FibromyalgiaNCT02969707
Use of Repetitive Transcranial Magnetic Stimulation to Augment Hypnotic Analgesia
A study testing MagPro TMS system (MagVenture, Denmark) and Hypnosis in people with Fibromyalgia, run by Stanford University at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Fibromyalgia
- What is being tested?
- MagPro TMS system (MagVenture, Denmark) and Hypnosis
- Type of treatment
- Medical device, Lifestyle or therapy programme
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 101 participants
- Where
- 1 siteUnited States
- Study dates
- 24 Apr 2017to 21 Dec 2019
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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)
Show all 11Show fewer
- 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
Who cannot join
- 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
Show all 11Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read the 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).
- During the course of the study and upon consultation with the manufacturer, sham setting intensity was lowered to reduce the risk adverse events (e.g., scalp damage).
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.
- Conditions
- Fibromyalgia
- Being tested
- MagPro TMS system (MagVenture, Denmark), Hypnosis
- Keywords
- repetitive Transcranial Magnetic Stimulation, functional MRI, Fibromyalgia, Hypnosis, Pain Assessment
- Medical subject headings
- Fibromyalgia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MagPro TMS system (MagVenture, Denmark)Device
Also called rTMS will be delivered using the 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).
HypnosisBehavioural
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.
| Study group | Role | What they receive |
|---|---|---|
| Active rTMS | Experimental | The active group will receive repetitive Transcranial Magnetic Stimulation Receives: Device: MagPro TMS system (MagVenture, Denmark); Behavioral: Hypnosis |
| Sham rTMS | Sham comparator | The sham repetitive Transcranial Magnetic Stimulation group will have the stimulation blocked. Receives: Device: MagPro TMS system (MagVenture, Denmark); Behavioral: Hypnosis |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: Baseline and at 15-20 min post-TMS (up to 30 min)
Secondary outcomes (19)
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.
Measured: Baseline and 2 hours
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).
Measured: 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).
Measured: 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).
Measured: 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.
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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).
Measured: 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.
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Baseline Scan and at 15-20 min post-TMS (up to 30 min)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Nov 2016 (estimated)
- Study start24 Apr 2017
- Primary completion21 Dec 2019
- Study completion21 Dec 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (16)Papers the sponsor has linked to this study.
- Other trials for FibromyalgiaStudies of the same condition, open and under way.
- More trials run by Stanford UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 101 participants (actual)
Sponsor and investigators
- Lead sponsor
- Stanford University
- Sponsor type
- University, hospital or other
- Collaborators
- National Institutes of Health (NIH), National Center for Complementary and Integrative Health (NCCIH)
- Responsible party
- Principal investigator, David Spiegel, Stanford University
- Investigators
- Nolan Williams, M.D., Principal investigator, Stanford University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02969707
- Sponsor's protocol ID
- 38138
- Other IDs
- 1R33AT009305-01
- Status last verified
- Nov 2024
- First submitted
- 16 Nov 2016
- Last updated
- 20 Dec 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- Yes
- Individual data sharing
- No
Publications
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.
PubMed 26049149Jiang 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.
PubMed 27469596Raz 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.
PubMed 15994228Raz 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.
PubMed 12470132Rainville 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.
PubMed 10467921Rainville 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.
PubMed 9252330Burgmer 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.
PubMed 19937376Short 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.
PubMed 21764215Wik 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.
PubMed 10700332Derbyshire 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.
PubMed 18653363Orosz 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.
PubMed 22613775Nettekoven 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.
PubMed 24828639Poreisz 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.
PubMed 18185107Goldsworthy 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.
PubMed 22835528Goldsworthy 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.
PubMed 25505220
Study at a glance
From the registry record, last updated by the sponsor on 20 Dec 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Use of Repetitive Transcranial Magnetic Stimulation to Augment Hypnotic Analgesia
- ClinicalTrials.gov ID
- NCT02969707
- Acronym / sponsor ID
- 38138
- Conditions
- Fibromyalgia
- Keywords
- repetitive Transcranial Magnetic Stimulation, functional MRI, Fibromyalgia, Hypnosis, Pain Assessment
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 101 participants (actual)
- Lead sponsor
- Stanford UniversityUniversity, hospital or other
- Collaborators
- National Institutes of Health (NIH), National Center for Complementary and Integrative Health (NCCIH)
- Study start
- 24 Apr 2017 (actual)
- Primary completion
- 21 Dec 2019 (actual)
- Study completion
- 21 Dec 2019 (actual)
- First posted
- 21 Nov 2016 (estimated)
- Results
- Posted 30 Aug 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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).
- During the course of the study and upon consultation with the manufacturer, sham setting intensity was lowered to reduce the risk adverse events (e.g., scalp damage).
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.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Active rTMS | Experimental | Device: MagPro TMS system (MagVenture, Denmark), Behavioral: HypnosisThe active group will receive repetitive Transcranial Magnetic Stimulation |
| Sham rTMS | Sham comparator | Device: MagPro TMS system (MagVenture, Denmark), Behavioral: HypnosisThe sham repetitive Transcranial Magnetic Stimulation group will have the stimulation blocked. |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- 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
Key exclusion criteria (11 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MagPro TMS system (MagVenture, Denmark)Also: rTMS will be delivered using the 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). | Device | Active rTMS, Sham rTMS |
| HypnosisHypnotizability 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. | Behavioural | Active rTMS, Sham rTMS |
Primary outcome
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).
19 secondary outcomes
The Change in the Neural Network Underlying Hypnotic Intensity
Time frame: Baseline and 2 hours
Change in Hypnotic Induction Profile Score
Time frame: Baseline and Immediately post rTMS (up to 30 min)
Change in The Hypnosis Intensity Scale
Time frame: Baseline and immediately post rTMS (up to 2 hrs)
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)
The Change in Stroop Performance
Time frame: Baseline and at 15-20 min post-TMS (up to 30 min)
Stroop Task
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Baseline and at 15-20 min post-TMS (up to 1 hr)
Change in the Numeric Pain Rating Scale
Time frame: Baseline and immediately post-rTMS (up to 30 minutes)
Change in Sense of Agency Rating Scale (SOARS)
Time frame: Baseline and immediately post-rTMS (up to 30 min)
Metabolic Alterations in Fibromyalgia (FMS) Defined by Excitatory / Inhibitory Ratio
Time frame: Baseline Scan (up to 15 min)
Alterations in Pain Perception in Fibromyalgia
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: Baseline visit (up to 45 min)
Metabolic Changes in L-DLPFC Pre- and Post-rTMS
Time frame: Baseline Scan and at 15-20 min post-TMS (up to 30 min)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Dec 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 26049149Cojan 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.
- Background: PubMed 27469596Jiang 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.
- Background: PubMed 15994228Raz 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.
- Background: PubMed 12470132Raz 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.
- Background: PubMed 10467921Rainville 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.
- Background: PubMed 9252330Rainville 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.
- Background: PubMed 19937376Burgmer 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.
- Background: PubMed 21764215Short 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.
- Background: PubMed 10700332Wik 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.
- Background: PubMed 18653363Derbyshire 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.
- Background: PubMed 22613775Orosz 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.
- Background: PubMed 24828639Nettekoven 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.
- Individual participant dataSharing planned: No
Related trials for Fibromyalgia
Active, not recruiting
Objective Measurement of Pain Regulation in Individuals Who Have Received Internet-delivered Exposure-based Cognitive Behavior Therapy
Fibromyalgia
Enrolling by invitationPhase 3
Open-Label Safety Study of AXS-14 in Subjects With Fibromyalgia
Fibromyalgia
Recruiting
Exercise Interventions and Dietary Advice in Fibromyalgia and IBS
Fibromyalgia, Irritable Bowel Syndrome
Recruiting
Whole-body Cryotherapy in Those With Chronic Fatigue: A Feasibility Study
ME/CFS, Fibromyalgia (FM)
Recruiting
Auricular Acupuncture for Autonomic Balance and Pain in Fibromyalgia
Fibromyalgia Syndrome
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Nolan Williams, M.D. principal investigator
Stanford University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing MagPro TMS system (MagVenture, Denmark) and Hypnosis in people with Fibromyalgia, run by Stanford University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 20 Dec 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 30 Aug 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome 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)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02969707, which also lists 16 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Dec 2024.