Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Use of Repetitive Transcranial Magnetic Stimulation to Augment Hypnotic Analgesia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02969707
Recruitment Status : Completed
First Posted : November 21, 2016
Results First Posted : August 30, 2021
Last Update Posted : August 30, 2021
Sponsor:
Collaborators:
National Institutes of Health (NIH)
National Center for Complementary and Integrative Health (NCCIH)
Information provided by (Responsible Party):
David Spiegel, Stanford University

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Fibromyalgia Device: MagPro TMS system (MagVenture, Denmark) Behavioral: Hypnosis Not Applicable

Detailed Description:

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 101 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
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
Primary Purpose: Basic Science
Official Title: Use of Repetitive Transcranial Magnetic Stimulation to Augment Hypnotic Analgesia
Actual Study Start Date : April 24, 2017
Actual Primary Completion Date : December 21, 2019
Actual Study Completion Date : December 21, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Active rTMS
The active group will receive repetitive Transcranial Magnetic Stimulation
Device: MagPro TMS system (MagVenture, Denmark)
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).
Other Name: rTMS will be delivered using the MagPro TMS system (MagVenture, Denmark).

Behavioral: Hypnosis
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.

Sham Comparator: Sham rTMS
The sham repetitive Transcranial Magnetic Stimulation group will have the stimulation blocked.
Device: MagPro TMS system (MagVenture, Denmark)
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).
Other Name: rTMS will be delivered using the MagPro TMS system (MagVenture, Denmark).

Behavioral: Hypnosis
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.




Primary Outcome Measures :
  1. 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) ]
    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).


Secondary Outcome Measures :
  1. The Change in the Neural Network Underlying Hypnotic Intensity [ Time Frame: Baseline and 2 hours ]
    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.

  2. Change in Hypnotic Induction Profile Score [ Time Frame: Baseline and Immediately post rTMS (up to 30 min) ]

    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).


  3. Change in The Hypnosis Intensity Scale [ Time Frame: Baseline and immediately post rTMS (up to 2 hrs) ]

    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).


  4. 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) ]
    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).

  5. The Change in Stroop Performance [ Time Frame: Baseline and at 15-20 min post-TMS (up to 30 min) ]
    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.

  6. Stroop Task [ Time Frame: Baseline and at 15-20 min post-TMS (up to 30 min) ]
    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).

  7. 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) ]
    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.

  8. 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) ]
    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.

  9. 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) ]

    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.


  10. 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) ]

    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.


  11. Change in the Numeric Pain Rating Scale [ Time Frame: Baseline and immediately post-rTMS (up to 30 minutes) ]

    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).


  12. Change in Sense of Agency Rating Scale (SOARS) [ Time Frame: Baseline and immediately post-rTMS (up to 30 min) ]

    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).


  13. Metabolic Alterations in Fibromyalgia (FMS) Defined by Excitatory / Inhibitory Ratio [ Time Frame: Baseline Scan (up to 15 min) ]
    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.

  14. Alterations in Pain Perception in Fibromyalgia [ Time Frame: Baseline visit (up to 30 min) ]
    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).

  15. 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) ]
    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.

  16. 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) ]
    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.

  17. 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) ]
    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.

  18. 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) ]
    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.

  19. Metabolic Changes in L-DLPFC Pre- and Post-rTMS [ Time Frame: Baseline Scan and at 15-20 min post-TMS (up to 30 min) ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Fulfill 2010 Fibromyalgia Diagnostic Criteria
  • Age 18 - 70
  • Right-handed
  • Agree to and able to have two fMRI scans as well as rTMS sessions
  • Willingness to suspend use of analgesic drugs or cough suppressants for 24 hours prior to the scans
  • Willingness to suspend us of antidepressant drugs for 2 weeks prior to the scans (6 weeks for fluoxetine)
  • Proficiency in English sufficient to complete questionnaires/follow instructions during fMRI assessments
  • US Citizen or resident able to receive payment legally
  • Low-Moderate Hypnotizability in the Hypnotic Induction Profile (score of 0-8)
  • Normal color vision
  • Women of childbearing potential must agree to use adequate contraception prior to study entry and continue this for the duration of the study

Exclusion Criteria:

  • A medical condition that would contraindicate the use of rTMS
  • Any condition that would contraindicate MRI (like ferromagnetic metal in the body)
  • Pregnancy or breast feeding
  • Any significant neurologic disease, including dementia, multi-infarct dementia, Parkinson's or Huntington's disease, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, history of significant head trauma
  • Current antidepressant use (must be washed out for two weeks prior to starting protocol)
  • Inability to stop taking medication contraindicated with treatment
  • High Hypnotizability in the Hypnotic Induction Profile (score >8)
  • Any significant psychiatric disorder as identified on the Mini Mental State Exam (Dysthymia not an exclusion criteria)
  • Color blindness
  • Any significant psychiatric disorder as identified on the Mini International Neuropsychiatric Interview
  • Previous exposure to rTMS

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02969707


Locations
Layout table for location information
United States, California
Stanford University
Palo Alto, California, United States, 94305
Sponsors and Collaborators
Stanford University
National Institutes of Health (NIH)
National Center for Complementary and Integrative Health (NCCIH)
Investigators
Layout table for investigator information
Principal Investigator: Nolan Williams, M.D. Stanford University
  Study Documents (Full-Text)

Documents provided by David Spiegel, Stanford University:
Informed Consent Form  [PDF] May 28, 2019

Publications:

Layout table for additonal information
Responsible Party: David Spiegel, 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, Stanford University
ClinicalTrials.gov Identifier: NCT02969707    
Other Study ID Numbers: 38138
1R33AT009305-01 ( U.S. NIH Grant/Contract )
First Posted: November 21, 2016    Key Record Dates
Results First Posted: August 30, 2021
Last Update Posted: August 30, 2021
Last Verified: August 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
Keywords provided by David Spiegel, Stanford University:
repetitive Transcranial Magnetic Stimulation
functional MRI
Fibromyalgia
Hypnosis
Pain Assessment
Additional relevant MeSH terms:
Layout table for MeSH terms
Fibromyalgia
Myofascial Pain Syndromes
Muscular Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Neuromuscular Diseases
Nervous System Diseases