pairs linking Ventral Attentional Network (VAN) to the DMN. Parcels are determined by extracting mean resting state BOLD time-series for each region of the Schaefer 100 parcellation. A correlation matrix between all parcels is created and FC weights for each pair are established by estimating z-transformed correlation coefficients (CC) (-1 to 1). Each parcel pair is then assigned to one of the 7 resting state networks defined by Yeo et al., (2011). Negative FC is defined for parcel pairs with a weight &lt; 0, positive FC pairs with weight &gt; 0 and total FC includes all pairs. FC is thus the average value between parcel pairs in the DMN and VAN pre/post TMS. Greater sums of weighted pairs correspond to more significant levels of coordinated activity (positive, negative, or total).</description>
        <time_frame>Baseline and at 15-20 min post-TMS (up to 30 min)</time_frame>
        <population>Subjects who had pre and post TMS resting-state fMRI scans that passed QC and motion-based inclusion criteria</population>
        <group_list>
          <group group_id="O1">
            <title>Active rTMS</title>
            <description>The active group will receive repetitive Transcranial Magnetic Stimulation&#xD;
repetitive Transcranial Magnetic Stimulation: The investigators will perform two applications of 40s of continuous theta-burst stimulation (cTBS) form of rTMS at 80% resting motor threshold (previously determined), with a 15 minute intersession interval. The standardized treatment location for the left DLPFC will be determined by Localite Neuronavigation and targeted at the posterior middle frontal gyrus. The baseline structural scan obtained during the scan 1 will be utilized for this localization process. rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark).</description>
          </group>
          <group group_id="O2">
            <title>Sham rTMS</title>
            <description>The sham repetitive Transcranial Magnetic Stimulation group will have the stimulation blocked.&#xD;
Sham repetitive Transcranial Magnetic Stimulation: This will be identical to active rTMS except the stimulation will be blocked. Both active and sham repetitive Transcranial Magnetic Stimulation will receive simulation from a specially designed coil which is capable of delivering either active rTMS or sham rTMS in a manner, which is randomized by the system itself and therefore blinded to the treater. rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark).</description>
          </group>
        </group_list>
        <measure>
          <title>Stroop Task</title>
          <description>Active, inhibitory cTBS effect over L-DLPFC on the neural network that underlies the hypnotic Stroop modulation effect was determined by first estimating the average of connectivity weights for all parcel pairs linking Ventral Attentional Network (VAN) to the DMN. Parcels are determined by extracting mean resting state BOLD time-series for each region of the Schaefer 100 parcellation. A correlation matrix between all parcels is created and FC weights for each pair are established by estimating z-transformed correlation coefficients (CC) (-1 to 1). Each parcel pair is then assigned to one of the 7 resting state networks defined by Yeo et al., (2011). Negative FC is defined for parcel pairs with a weight &lt; 0, positive FC pairs with weight &gt; 0 and total FC includes all pairs. FC is thus the average value between parcel pairs in the DMN and VAN pre/post TMS. Greater sums of weighted pairs correspond to more significant levels of coordinated activity (positive, negative, or total).</description>
          <population>Subjects who had pre and post TMS resting-state fMRI scans that passed QC and motion-based inclusion criteria</population>
          <units>Z-transformed CC</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="27"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.026" spread="0.0265"/>
                    <measurement group_id="O2" value="0.155" spread="0.0297"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.037</p_value>
            <method>t-test, 2 sided</method>
            <method_desc>2-sample t-test</method_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.063</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.31</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Linear Relationship Between the Change in FC of the VAN to the DMN and the Change in Stroop Performance (Correlation Coefficient) With no Hypnosis Intervention.</title>
        <description>Spearman's correlation was used to determine the linear relationship between the response time taken to answer incongruent Stroop task blocks (a measure of Stroop performance) and the change the resting-state network FC between the VAN and the DMN when no hypnosis intervention was implemented.</description>
        <time_frame>Baseline and at 15-20 min post-TMS (up to 1 hr)</time_frame>
        <population>Population consisted of patients with fibromyalgia who underwent either active or sham cTBS either in combination with hypnosis or without it. Participants were excluded from the original sample for 1) poor Stroop task performance, 2) fMRI imaging problems, 3) missing data. Subjects who had pre and post TMS resting-state fMRI scans that passed QC and motion-based inclusion criteria were included.</population>
        <group_list>
          <group group_id="O1">
            <title>Active rTMS</title>
            <description>The active group received active repetitive Transcranial Magnetic Stimulation Active repetitive Transcranial Magnetic Stimulation: The investigators performed two applications of 40s of continuous theta-burst stimulation (cTBS) form of rTMS at 80% resting motor threshold (previously determined), with a 15 minute intersession interval. The standardized treatment location for the left DLPFC was determined by Localite Neuronavigation and targeted at the posterior middle frontal gyrus. The baseline structural scan obtained during the scan 1 was utilized for this localization process. rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).utilized for this localization process. rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark).</description>
          </group>
          <group group_id="O2">
            <title>Sham rTMS</title>
            <description>The sham repetitive Transcranial Magnetic Stimulation group had the stimulation blocked.&#xD;
Sham repetitive Transcranial Magnetic Stimulation: This was identical to active rTMS except the stimulation was blocked. Both active and sham repetitive Transcranial Magnetic Stimulation received simulation from a specially designed coil which is capable of delivering either active rTMS or sham rTMS in a manner, which is randomized by the system itself and therefore blinded to the treater. Sham rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).</description>
          </group>
        </group_list>
        <measure>
          <title>Linear Relationship Between the Change in FC of the VAN to the DMN and the Change in Stroop Performance (Correlation Coefficient) With no Hypnosis Intervention.</title>
          <description>Spearman's correlation was used to determine the linear relationship between the response time taken to answer incongruent Stroop task blocks (a measure of Stroop performance) and the change the resting-state network FC between the VAN and the DMN when no hypnosis intervention was implemented.</description>
          <population>Population consisted of patients with fibromyalgia who underwent either active or sham cTBS either in combination with hypnosis or without it. Participants were excluded from the original sample for 1) poor Stroop task performance, 2) fMRI imaging problems, 3) missing data. Subjects who had pre and post TMS resting-state fMRI scans that passed QC and motion-based inclusion criteria were included.</population>
          <units>Correlation Coefficient</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="27"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.18"/>
                    <measurement group_id="O2" value="-0.58"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Linear Relationship Between the Change in FC of the VAN to the DMN and the Change in Stroop Performance (Correlation Coefficient) With Hypnosis Intervention.</title>
        <description>Spearman's correlation was used to determine the linear relationship between the response time taken to answer incongruent Stroop task blocks (a measure of Stroop performance) and the change the resting-state network FC between the VAN and the DMN when the hypnosis intervention was implemented.</description>
        <time_frame>Baseline and at 15-20 min post-TMS (up to 1 hr)</time_frame>
        <population>Population consisted of patients with fibromyalgia who underwent either active or sham cTBS either in combination with hypnosis or without it. Participants were excluded from the original sample for 1) poor Stroop task performance, 2) fMRI imaging problems, 3) missing data. Subjects who had pre and post TMS resting-state fMRI scans that passed QC and motion-based inclusion criteria were included.</population>
        <group_list>
          <group group_id="O1">
            <title>Active rTMS</title>
            <description>The active group received active repetitive Transcranial Magnetic Stimulation Active repetitive Transcranial Magnetic Stimulation: The investigators performed two applications of 40s of continuous theta-burst stimulation (cTBS) form of rTMS at 80% resting motor threshold (previously determined), with a 15 minute intersession interval. The standardized treatment location for the left DLPFC was determined by Localite Neuronavigation and targeted at the posterior middle frontal gyrus. The baseline structural scan obtained during the scan 1 was utilized for this localization process. rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).utilized for this localization process. rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark).</description>
          </group>
          <group group_id="O2">
            <title>Sham rTMS</title>
            <description>The sham repetitive Transcranial Magnetic Stimulation group had the stimulation blocked.&#xD;
Sham repetitive Transcranial Magnetic Stimulation: This was identical to active rTMS except the stimulation was blocked. Both active and sham repetitive Transcranial Magnetic Stimulation received simulation from a specially designed coil which is capable of delivering either active rTMS or sham rTMS in a manner, which is randomized by the system itself and therefore blinded to the treater. Sham rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).</description>
          </group>
        </group_list>
        <measure>
          <title>Linear Relationship Between the Change in FC of the VAN to the DMN and the Change in Stroop Performance (Correlation Coefficient) With Hypnosis Intervention.</title>
          <description>Spearman's correlation was used to determine the linear relationship between the response time taken to answer incongruent Stroop task blocks (a measure of Stroop performance) and the change the resting-state network FC between the VAN and the DMN when the hypnosis intervention was implemented.</description>
          <population>Population consisted of patients with fibromyalgia who underwent either active or sham cTBS either in combination with hypnosis or without it. Participants were excluded from the original sample for 1) poor Stroop task performance, 2) fMRI imaging problems, 3) missing data. Subjects who had pre and post TMS resting-state fMRI scans that passed QC and motion-based inclusion criteria were included.</population>
          <units>Correlation Coefficient</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="27"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.16"/>
                    <measurement group_id="O2" value="0.16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Linear Relationship Between the Change in FC of the VAN to the DMN and the Change in Stroop Interference (Correlation Coefficient) With no Hypnosis Intervention.</title>
        <description>Spearman's correlation was used to determine the linear relationship between the Stroop interference and the change the resting-state network FC between the VAN and the DMN when no hypnosis intervention was implemented.&#xD;
In psychology, the Stroop effect is the delay in reaction time between congruent and incongruent stimuli.</description>
        <time_frame>Baseline and at 15-20 min post-TMS (up to 1 hr)</time_frame>
        <population>Population consisted of patients with fibromyalgia who underwent either active or sham cTBS either in combination with hypnosis or without it. Participants were excluded from the original sample for 1) poor Stroop task performance, 2) fMRI imaging problems, 3) missing data. Subjects who had pre and post TMS resting-state fMRI scans that passed QC and motion-based inclusion criteria were included.</population>
        <group_list>
          <group group_id="O1">
            <title>Active rTMS</title>
            <description>The active group received active repetitive Transcranial Magnetic Stimulation Active repetitive Transcranial Magnetic Stimulation: The investigators performed two applications of 40s of continuous theta-burst stimulation (cTBS) form of rTMS at 80% resting motor threshold (previously determined), with a 15 minute intersession interval. The standardized treatment location for the left DLPFC was determined by Localite Neuronavigation and targeted at the posterior middle frontal gyrus. The baseline structural scan obtained during the scan 1 was utilized for this localization process. rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).utilized for this localization process. rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark).</description>
          </group>
          <group group_id="O2">
            <title>Sham rTMS</title>
            <description>The sham repetitive Transcranial Magnetic Stimulation group had the stimulation blocked.&#xD;
Sham repetitive Transcranial Magnetic Stimulation: This was identical to active rTMS except the stimulation was blocked. Both active and sham repetitive Transcranial Magnetic Stimulation received simulation from a specially designed coil which is capable of delivering either active rTMS or sham rTMS in a manner, which is randomized by the system itself and therefore blinded to the treater. Sham rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).</description>
          </group>
        </group_list>
        <measure>
          <title>Linear Relationship Between the Change in FC of the VAN to the DMN and the Change in Stroop Interference (Correlation Coefficient) With no Hypnosis Intervention.</title>
          <description>Spearman's correlation was used to determine the linear relationship between the Stroop interference and the change the resting-state network FC between the VAN and the DMN when no hypnosis intervention was implemented.&#xD;
In psychology, the Stroop effect is the delay in reaction time between congruent and incongruent stimuli.</description>
          <population>Population consisted of patients with fibromyalgia who underwent either active or sham cTBS either in combination with hypnosis or without it. Participants were excluded from the original sample for 1) poor Stroop task performance, 2) fMRI imaging problems, 3) missing data. Subjects who had pre and post TMS resting-state fMRI scans that passed QC and motion-based inclusion criteria were included.</population>
          <units>Correlation Coefficient</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="27"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.24"/>
                    <measurement group_id="O2" value="-0.44"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Linear Relationship Between the Change in FC of the VAN to the DMN and the Change in Stroop Interference (Correlation Coefficient) With Hypnosis Intervention.</title>
        <description>Spearman's correlation was used to determine the linear relationship between the Stroop interference and the change the resting-state network FC between the VAN and the DMN when the hypnosis intervention was implemented.&#xD;
In psychology, the Stroop effect is the delay in reaction time between congruent and incongruent stimuli.</description>
        <time_frame>Baseline and at 15-20 min post-TMS (up to 1 hr)</time_frame>
        <population>Population consisted of patients with fibromyalgia who underwent either active or sham cTBS either in combination with hypnosis or without it. Participants were excluded from the original sample for 1) poor Stroop task performance, 2) fMRI imaging problems, 3) missing data. Subjects who had pre and post TMS resting-state fMRI scans that passed QC and motion-based inclusion criteria were included.</population>
        <group_list>
          <group group_id="O1">
            <title>Active rTMS</title>
            <description>The active group received active repetitive Transcranial Magnetic Stimulation Active repetitive Transcranial Magnetic Stimulation: The investigators performed two applications of 40s of continuous theta-burst stimulation (cTBS) form of rTMS at 80% resting motor threshold (previously determined), with a 15 minute intersession interval. The standardized treatment location for the left DLPFC was determined by Localite Neuronavigation and targeted at the posterior middle frontal gyrus. The baseline structural scan obtained during the scan 1 was utilized for this localization process. rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).utilized for this localization process. rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark).</description>
          </group>
          <group group_id="O2">
            <title>Sham rTMS</title>
            <description>The sham repetitive Transcranial Magnetic Stimulation group had the stimulation blocked.&#xD;
Sham repetitive Transcranial Magnetic Stimulation: This was identical to active rTMS except the stimulation was blocked. Both active and sham repetitive Transcranial Magnetic Stimulation received simulation from a specially designed coil which is capable of delivering either active rTMS or sham rTMS in a manner, which is randomized by the system itself and therefore blinded to the treater. Sham rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).</description>
          </group>
        </group_list>
        <measure>
          <title>Linear Relationship Between the Change in FC of the VAN to the DMN and the Change in Stroop Interference (Correlation Coefficient) With Hypnosis Intervention.</title>
          <description>Spearman's correlation was used to determine the linear relationship between the Stroop interference and the change the resting-state network FC between the VAN and the DMN when the hypnosis intervention was implemented.&#xD;
In psychology, the Stroop effect is the delay in reaction time between congruent and incongruent stimuli.</description>
          <population>Population consisted of patients with fibromyalgia who underwent either active or sham cTBS either in combination with hypnosis or without it. Participants were excluded from the original sample for 1) poor Stroop task performance, 2) fMRI imaging problems, 3) missing data. Subjects who had pre and post TMS resting-state fMRI scans that passed QC and motion-based inclusion criteria were included.</population>
          <units>Correlation Coefficient</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="27"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.07"/>
                    <measurement group_id="O2" value="0.28"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in the Numeric Pain Rating Scale</title>
        <description>To determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC on modulating the neural network that underlies hypnotic analgesia (HA).&#xD;
Numeric Pain Rating Scale scores range from 0 to 10 (low to high pain intensity).</description>
        <time_frame>Baseline and immediately post-rTMS (up to 30 minutes)</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Active rTMS</title>
            <description>The active group will receive repetitive Transcranial Magnetic Stimulation&#xD;
repetitive Transcranial Magnetic Stimulation: The investigators will perform two applications of 40s of continuous theta-burst stimulation (cTBS) form of rTMS at 80% resting motor threshold (previously determined), with a 15 minute intersession interval. The standardized treatment location for the left DLPFC will be determined by Localite Neuronavigation and targeted at the posterior middle frontal gyrus. The baseline structural scan obtained during the scan 1 will be utilized for this localization process. rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark).</description>
          </group>
          <group group_id="O2">
            <title>Sham rTMS</title>
            <description>The sham repetitive Transcranial Magnetic Stimulation group will have the stimulation blocked.&#xD;
Sham repetitive Transcranial Magnetic Stimulation: This will be identical to active rTMS except the stimulation will be blocked. Both active and sham repetitive Transcranial Magnetic Stimulation will receive simulation from a specially designed coil which is capable of delivering either active rTMS or sham rTMS in a manner, which is randomized by the system itself and therefore blinded to the treater. rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark).</description>
          </group>
        </group_list>
        <measure>
          <title>Change in the Numeric Pain Rating Scale</title>
          <description>To determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC on modulating the neural network that underlies hypnotic analgesia (HA).&#xD;
Numeric Pain Rating Scale scores range from 0 to 10 (low to high pain intensity).</description>
          <units>mean change of scores on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="43"/>
                <count group_id="O2" value="40"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Non-hypnosis condition</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.907" spread="1.238"/>
                    <measurement group_id="O2" value=".2421" spread="1.662"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hypnosis condition</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.600" spread="1.853"/>
                    <measurement group_id="O2" value="5.470" spread="1.705"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>We used standard mixed-effects modeling to estimate the change (slope) in pain in our 2*2 pre- and post-assessment design. Pain ratings were calculated by averaging pain ratings at trials 2, 3, and 4 under four conditions (TMS with hypnosis, TMS without hypnosis, Sham with hypnosis, Sham without hypnosis). Based on these change estimates, we derived the two main effects (TMS, Hypnosis) and their interaction effect on the change in pain from the pre- to post-treatment assessment.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>We assessed the superiority of active over sham.</non_inferiority_desc>
            <p_value>.208</p_value>
            <method>Mixed Models Analysis</method>
            <param_type>Cohen's d</param_type>
            <param_value>-0.234</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Sense of Agency Rating Scale (SOARS)</title>
        <description>The investigators used the Sense of Agency Rating Scale (SOARS) to determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC on altering the subjective sense of agency during hypnotizability.&#xD;
SOARS scores are calculated for Involuntariness and Effortlessness, each range from 0 to 35 (low to high).</description>
        <time_frame>Baseline and immediately post-rTMS (up to 30 min)</time_frame>
        <population>Participants who completed the protocol and completed all items of the SOARS are included in the analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Active rTMS</title>
            <description>The active group will receive repetitive Transcranial Magnetic Stimulation&#xD;
repetitive Transcranial Magnetic Stimulation: The investigators will perform two applications of 40s of continuous theta-burst stimulation (cTBS) form of rTMS at 80% resting motor threshold (previously determined), with a 15 minute intersession interval. The standardized treatment location for the left DLPFC will be determined by Localite Neuronavigation and targeted at the posterior middle frontal gyrus. The baseline structural scan obtained during the scan 1 will be utilized for this localization process. rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark).</description>
          </group>
          <group group_id="O2">
            <title>Sham rTMS</title>
            <description>The sham repetitive Transcranial Magnetic Stimulation group will have the stimulation blocked.&#xD;
Sham repetitive Transcranial Magnetic Stimulation: This will be identical to active rTMS except the stimulation will be blocked. Both active and sham repetitive Transcranial Magnetic Stimulation will receive simulation from a specially designed coil which is capable of delivering either active rTMS or sham rTMS in a manner, which is randomized by the system itself and therefore blinded to the treater. rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark).</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Sense of Agency Rating Scale (SOARS)</title>
          <description>The investigators used the Sense of Agency Rating Scale (SOARS) to determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC on altering the subjective sense of agency during hypnotizability.&#xD;
SOARS scores are calculated for Involuntariness and Effortlessness, each range from 0 to 35 (low to high).</description>
          <population>Participants who completed the protocol and completed all items of the SOARS are included in the analysis.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="35"/>
                <count group_id="O2" value="33"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Involuntariness</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value=".3529" spread="3.3654"/>
                    <measurement group_id="O2" value="1.1034" spread="3.8391"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Effortlessness</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value=".8857" spread="3.5378"/>
                    <measurement group_id="O2" value=".2727" spread="3.1551"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Pre- to post-rTMS change in SOARS scores were calculated for both Active and Sham conditions. Two-tailed t-tests were used to evaluate the difference between the two conditions' change scores.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>We assessed the superiority of active over sham.</non_inferiority_desc>
            <p_value>=.454</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Metabolic Alterations in Fibromyalgia (FMS) Defined by Excitatory / Inhibitory Ratio</title>
        <description>E/I ratio is defined as the logarithm of the concentration of Glx (excitatory neurotransmitter metabolite complex) /GABA+ (inhibitory neurotransmitter metabolite complex) relative to either water or creatine peak signal and it is a unitless measure ranging from -1 to 1. Logarithmic transformations are used to account for non-normal distributions of metabolite concentrations across participants and ratios &gt; 0 are thought to be excitatory neurotransmitter dominant while ratios &lt;0 are thought to be inhibition dominant.</description>
        <time_frame>Baseline Scan (up to 15 min)</time_frame>
        <population>Participants who completed the protocol were included in analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Baseline Fibromyalgia MRSPEC Analysis</title>
            <description>MEGA-PRESS (Mescher M, Merkle H, Kirsch J, Garwood M, Gruetter R, 1998) Spectra were acquired during baseline scanning for TMS-naive participants with Fibromyalgia before any intervention as part of an F32 grant.</description>
          </group>
        </group_list>
        <measure>
          <title>Metabolic Alterations in Fibromyalgia (FMS) Defined by Excitatory / Inhibitory Ratio</title>
          <description>E/I ratio is defined as the logarithm of the concentration of Glx (excitatory neurotransmitter metabolite complex) /GABA+ (inhibitory neurotransmitter metabolite complex) relative to either water or creatine peak signal and it is a unitless measure ranging from -1 to 1. Logarithmic transformations are used to account for non-normal distributions of metabolite concentrations across participants and ratios &gt; 0 are thought to be excitatory neurotransmitter dominant while ratios &lt;0 are thought to be inhibition dominant.</description>
          <population>Participants who completed the protocol were included in analysis.</population>
          <units>Ratio</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="51"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>GABA+/Cr</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.10" spread="0.02"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>GABA+/Water</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.72" spread="0.33"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Glx/Cr</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.09" spread="0.01"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Glx/Water</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.43" spread="0.82"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Log E/I Cr</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.06" spread="0.08"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Log E/I Water</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.50" spread="0.08"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>In people with FMS, the linear relationship between Thermal Pain Tolerance and E/I ratio as it relates to water was assessed.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Linear regression was used to evaluate the scalar relationship between E/I ratio as it relates to water and Thermal Pain Tolerance with E/I as the independent variable and Thermal Pain Tolerance as the dependent variable.</non_inferiority_desc>
            <p_value>0.023</p_value>
            <method>Regression, Linear</method>
            <method_desc>(R² = .104, F(2,48) = 2.794, β = .320, p = .023)</method_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>In people with FMS, the linear relationship between Thermal Pain Threshold and E/I ratio as it relates to water was assessed.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Linear regression was used to evaluate the scalar relationship between E/I ratio as it relates to water and Thermal Pain Threshold with E/I as the independent variable and Thermal Pain Threshold as the dependent variable.</non_inferiority_desc>
            <p_value>0.043</p_value>
            <method>Regression, Linear</method>
            <method_desc>(R² = .081, F(1,49) = 4.315, β = .284, p = .043)</method_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>In people with FMS, the linear relationship between Thermal Pain Tolerance and E/I ratio as it relates to creatine was assessed.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Linear regression was used to evaluate the scalar relationship between E/I ratio as it relates to creatine and Thermal Pain Tolerance with E/I as the independent variable and Thermal Pain Tolerance as the dependent variable.</non_inferiority_desc>
            <p_value>0.022</p_value>
            <method>Regression, Linear</method>
            <method_desc>(R² = .103, F(1,49) = 5.632, β = .321, p = .022)</method_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>In people with FMS, the linear relationship between Thermal Pain Threshold and E/I ratio as it relates to creatine was assessed.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Linear regression was used to evaluate the scalar relationship between E/I ratio as it relates to creatine and Thermal Pain Threshold with E/I as the independent variable and Thermal Pain Threshold as the dependent variable.</non_inferiority_desc>
            <p_value>0.041</p_value>
            <method>Regression, Linear</method>
            <method_desc>(R² = .083, F(1,49) = 4.425, β = .288, p = .041)</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Alterations in Pain Perception in Fibromyalgia</title>
        <description>To characterize clinical pain measures, which are defined as thermal pain threshold and thermal pain tolerance. Thermal pain threshold is determined as the temperature of a thermode determined as painful (degrees Celsius) by a participant. Thermal pain tolerance extends this to the point at which discontinuation is necessary (degrees Celsius).</description>
        <time_frame>Baseline visit (up to 30 min)</time_frame>
        <population>Participants who completed the protocol were included in analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Baseline Fibromyalgia MRSPEC Analysis</title>
            <description>MEGA-PRESS (Mescher M, Merkle H, Kirsch J, Garwood M, Gruetter R, 1998) Spectra were acquired during baseline scanning for TMS-naive participants with Fibromyalgia before any intervention as part of an F32 grant.</description>
          </group>
        </group_list>
        <measure>
          <title>Alterations in Pain Perception in Fibromyalgia</title>
          <description>To characterize clinical pain measures, which are defined as thermal pain threshold and thermal pain tolerance. Thermal pain threshold is determined as the temperature of a thermode determined as painful (degrees Celsius) by a participant. Thermal pain tolerance extends this to the point at which discontinuation is necessary (degrees Celsius).</description>
          <population>Participants who completed the protocol were included in analysis.</population>
          <units>Degrees Celsius</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="51"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Thermal Pain Tolerance (degrees Celsius)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="47.8" spread="2.51"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Thermal Pain Threshold (degrees Celsius)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="44.6" spread="3.55"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Linear Regression of Thermal Pain Threshold to Logarithm of E/I Ratio as it Relates to Water in Fibromyalgia (Coefficient of Determination)</title>
        <description>Linear regression was used to evaluate the scalar relationship between E/I ratio as it relates to water and Thermal Pain Threshold with E/I as the independent variable and Thermal Pain Threshold as the dependent variable.</description>
        <time_frame>Baseline visit (up to 45 min)</time_frame>
        <population>Participants who completed the protocol were included in analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Baseline Fibromyalgia MRSPEC Analysis</title>
            <description>MEGA-PRESS (Mescher M, Merkle H, Kirsch J, Garwood M, Gruetter R, 1998) Spectra were acquired during baseline scanning for TMS-naive participants with Fibromyalgia before any intervention as part of an F32 grant.</description>
          </group>
        </group_list>
        <measure>
          <title>Linear Regression of Thermal Pain Threshold to Logarithm of E/I Ratio as it Relates to Water in Fibromyalgia (Coefficient of Determination)</title>
          <description>Linear regression was used to evaluate the scalar relationship between E/I ratio as it relates to water and Thermal Pain Threshold with E/I as the independent variable and Thermal Pain Threshold as the dependent variable.</description>
          <population>Participants who completed the protocol were included in analysis.</population>
          <units>Coefficient of determination</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="51"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.104"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Linear Regression of Thermal Pain Tolerance to Logarithm of E/I Ratio as it Relates to Water in Fibromyalgia (Coefficient of Determination)</title>
        <description>Linear regression was used to evaluate the scalar relationship between E/I ratio as it relates to water and Thermal Pain Tolerance with E/I as the independent variable and Thermal Pain Tolerance as the dependent variable.</description>
        <time_frame>Baseline visit (up to 45 min)</time_frame>
        <population>Participants who completed the protocol were included in analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Baseline Fibromyalgia MRSPEC Analysis</title>
            <description>MEGA-PRESS (Mescher M, Merkle H, Kirsch J, Garwood M, Gruetter R, 1998) Spectra were acquired during baseline scanning for TMS-naive participants with Fibromyalgia before any intervention as part of an F32 grant.</description>
          </group>
        </group_list>
        <measure>
          <title>Linear Regression of Thermal Pain Tolerance to Logarithm of E/I Ratio as it Relates to Water in Fibromyalgia (Coefficient of Determination)</title>
          <description>Linear regression was used to evaluate the scalar relationship between E/I ratio as it relates to water and Thermal Pain Tolerance with E/I as the independent variable and Thermal Pain Tolerance as the dependent variable.</description>
          <population>Participants who completed the protocol were included in analysis.</population>
          <units>Coefficient of determination</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="51"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.104"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Linear Regression of Thermal Pain Threshold to Logarithm of E/I Ratio as it Relates to Creatine in Fibromyalgia (Coefficient of Determination)</title>
        <description>Linear regression was used to evaluate the scalar relationship between E/I ratio as it relates to creatine and Thermal Pain Threshold with E/I as the independent variable and Thermal Pain Threshold as the dependent variable.</description>
        <time_frame>Baseline visit (up to 45 min)</time_frame>
        <population>Participants who completed the protocol were included in analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Baseline Fibromyalgia MRSPEC Analysis</title>
            <description>MEGA-PRESS (Mescher M, Merkle H, Kirsch J, Garwood M, Gruetter R, 1998) Spectra were acquired during baseline scanning for TMS-naive participants with Fibromyalgia before any intervention as part of an F32 grant.</description>
          </group>
        </group_list>
        <measure>
          <title>Linear Regression of Thermal Pain Threshold to Logarithm of E/I Ratio as it Relates to Creatine in Fibromyalgia (Coefficient of Determination)</title>
          <description>Linear regression was used to evaluate the scalar relationship between E/I ratio as it relates to creatine and Thermal Pain Threshold with E/I as the independent variable and Thermal Pain Threshold as the dependent variable.</description>
          <population>Participants who completed the protocol were included in analysis.</population>
          <units>Coefficient of determination</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="51"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.083"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Linear Regression of Thermal Pain Tolerance to Logarithm of E/I Ratio as it Relates to Creatine in Fibromyalgia (Coefficient of Determination)</title>
        <description>Linear regression was used to evaluate the scalar relationship between E/I ratio as it relates to creatine and Thermal Pain Tolerance with E/I as the independent variable and Thermal Pain Tolerance as the dependent variable.</description>
        <time_frame>Baseline visit (up to 45 min)</time_frame>
        <population>Participants who completed the protocol were included in analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Baseline Fibromyalgia MRSPEC Analysis</title>
            <description>MEGA-PRESS (Mescher M, Merkle H, Kirsch J, Garwood M, Gruetter R, 1998) Spectra were acquired during baseline scanning for TMS-naive participants with Fibromyalgia before any intervention as part of an F32 grant.</description>
          </group>
        </group_list>
        <measure>
          <title>Linear Regression of Thermal Pain Tolerance to Logarithm of E/I Ratio as it Relates to Creatine in Fibromyalgia (Coefficient of Determination)</title>
          <description>Linear regression was used to evaluate the scalar relationship between E/I ratio as it relates to creatine and Thermal Pain Tolerance with E/I as the independent variable and Thermal Pain Tolerance as the dependent variable.</description>
          <population>Participants who completed the protocol were included in analysis.</population>
          <units>Coefficient of determination</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="51"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.103"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Metabolic Changes in L-DLPFC Pre- and Post-rTMS</title>
        <description>To determine the relationship between the metabolic alterations pre and post-rTMS. Metabolic changes as measured by MEGA-PRESS spectroscopy were assessed by quantification of excitatory (Glx) and inhibitory (GABA+) neurotransmitter complexes. The E/I ratio is defined as the logarithm of the concentration of Glx/GABA+relative to either the reference water or creatine signal and it is a unitless measure ranging from -1 to 1. Logarithmic transformations are used to account for non-normal distributions of metabolite concentrations across participants and ratios &gt; 0 are thought to be excitatory neurotransmitter dominant while ratios &lt;0 are thought to be inhibition dominant.</description>
        <time_frame>Baseline Scan and at 15-20 min post-TMS (up to 30 min)</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Active rTMS</title>
            <description>The active group will receive repetitive Transcranial Magnetic Stimulation&#xD;
repetitive Transcranial Magnetic Stimulation: The investigators will perform two applications of 40s of continuous theta-burst stimulation (cTBS) form of rTMS at 80% resting motor threshold (previously determined), with a 15 minute intersession interval. The standardized treatment location for the left DLPFC will be determined by Localite Neuronavigation and targeted at the posterior middle frontal gyrus. The baseline structural scan obtained during the scan 1 will be utilized for this localization process. rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark).</description>
          </group>
          <group group_id="O2">
            <title>Sham rTMS</title>
            <description>The sham repetitive Transcranial Magnetic Stimulation group will have the stimulation blocked.&#xD;
Sham repetitive Transcranial Magnetic Stimulation: This will be identical to active rTMS except the stimulation will be blocked. Both active and sham repetitive Transcranial Magnetic Stimulation will receive simulation from a specially designed coil which is capable of delivering either active rTMS or sham rTMS in a manner, which is randomized by the system itself and therefore blinded to the treater. rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark).</description>
          </group>
        </group_list>
        <measure>
          <title>Metabolic Changes in L-DLPFC Pre- and Post-rTMS</title>
          <description>To determine the relationship between the metabolic alterations pre and post-rTMS. Metabolic changes as measured by MEGA-PRESS spectroscopy were assessed by quantification of excitatory (Glx) and inhibitory (GABA+) neurotransmitter complexes. The E/I ratio is defined as the logarithm of the concentration of Glx/GABA+relative to either the reference water or creatine signal and it is a unitless measure ranging from -1 to 1. Logarithmic transformations are used to account for non-normal distributions of metabolite concentrations across participants and ratios &gt; 0 are thought to be excitatory neurotransmitter dominant while ratios &lt;0 are thought to be inhibition dominant.</description>
          <units>Ratio</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="14"/>
                <count group_id="O2" value="21"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Log E/I Water Pre-TMS</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.487" spread="0.075"/>
                    <measurement group_id="O2" value="0.486" spread="0.092"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Log E/I Water Post-TMS</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.494" spread="0.073"/>
                    <measurement group_id="O2" value="0.505" spread="0.109"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Log E/I Creatine Pre-TMS</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.075" spread="0.075"/>
                    <measurement group_id="O2" value="-0.076" spread="0.092"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Log E/I Creatine Post-TMS</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.068" spread="0.073"/>
                    <measurement group_id="O2" value="-0.057" spread="0.108"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Standard ANCOVA testing whether the Post-TMS E/I relative to creatine is predicted for each subject by the intervention (Active / Sham) while covarying for the Pre-TMS E/I ratio relative to creatine.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.728</p_value>
            <method>ANCOVA</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Standard ANCOVA testing whether the Post-TMS E/I relative to water is predicted for each subject by the intervention (Active / Sham) while covarying for the Pre-TMS E/I ratio relative to water.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.720</p_value>
            <method>ANCOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Up to 30 days</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Active rTMS</title>
          <description>The active group will receive repetitive Transcranial Magnetic Stimulation&#xD;
repetitive Transcranial Magnetic Stimulation: The investigators will perform two applications of 40s of continuous theta-burst stimulation (cTBS) form of rTMS at 80% resting motor threshold (previously determined), with a 15 minute intersession interval. The standardized treatment location for the left DLPFC will be determined by Localite Neuronavigation and targeted at the posterior middle frontal gyrus. The baseline structural scan obtained during the scan 1 will be utilized for this localization process. rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark).</description>
        </group>
        <group group_id="E2">
          <title>Sham rTMS</title>
          <description>The sham repetitive Transcranial Magnetic Stimulation group will have the stimulation blocked.&#xD;
Sham repetitive Transcranial Magnetic Stimulation: This will be identical to active rTMS except the stimulation will be blocked. Both active and sham repetitive Transcranial Magnetic Stimulation will receive simulation from a specially designed coil which is capable of delivering either active rTMS or sham rTMS in a manner, which is randomized by the system itself and therefore blinded to the treater. rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark).</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="52"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="52"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="52"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <description>Dizziness from MRI machine during scanning session</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="52"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Medication Withdrawal During Washout</sub_title>
                <description>One patient experienced medication withdrawal during the washout period for the study.</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="52"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Headache / Scalp Irritation</sub_title>
                <description>One Participant experienced a headache and scalp irritation under the site of the TMS coil (a common side effect) during active treatment.</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="49"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="52"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>fMRI BOLD data were preprocessed using fMRIPrep 1.5.10 (Esteban, Markiewicz, et al. (2018); Esteban, Blair, et al. (2018); RRID:SCR_016216), which is based on Nipype 1.4.2 (Gorgolewski et al. (2011); Gorgolewski et al. (2018); RRID:SCR_002502) with MNI152NLin2009cAsym and anatomical output spaces. BOLD time series were bandpass filtered to include data in the window of 0.0025-0.025 Hz, which is on the low end of the spectrum. A more typical bandpass window is 0.01 - 0.1 Hz.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Dr. David Spiegel</name_or_title>
      <organization>Stanford University</organization>
      <phone>650-723-6421</phone>
      <email>dspiegel@stanford.edu</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02969707
org study id: 38138
secondary id: 1R33AT009305-01
nct id: NCT02969707
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: Yes
The investigators plan to use functional neuroimaging (fMRI) to understand the brain systems
      affected when hypnosis and hypnotic analgesia are augmented with repetitive transcranial
      magnetic stimulation (rTMS), a form of non-invasive brain stimulation to 100 people with
      fibromyalgia, a chronic pain condition. The investigators will measure the effect of
      rTMS-augmentation on the brain networks underlying hypnotizability, as well as the effect of
      rTMS-augmentation on hypnotic analgesia networks. The investigators hope to demonstrate that
      a combination of these psychological and neuromodulatory treatments will be more effective
      than hypnosis alone, thereby enhancing the depth of hypnosis, range of hypnosis and the
      efficacy of hypnotic analgesia and hopefully creating a new treatment modality for
      individuals suffering from pain syndromes such as fibromyalgia pain.
Overall Study Design. The investigators propose to develop a combinatory approach where an
      integrative technique (hypnosis) is augmented with a neurotechnology (repetitive transcranial
      magnetic stimulation). This application seeks to utilize the previously established
      brain-based mechanisms of both hypnosis and repetitive transcranial magnetic stimulation as
      biomarkers to assess the potential synergistic mechanism of this combinatory approach. 100
      low-moderately hypnotizable subjects with fibromyalgia will be identified. The subjects'
      response to rTMS-augmentation of hypnosis will be measured. The volunteers will be randomized
      to active or sham rTMS. Two scan sessions will be performed for each subject, with the first
      scan session investigating the effect of rTMS-augmentation on hypnosis and hypnotizability
      (120 min scan session) and the second scan session focused on the effect of rTMS-augmented
      hypnotic analgesia (120 min scan session).

      The study will require that participants participate in an in-person screening visit, a
      screening MRI scan and 2 MRI scan sessions that include the TMS and hypnosis.

      Experimental design. Before each MRI scan session, participants will undergo a preparation
      session, where hypnotizability and either psychological testing or experimental pain training
      will be conducted. Volunteer subjects will then participate in 2 MRI scan sessions on two
      separate days, each lasting approximately 120 mins.

      Hypnosis induction procedures. Hypnosis will be induced while the subject is in the scanner
      though the use of headphones and a pre-recorded induction script. Hypnotic instructions will
      be standardized, and will involve a simple induction instruction used in our prior research
      on the brain signature of the hypnotic state and in clinical care. The ability to enter and
      maintain the hypnotic state through such an induction mechanism in the fMRI environment has
      been previously demonstrated.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Basic Science
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: Double blind sham vs. real rTMS; data analysts blind to group assignment; subjects debriefed on their guess about sham vs. real - no better than chance
measure: The Change in Functional Connectivity (FC) Between the Left Dorsolateral Prefrontal Cortex (L-DLPFC) and the Dorsal Anterior Cingulate Cortex (dACC)
time frame: Baseline and at 15-20 min post-TMS (up to 30 min)
description: Functional MRI (fMRI) measures changes in oxygenated blood in the brain; at rest these levels fluctuate over time. These fluctuations can be similar between different brain regions. FC is the similarity in fluctuations of these fMRI signals and suggests how strongly two regions communicate with each other. We measured how inhibitory continuous theta-burst stimulation (cTBS) over L-DLPFC changes FC between L-DLPFC and dACC. This was done by estimating z-transformed correlation coefficients (CC) for each voxel (-1 to 1) between the L-DLPFC and dACC pre and post cTBS intervention. Negative FC was assigned to voxels with a weight < 0, positive FC to voxels with weight> 0. Total FC includes positive and negative voxels. The change in FC is regarded as the change in the sum of these weighted voxels from pre to post cTBS for total, positive and negative FC, respectively. Greater sums of voxels correspond to more significant levels of coordinated activity (positive, negative, or total).
measure: The Change in the Neural Network Underlying Hypnotic Intensity
time frame: Baseline and 2 hours
description: Blood oxygen level dependent (BOLD) signal and interleaved TMS-BOLD analyses will be used to determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC on modulating the neural network that underlies hypnotic intensity.
measure: Change in Hypnotic Induction Profile Score
time frame: Baseline and Immediately post rTMS (up to 30 min)
description: The investigators used the Hypnotic Induction Profile (HIP) to determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC on enhancing hypnotizability.
HIP scores range from 0 to 10 (low to high hypnotizability).
measure: Change in The Hypnosis Intensity Scale
time frame: Baseline and immediately post rTMS (up to 2 hrs)
description: The investigators used the Hypnotic Intensity Scale (HIS) to determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC on enhancing hypnotic intensity.
HIS scores range from 0 to 10 (low to high hypnotic intensity).
measure: The Change in Functional Connectivity (FC) Within The Neural Network Underlying Conflict Regulation.
time frame: Baseline and at 15-20 min post-TMS (up to 30 min)
description: We examined the effect of active, inhibitory cTBS over L-DLPFC on functional connectivity (FC) in key nodes in the neural network underlying the conflict regulation system. FC between each voxel in the L-DLPFC and the entire dACC was established by estimating z-transformed correlation coefficients (CC) for each voxel (-1 to 1) pre and post cTBS intervention. This paradigm was also used for voxels in the Default Mode Network (DMN) (Schaefer, 2018; Yeo, 2011) to the entire right inferior frontal gyrus (rIFG). Negative FC was assigned to voxels with a weight < 0, positive FC to voxels with weight > 0. Total FC includes positive and negative voxels. The change in FC is regarded as the change in the sum of these weighted voxels from pre to post cTBS for total, positive and negative FC, respectively. Greater sums of voxels correspond to more significant levels of coordinated activity (positive, negative, or total).
measure: The Change in Stroop Performance
time frame: Baseline and at 15-20 min post-TMS (up to 30 min)
description: Stroop effect is measured by the response time of a participant during the stroop task. Increases in response time indicate increased stroop effect (SE) and vice versa.
measure: Stroop Task
time frame: Baseline and at 15-20 min post-TMS (up to 30 min)
description: Active, inhibitory cTBS effect over L-DLPFC on the neural network that underlies the hypnotic Stroop modulation effect was determined by first estimating the average of connectivity weights for all parcel pairs linking Ventral Attentional Network (VAN) to the DMN. Parcels are determined by extracting mean resting state BOLD time-series for each region of the Schaefer 100 parcellation. A correlation matrix between all parcels is created and FC weights for each pair are established by estimating z-transformed correlation coefficients (CC) (-1 to 1). Each parcel pair is then assigned to one of the 7 resting state networks defined by Yeo et al., (2011). Negative FC is defined for parcel pairs with a weight < 0, positive FC pairs with weight > 0 and total FC includes all pairs. FC is thus the average value between parcel pairs in the DMN and VAN pre/post TMS. Greater sums of weighted pairs correspond to more significant levels of coordinated activity (positive, negative, or total).
measure: Linear Relationship Between the Change in FC of the VAN to the DMN and the Change in Stroop Performance (Correlation Coefficient) With no Hypnosis Intervention.
time frame: Baseline and at 15-20 min post-TMS (up to 1 hr)
description: Spearman's correlation was used to determine the linear relationship between the response time taken to answer incongruent Stroop task blocks (a measure of Stroop performance) and the change the resting-state network FC between the VAN and the DMN when no hypnosis intervention was implemented.
measure: Linear Relationship Between the Change in FC of the VAN to the DMN and the Change in Stroop Performance (Correlation Coefficient) With Hypnosis Intervention.
time frame: Baseline and at 15-20 min post-TMS (up to 1 hr)
description: Spearman's correlation was used to determine the linear relationship between the response time taken to answer incongruent Stroop task blocks (a measure of Stroop performance) and the change the resting-state network FC between the VAN and the DMN when the hypnosis intervention was implemented.
measure: Linear Relationship Between the Change in FC of the VAN to the DMN and the Change in Stroop Interference (Correlation Coefficient) With no Hypnosis Intervention.
time frame: Baseline and at 15-20 min post-TMS (up to 1 hr)
description: Spearman's correlation was used to determine the linear relationship between the Stroop interference and the change the resting-state network FC between the VAN and the DMN when no hypnosis intervention was implemented.
In psychology, the Stroop effect is the delay in reaction time between congruent and incongruent stimuli.
measure: Linear Relationship Between the Change in FC of the VAN to the DMN and the Change in Stroop Interference (Correlation Coefficient) With Hypnosis Intervention.
time frame: Baseline and at 15-20 min post-TMS (up to 1 hr)
description: Spearman's correlation was used to determine the linear relationship between the Stroop interference and the change the resting-state network FC between the VAN and the DMN when the hypnosis intervention was implemented.
In psychology, the Stroop effect is the delay in reaction time between congruent and incongruent stimuli.
measure: Change in the Numeric Pain Rating Scale
time frame: Baseline and immediately post-rTMS (up to 30 minutes)
description: To determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC on modulating the neural network that underlies hypnotic analgesia (HA).
Numeric Pain Rating Scale scores range from 0 to 10 (low to high pain intensity).
measure: Change in Sense of Agency Rating Scale (SOARS)
time frame: Baseline and immediately post-rTMS (up to 30 min)
description: The investigators used the Sense of Agency Rating Scale (SOARS) to determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC on altering the subjective sense of agency during hypnotizability.
SOARS scores are calculated for Involuntariness and Effortlessness, each range from 0 to 35 (low to high).
measure: Metabolic Alterations in Fibromyalgia (FMS) Defined by Excitatory / Inhibitory Ratio
time frame: Baseline Scan (up to 15 min)
description: E/I ratio is defined as the logarithm of the concentration of Glx (excitatory neurotransmitter metabolite complex) /GABA+ (inhibitory neurotransmitter metabolite complex) relative to either water or creatine peak signal and it is a unitless measure ranging from -1 to 1. Logarithmic transformations are used to account for non-normal distributions of metabolite concentrations across participants and ratios > 0 are thought to be excitatory neurotransmitter dominant while ratios <0 are thought to be inhibition dominant.
measure: Alterations in Pain Perception in Fibromyalgia
time frame: Baseline visit (up to 30 min)
description: To characterize clinical pain measures, which are defined as thermal pain threshold and thermal pain tolerance. Thermal pain threshold is determined as the temperature of a thermode determined as painful (degrees Celsius) by a participant. Thermal pain tolerance extends this to the point at which discontinuation is necessary (degrees Celsius).
measure: Linear Regression of Thermal Pain Threshold to Logarithm of E/I Ratio as it Relates to Water in Fibromyalgia (Coefficient of Determination)
time frame: Baseline visit (up to 45 min)
description: Linear regression was used to evaluate the scalar relationship between E/I ratio as it relates to water and Thermal Pain Threshold with E/I as the independent variable and Thermal Pain Threshold as the dependent variable.
measure: Linear Regression of Thermal Pain Tolerance to Logarithm of E/I Ratio as it Relates to Water in Fibromyalgia (Coefficient of Determination)
time frame: Baseline visit (up to 45 min)
description: Linear regression was used to evaluate the scalar relationship between E/I ratio as it relates to water and Thermal Pain Tolerance with E/I as the independent variable and Thermal Pain Tolerance as the dependent variable.
measure: Linear Regression of Thermal Pain Threshold to Logarithm of E/I Ratio as it Relates to Creatine in Fibromyalgia (Coefficient of Determination)
time frame: Baseline visit (up to 45 min)
description: Linear regression was used to evaluate the scalar relationship between E/I ratio as it relates to creatine and Thermal Pain Threshold with E/I as the independent variable and Thermal Pain Threshold as the dependent variable.
measure: Linear Regression of Thermal Pain Tolerance to Logarithm of E/I Ratio as it Relates to Creatine in Fibromyalgia (Coefficient of Determination)
time frame: Baseline visit (up to 45 min)
description: Linear regression was used to evaluate the scalar relationship between E/I ratio as it relates to creatine and Thermal Pain Tolerance with E/I as the independent variable and Thermal Pain Tolerance as the dependent variable.
measure: Metabolic Changes in L-DLPFC Pre- and Post-rTMS
time frame: Baseline Scan and at 15-20 min post-TMS (up to 30 min)
description: To determine the relationship between the metabolic alterations pre and post-rTMS. Metabolic changes as measured by MEGA-PRESS spectroscopy were assessed by quantification of excitatory (Glx) and inhibitory (GABA+) neurotransmitter complexes. The E/I ratio is defined as the logarithm of the concentration of Glx/GABA+relative to either the reference water or creatine signal and it is a unitless measure ranging from -1 to 1. Logarithmic transformations are used to account for non-normal distributions of metabolite concentrations across participants and ratios > 0 are thought to be excitatory neurotransmitter dominant while ratios <0 are thought to be inhibition dominant.
arm group label: Active rTMS
arm group type: Experimental
description: The active group will receive repetitive Transcranial Magnetic Stimulation
arm group label: Sham rTMS
arm group type: Sham Comparator
description: The sham repetitive Transcranial Magnetic Stimulation group will have the stimulation blocked.
intervention type: Device
intervention name: MagPro TMS system (MagVenture, Denmark)
description: The investigators will perform two applications of 40s of continuous theta-burst stimulation (cTBS) form of rTMS at 80% resting motor threshold (previously determined), with a 15 minute intersession interval. The standardized treatment location for the left DLPFC will be determined by Localite Neuronavigation and targeted at the posterior middle frontal gyrus. The baseline structural scan obtained during the scan 1 will be utilized for this localization process. rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark). sham rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark).sham rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark).
arm group label: Active rTMS
arm group label: Sham rTMS
other name: rTMS will be delivered using the MagPro TMS system (MagVenture, Denmark).
intervention type: Behavioral
intervention name: Hypnosis
description: Hypnotizability will be measured using the Hypnotic Induction Profile before and after administration of real vs. sham rTMS. Hypnotizability will be measured using the Hypnotic Induction Profile before and after administration of real vs. sham rTMS. Hypnosis will be employed to influence Stroop performance (conflict detection) and for pain management. The hypnotic instructions for this will be pre-recorded and played during fMRI.
arm group label: Active rTMS
arm group label: Sham rTMS
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Nolan Williams, M.D.
role: Principal Investigator
affiliation: Stanford University
facility: 
country: United States
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PMID: 26049149
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PMID: 27469596
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PMID: 15994228
citation: Raz A, Shapiro T, Fan J, Posner MI. Hypnotic suggestion and the modulation of Stroop interference. Arch Gen Psychiatry. 2002 Dec;59(12):1155-61. doi: 10.1001/archpsyc.59.12.1155.
PMID: 12470132
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PMID: 10467921
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PMID: 9252330
citation: Burgmer M, Pogatzki-Zahn E, Gaubitz M, Stuber C, Wessoleck E, Heuft G, Pfleiderer B. Fibromyalgia unique temporal brain activation during experimental pain: a controlled fMRI Study. J Neural Transm (Vienna). 2010 Jan;117(1):123-31. doi: 10.1007/s00702-009-0339-1. Epub 2009 Nov 25.
PMID: 19937376
citation: Short BE, Borckardt JJ, Anderson BS, Frohman H, Beam W, Reeves ST, George MS. Ten sessions of adjunctive left prefrontal rTMS significantly reduces fibromyalgia pain: a randomized, controlled pilot study. Pain. 2011 Nov;152(11):2477-2484. doi: 10.1016/j.pain.2011.05.033. Epub 2011 Jul 20.
PMID: 21764215
citation: Wik G, Fischer H, Bragee B, Finer B, Fredrikson M. Functional anatomy of hypnotic analgesia: a PET study of patients with fibromyalgia. Eur J Pain. 1999 Mar;3(1):7-12. doi: 10.1053/eujp.1998.0093.
PMID: 10700332
citation: Derbyshire SW, Whalley MG, Oakley DA. Fibromyalgia pain and its modulation by hypnotic and non-hypnotic suggestion: an fMRI analysis. Eur J Pain. 2009 May;13(5):542-50. doi: 10.1016/j.ejpain.2008.06.010. Epub 2008 Jul 23.
PMID: 18653363
citation: Orosz A, Jann K, Wirth M, Wiest R, Dierks T, Federspiel A. Theta burst TMS increases cerebral blood flow in the primary motor cortex during motor performance as assessed by arterial spin labeling (ASL). Neuroimage. 2012 Jul 2;61(3):599-605. doi: 10.1016/j.neuroimage.2012.03.084. Epub 2012 Apr 12.
PMID: 22613775
citation: Nettekoven C, Volz LJ, Kutscha M, Pool EM, Rehme AK, Eickhoff SB, Fink GR, Grefkes C. Dose-dependent effects of theta burst rTMS on cortical excitability and resting-state connectivity of the human motor system. J Neurosci. 2014 May 14;34(20):6849-59. doi: 10.1523/JNEUROSCI.4993-13.2014.
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PMID: 22835528
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PMID: 25505220
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PMID: 23026956
responsible party type: Principal Investigator
investigator affiliation: Stanford University
investigator full name: David Spiegel
investigator title: Willson Professor and Associate Chair of Psychiatry & Behavioral Sciences, Director of the Center on Stress and Health, and Medical Director of the Center for Integrative Medicine at Stanford University School of Medicine
mesh term: Fibromyalgia
mesh term: Myofascial Pain Syndromes
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: fMRI BOLD data were preprocessed using fMRIPrep 1.5.10 (Esteban, Markiewicz, et al. (2018); Esteban, Blair, et al. (2018); RRID:SCR_016216), which is based on Nipype 1.4.2 (Gorgolewski et al. (2011); Gorgolewski et al. (2018); RRID:SCR_002502) with MNI152NLin2009cAsym and anatomical output spaces. BOLD time series were bandpass filtered to include data in the window of 0.0025-0.025 Hz, which is on the low end of the spectrum. A more typical bandpass window is 0.01 - 0.1 Hz.
point of contact: 