Use of Repetitive Transcranial Magnetic Stimulation to Augment Hypnotic Analgesia

NCT02969707 | Completed Results DMC FDA Device

• 2 other identifiers: 381381R33AT009305-01
• Study Type: interventional
• Target: 101
• Locations: 1 country
• Sites: 1

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.

Conditions

Fibromyalgia

Keywords

repetitive Transcranial Magnetic Stimulation; functional MRI; Fibromyalgia; Hypnosis; Pain Assessment

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (19)

• The Change in the Neural Network Underlying Hypnotic Intensity

  Baseline and 2 hours

• Change in Hypnotic Induction Profile Score

  Baseline and Immediately post rTMS (up to 30 min)

• Change in The Hypnosis Intensity Scale

  Baseline and immediately post rTMS (up to 2 hrs)

• The Change in Functional Connectivity (FC) Within The Neural Network Underlying Conflict Regulation.

  Baseline and at 15-20 min post-TMS (up to 30 min)

• The Change in Stroop Performance

  Baseline and at 15-20 min post-TMS (up to 30 min)

Study Arms (2)

Active rTMS

EXPERIMENTAL

The active group will receive repetitive Transcranial Magnetic Stimulation

Device: MagPro TMS system (MagVenture, Denmark); Behavioral: Hypnosis

Sham rTMS

SHAM COMPARATOR

The sham repetitive Transcranial Magnetic Stimulation group will have the stimulation blocked.

Device: MagPro TMS system (MagVenture, Denmark); Behavioral: Hypnosis

Interventions

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).

Also known as: rTMS will be delivered using the MagPro TMS system (MagVenture, Denmark).

Active rTMS; Sham rTMS

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.

Active rTMS; Sham rTMS

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)
• Color blindness
• Any significant psychiatric disorder as identified on the Mini International Neuropsychiatric Interview
• Previous exposure to rTMS

Sponsors & Collaborators

• Stanford University: lead
• National Institutes of Health (NIH): collaborator
• National Center for Complementary and Integrative Health (NCCIH): collaborator

Study Sites (1)

Stanford University

Palo Alto, California, 94305, United States

Location

Related Publications (16)

• 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.

  PMID: 26049149 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.

  PMID: 27469596 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.

  PMID: 15994228 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.

  PMID: 12470132 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.

  PMID: 10467921 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.

  PMID: 9252330 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.

  PMID: 19937376 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.

  PMID: 21764215 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.

  PMID: 10700332 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.

  PMID: 18653363 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.

  PMID: 22613775 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.

  PMID: 24828639 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.

  PMID: 18185107 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.

  PMID: 22835528 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.

  PMID: 25505220 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.

  PMID: 23026956 BACKGROUND

MeSH Terms

Conditions

Fibromyalgia

Interventions

Hypnosis

Condition Hierarchy (Ancestors)

Muscular Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Neuromuscular Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Mind-Body Therapies; Complementary Therapies; Therapeutics; Psychotherapy; Behavioral Disciplines and Activities

Limitations and Caveats

fMRI BOLD data were preprocessed using fMRIPrep 1.5.10 (Esteban, Markiewicz, et al. (2018); Esteban, Blair, et al. (2018); RRID:SCR\_016216), which is based on Nipype 1.4.2 (Gorgolewski et al. (2011); Gorgolewski et al. (2018); RRID:SCR\_002502) with MNI152NLin2009cAsym and anatomical output spaces. BOLD time series were bandpass filtered to include data in the window of 0.0025-0.025 Hz, which is on the low end of the spectrum. A more typical bandpass window is 0.01 - 0.1 Hz.

Results Point of Contact

• Title: Dr. David Spiegel
• Organization: Stanford University

dspiegel@stanford.edu

650-723-6421

Study Officials

• Nolan Williams, M.D.

  Stanford University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Willson Professor and Associate Chair of Psychiatry & Behavioral Sciences, Director of the Center on Stress and Health, and Medical Director of the Center for Integrative Medicine at Stanford University School of Medicine

Study Record Dates

• First Submitted: November 16, 2016
• First Posted: November 21, 2016
• Study Start: April 24, 2017
• Primary Completion: December 21, 2019
• Study Completion: December 21, 2019
• Last Updated: December 20, 2024
• Results First Posted: August 30, 2021

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)