Use of Repetitive Transcranial Magnetic Stimulation to Augment Hypnotic Analgesia

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.

Study Overview

• Status: Completed
• Conditions: Fibromyalgia
• Intervention / Treatment: Device: MagPro TMS system (MagVenture, Denmark); Behavioral: Hypnosis

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.

• Study Type: Interventional
• Enrollment (Actual): 101
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • Palo Alto, California, United States, 94305
      • Stanford University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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 Names: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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)

Secondary Outcome Measures

Outcome Measure	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
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)

Collaborators and Investigators

• Sponsor: Stanford University
• Collaborators: National Institutes of Health (NIH); National Center for Complementary and Integrative Health (NCCIH)
• Investigators: Principal Investigator: Nolan Williams, M.D., Stanford University

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Hoeft F, Gabrieli JD, Whitfield-Gabrieli S, Haas BW, Bammer R, Menon V, Spiegel D. Functional brain basis of hypnotizability. Arch Gen Psychiatry. 2012 Oct;69(10):1064-72. doi: 10.1001/archgenpsychiatry.2011.2190. Erratum In: JAMA Psychiatry. 2013 Jan;70(1):97.

Study record dates

Study Major Dates

• Study Start (Actual): April 24, 2017
• Primary Completion (Actual): December 21, 2019
• Study Completion (Actual): December 21, 2019

Study Registration Dates

• First Submitted: November 16, 2016
• First Submitted That Met QC Criteria: November 18, 2016
• First Posted (Estimate): November 21, 2016

Study Record Updates

• Last Update Posted (Actual): August 30, 2021
• Last Update Submitted That Met QC Criteria: August 4, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: functional MRI; Hypnosis; Fibromyalgia; repetitive Transcranial Magnetic Stimulation; Pain Assessment
• Additional Relevant MeSH Terms: Nervous System Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Muscular Diseases; Neuromuscular Diseases; Fibromyalgia; Myofascial Pain Syndromes
• Other Study ID Numbers: 38138; 1R33AT009305-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes