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| ID | Type | Description | Link |
|---|---|---|---|
| 1R33AT009305-01 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institutes of Health (NIH) | NIH |
| National Center for Complementary and Integrative Health (NCCIH) | NIH |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Active rTMS | Experimental | The active group will receive repetitive Transcranial Magnetic Stimulation |
|
| Sham rTMS | Sham Comparator | The sham repetitive Transcranial Magnetic Stimulation group will have the stimulation blocked. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| MagPro TMS system (MagVenture, Denmark) | Device | 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). |
| Measure | Description | Time Frame |
|---|---|---|
| The Change in Functional Connectivity (FC) Between the Left Dorsolateral Prefrontal Cortex (L-DLPFC) and the Dorsal Anterior Cingulate Cortex (dACC) | 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). | Baseline and at 15-20 min post-TMS (up to 30 min) |
| Measure | Description | Time Frame |
|---|---|---|
| The Change in the Neural Network Underlying Hypnotic Intensity | 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. | Baseline and 2 hours |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Nolan Williams, M.D. | Stanford University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Stanford University | Palo Alto | California | 94305 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 26049149 | Background | Cojan Y, Piguet C, Vuilleumier P. What makes your brain suggestible? Hypnotizability is associated with differential brain activity during attention outside hypnosis. Neuroimage. 2015 Aug 15;117:367-74. doi: 10.1016/j.neuroimage.2015.05.076. Epub 2015 Jun 3. | |
| 27469596 | Background | Jiang H, White MP, Greicius MD, Waelde LC, Spiegel D. Brain Activity and Functional Connectivity Associated with Hypnosis. Cereb Cortex. 2017 Aug 1;27(8):4083-4093. doi: 10.1093/cercor/bhw220. |
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1,058 individuals completed the online interest survey; 157 completed in-person screening, and 101 were randomized to a study arm.
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| ID | Title | Description |
|---|---|---|
| FG000 | Active rTMS | 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 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). |
| FG001 | Sham rTMS | The sham repetitive Transcranial Magnetic Stimulation group had the stimulation blocked. 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). |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Active rTMS | 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). |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | The Change in Functional Connectivity (FC) Between the Left Dorsolateral Prefrontal Cortex (L-DLPFC) and the Dorsal Anterior Cingulate Cortex (dACC) | 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). | 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. | Posted | Mean | Standard Error | Z-transformed CC | Baseline and at 15-20 min post-TMS (up to 30 min) |
Up to 30 days
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Active rTMS | The active group will receive repetitive Transcranial Magnetic Stimulation 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). |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Medication Withdrawal During Washout | Metabolism and nutrition disorders | Non-systematic Assessment | One patient experienced medication withdrawal during the washout period for the study. |
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.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. David Spiegel | Stanford University | 650-723-6421 | dspiegel@stanford.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan: Original Protocol and Statistical Methods | Feb 14, 2019 | Dec 11, 2020 | Prot_SAP_001.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan: Revised Statistical Analysis Plan | Jan 4, 2024 | Apr 8, 2024 | SAP_003.pdf |
| ICF | No | No | Yes | Informed Consent Form | May 28, 2019 | Dec 11, 2020 | ICF_002.pdf |
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| ID | Term |
|---|---|
| D005356 | Fibromyalgia |
| ID | Term |
|---|---|
| D009135 | Muscular Diseases |
| D009140 | Musculoskeletal Diseases |
| D012216 | Rheumatic Diseases |
| D009468 | Neuromuscular Diseases |
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| ID | Term |
|---|---|
| D006990 | Hypnosis |
| ID | Term |
|---|---|
| D026441 | Mind-Body Therapies |
| D000529 | Complementary Therapies |
| D013812 | Therapeutics |
| D011613 | Psychotherapy |
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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
|
|
| Hypnosis | Behavioral | 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. |
|
| Change in Hypnotic Induction Profile Score |
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). |
| Baseline and Immediately post rTMS (up to 30 min) |
| Change in The Hypnosis Intensity Scale | 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). | Baseline and immediately post rTMS (up to 2 hrs) |
| The Change in Functional Connectivity (FC) Within The Neural Network Underlying Conflict Regulation. | 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). | Baseline and at 15-20 min post-TMS (up to 30 min) |
| The Change in Stroop Performance | 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. | Baseline and at 15-20 min post-TMS (up to 30 min) |
| Stroop Task | 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). | Baseline and at 15-20 min post-TMS (up to 30 min) |
| 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. | 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. | Baseline and at 15-20 min post-TMS (up to 1 hr) |
| Linear Relationship Between the Change in FC of the VAN to the DMN and the Change in Stroop Performance (Correlation Coefficient) With Hypnosis Intervention. | 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. | Baseline and at 15-20 min post-TMS (up to 1 hr) |
| 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. | 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. | Baseline and at 15-20 min post-TMS (up to 1 hr) |
| Linear Relationship Between the Change in FC of the VAN to the DMN and the Change in Stroop Interference (Correlation Coefficient) With Hypnosis Intervention. | 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. | Baseline and at 15-20 min post-TMS (up to 1 hr) |
| Change in the Numeric Pain Rating Scale | 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). | Baseline and immediately post-rTMS (up to 30 minutes) |
| Change in Sense of Agency Rating Scale (SOARS) | 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). | Baseline and immediately post-rTMS (up to 30 min) |
| Metabolic Alterations in Fibromyalgia (FMS) Defined by Excitatory / Inhibitory Ratio | 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. | Baseline Scan (up to 15 min) |
| Alterations in Pain Perception in Fibromyalgia | 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). | Baseline visit (up to 30 min) |
| Linear Regression of Thermal Pain Threshold to Logarithm of E/I Ratio as it Relates to Water in Fibromyalgia (Coefficient of Determination) | 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. | Baseline visit (up to 45 min) |
| Linear Regression of Thermal Pain Tolerance to Logarithm of E/I Ratio as it Relates to Water in Fibromyalgia (Coefficient of Determination) | 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. | Baseline visit (up to 45 min) |
| Linear Regression of Thermal Pain Threshold to Logarithm of E/I Ratio as it Relates to Creatine in Fibromyalgia (Coefficient of Determination) | 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. | Baseline visit (up to 45 min) |
| Linear Regression of Thermal Pain Tolerance to Logarithm of E/I Ratio as it Relates to Creatine in Fibromyalgia (Coefficient of Determination) | 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. | Baseline visit (up to 45 min) |
| Metabolic Changes in L-DLPFC Pre- and Post-rTMS | 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. | Baseline Scan and at 15-20 min post-TMS (up to 30 min) |
| 15994228 | Background | Raz A, Fan J, Posner MI. Hypnotic suggestion reduces conflict in the human brain. Proc Natl Acad Sci U S A. 2005 Jul 12;102(28):9978-83. doi: 10.1073/pnas.0503064102. Epub 2005 Jun 30. |
| 12470132 | Background | 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. |
| 10467921 | Background | Rainville P, Carrier B, Hofbauer RK, Bushnell CM, Duncan GH. Dissociation of sensory and affective dimensions of pain using hypnotic modulation. Pain. 1999 Aug;82(2):159-171. doi: 10.1016/S0304-3959(99)00048-2. |
| 9252330 | Background | Rainville P, Duncan GH, Price DD, Carrier B, Bushnell MC. Pain affect encoded in human anterior cingulate but not somatosensory cortex. Science. 1997 Aug 15;277(5328):968-71. doi: 10.1126/science.277.5328.968. |
| 19937376 | Background | 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. |
| 21764215 | Background | 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. |
| 10700332 | Background | 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. |
| 18653363 | Background | 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. |
| 22613775 | Background | 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. |
| 24828639 | Background | 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. |
| 18185107 | Background | Poreisz C, Csifcsak G, Antal A, Levold M, Hillers F, Paulus W. Theta burst stimulation of the motor cortex reduces laser-evoked pain perception. Neuroreport. 2008 Jan 22;19(2):193-6. doi: 10.1097/WNR.0b013e3282f45498. |
| 22835528 | Background | 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. |
| 25505220 | Background | 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. |
| 23026956 | Background | 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. |
| Positive toxicology screen |
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| Claustrophobia |
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| Non-compliance |
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| BG001 | Sham rTMS | The sham repetitive Transcranial Magnetic Stimulation group had the stimulation blocked. 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). |
| BG002 | Total | Total of all reporting groups |
| Participants |
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| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Secondary | The Change in the Neural Network Underlying Hypnotic Intensity | 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. | During the study, data were not collected using interleaved TMS-BOLD, as originally planned. | Posted | Baseline and 2 hours |
|
|
| Secondary | Change in Hypnotic Induction Profile Score | 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). | Participants with available data are included in the analysis | Posted | Mean | Standard Deviation | score on a scale | Baseline and Immediately post rTMS (up to 30 min) |
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|
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| Secondary | Change in The Hypnosis Intensity Scale | 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). | Participants who completed the protocol and completed HIS ratings are included in the analysis. | Posted | Mean | Standard Deviation | score on a scale | Baseline and immediately post rTMS (up to 2 hrs) |
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| Secondary | The Change in Functional Connectivity (FC) Within The Neural Network Underlying Conflict Regulation. | 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). | 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. | Posted | Mean | Standard Deviation | Z-transformed CC | Baseline and at 15-20 min post-TMS (up to 30 min) |
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| Secondary | The Change in Stroop Performance | 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. | 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. | Posted | Mean | Standard Deviation | Seconds | Baseline and at 15-20 min post-TMS (up to 30 min) |
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| Secondary | Stroop Task | 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). | Subjects who had pre and post TMS resting-state fMRI scans that passed QC and motion-based inclusion criteria | Posted | Mean | Standard Error | Z-transformed CC | Baseline and at 15-20 min post-TMS (up to 30 min) |
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| Secondary | 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. | 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. | 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. | Posted | Number | Correlation Coefficient | Baseline and at 15-20 min post-TMS (up to 1 hr) |
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| Secondary | Linear Relationship Between the Change in FC of the VAN to the DMN and the Change in Stroop Performance (Correlation Coefficient) With Hypnosis Intervention. | 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. | 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. | Posted | Number | Correlation Coefficient | Baseline and at 15-20 min post-TMS (up to 1 hr) |
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| Secondary | 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. | 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. | 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. | Posted | Number | Correlation Coefficient | Baseline and at 15-20 min post-TMS (up to 1 hr) |
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| Secondary | Linear Relationship Between the Change in FC of the VAN to the DMN and the Change in Stroop Interference (Correlation Coefficient) With Hypnosis Intervention. | 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. | 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. | Posted | Number | Correlation Coefficient | Baseline and at 15-20 min post-TMS (up to 1 hr) |
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| Secondary | Change in the Numeric Pain Rating Scale | 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). | Participants with available data are included in the analysis | Posted | Mean | Standard Error | mean change of scores on a scale | Baseline and immediately post-rTMS (up to 30 minutes) |
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| Secondary | Change in Sense of Agency Rating Scale (SOARS) | 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). | Participants who completed the protocol and completed all items of the SOARS are included in the analysis. | Posted | Mean | Standard Deviation | score on a scale | Baseline and immediately post-rTMS (up to 30 min) |
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| Secondary | Metabolic Alterations in Fibromyalgia (FMS) Defined by Excitatory / Inhibitory Ratio | 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. | Participants with baseline MegaPress scan data | Posted | Mean | Standard Deviation | Ratio | Baseline Scan (up to 15 min) |
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| Secondary | Alterations in Pain Perception in Fibromyalgia | 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). | Participants with baseline MegaPress scan data | Posted | Mean | Standard Deviation | Degrees Celsius | Baseline visit (up to 30 min) |
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| Secondary | Linear Regression of Thermal Pain Threshold to Logarithm of E/I Ratio as it Relates to Water in Fibromyalgia (Coefficient of Determination) | 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. | Participants with baseline MegaPress scan data | Posted | Number | Coefficient of determination | Baseline visit (up to 45 min) |
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| Secondary | Linear Regression of Thermal Pain Tolerance to Logarithm of E/I Ratio as it Relates to Water in Fibromyalgia (Coefficient of Determination) | 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. | Participants with baseline MegaPress scan data | Posted | Number | Coefficient of determination | Baseline visit (up to 45 min) |
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| Secondary | Linear Regression of Thermal Pain Threshold to Logarithm of E/I Ratio as it Relates to Creatine in Fibromyalgia (Coefficient of Determination) | 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. | Participants with baseline MegaPress scan data | Posted | Number | Coefficient of determination | Baseline visit (up to 45 min) |
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| Secondary | Linear Regression of Thermal Pain Tolerance to Logarithm of E/I Ratio as it Relates to Creatine in Fibromyalgia (Coefficient of Determination) | 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. | Participants with baseline MegaPress scan data | Posted | Number | Coefficient of determination | Baseline visit (up to 45 min) |
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| Secondary | Metabolic Changes in L-DLPFC Pre- and Post-rTMS | 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. | Participants with available data | Posted | Mean | Standard Deviation | Ratio | Baseline Scan and at 15-20 min post-TMS (up to 30 min) |
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| 0 |
| 49 |
| 0 |
| 49 |
| 1 |
| 49 |
| EG001 | Sham rTMS | The sham repetitive Transcranial Magnetic Stimulation group will have the stimulation blocked. 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). | 0 | 52 | 0 | 52 | 2 | 52 |
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| Headache / Scalp Irritation | Skin and subcutaneous tissue disorders | Non-systematic Assessment | One Participant experienced a headache and scalp irritation under the site of the TMS coil (a common side effect) during active treatment. |
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| Dizziness | Ear and labyrinth disorders | Non-systematic Assessment | Dizziness from MRI machine during scanning session |
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Not provided
Not provided
| D009422 |
| Nervous System Diseases |
| D004191 |
| Behavioral Disciplines and Activities |
| Cohen's R |
| 0.25 |
| 2-Sided |
Estimate of effect size |
| Other |
| Change in sum of positive z-transformed CC in L-DLPFC. |
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| Change in sum of negative z-transformed CC in L-DLPFC. |
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| Change in sum of all z-transformed CC in DMN. |
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| Change in sum of positive z-transformed CC in DMN. |
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| Change in sum of negative z-transformed CC in DMN. |
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| Mean difference in change in Stroop effect (s) with hypnosis (TMS - no TMS) condition. |
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| Superiority |
| t-test, 2 sided | 0.31 | Superiority |
| Title | Measurements |
|---|---|
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| Glx/Water |
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| Log E/I Cr |
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| Log E/I Water |
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| In people with FMS, the linear relationship between Thermal Pain Threshold and E/I ratio as it relates to water was assessed. | Regression, Linear | (R² = .081, F(1,49) = 4.315, β = .284, p = .043) | 0.043 | Other | 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. |
| In people with FMS, the linear relationship between Thermal Pain Tolerance and E/I ratio as it relates to creatine was assessed. | Regression, Linear | (R² = .103, F(1,49) = 5.632, β = .321, p = .022) | 0.022 | Other | 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. |
| In people with FMS, the linear relationship between Thermal Pain Threshold and E/I ratio as it relates to creatine was assessed. | Regression, Linear | (R² = .083, F(1,49) = 4.425, β = .288, p = .041) | 0.041 | Other | 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. |
| Log E/I Creatine Pre-TMS |
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| Log E/I Creatine Post-TMS |
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| ANCOVA |
| 0.720 |
| Superiority |