Clinical trial NCT02969707: Use of Repetitive Transcranial Magnetic Stimulation to Augment Hypnotic Analgesia
Official title: Use of Repetitive Transcranial Magnetic Stimulation to Augment Hypnotic Analgesia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Fibromyalgia
Keywords: repetitive Transcranial Magnetic Stimulation
functional MRI
Fibromyalgia
Hypnosis
Pain Assessment
Lead sponsor: Stanford University
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: National Center for Complementary and Integrative Health (NCCIH)
First posted: 2016-11-21
Enrollment: 101
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

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.

Eligibility 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

Primary outcomes:
measure: The Change in Functional Connectivity (FC) Between the Left Dorsolateral Prefrontal Cortex (L-DLPFC) and the Dorsal Anterior Cingulate Cortex (dACC)
timeFrame: Baseline and at 15-20 min post-TMS (up to 30 min)
Secondary outcomes:
measure: The Change in the Neural Network Underlying Hypnotic Intensity
timeFrame: Baseline and 2 hours
measure: Change in Hypnotic Induction Profile Score
timeFrame: Baseline and Immediately post rTMS (up to 30 min)
measure: Change in The Hypnosis Intensity Scale
timeFrame: Baseline and immediately post rTMS (up to 2 hrs)
measure: The Change in Functional Connectivity (FC) Within The Neural Network Underlying Conflict Regulation.
timeFrame: Baseline and at 15-20 min post-TMS (up to 30 min)
measure: The Change in Stroop Performance
timeFrame: Baseline and at 15-20 min post-TMS (up to 30 min)
measure: Stroop Task
timeFrame: Baseline and at 15-20 min post-TMS (up to 30 min)
measure: 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.
timeFrame: Baseline and at 15-20 min post-TMS (up to 1 hr)
measure: Linear Relationship Between the Change in FC of the VAN to the DMN and the Change in Stroop Performance (Correlation Coefficient) With Hypnosis Intervention.
timeFrame: Baseline and at 15-20 min post-TMS (up to 1 hr)
measure: 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.
timeFrame: Baseline and at 15-20 min post-TMS (up to 1 hr)
measure: Linear Relationship Between the Change in FC of the VAN to the DMN and the Change in Stroop Interference (Correlation Coefficient) With Hypnosis Intervention.
timeFrame: Baseline and at 15-20 min post-TMS (up to 1 hr)
measure: Change in the Numeric Pain Rating Scale
timeFrame: Baseline and immediately post-rTMS (up to 30 minutes)
measure: Change in Sense of Agency Rating Scale (SOARS)
timeFrame: Baseline and immediately post-rTMS (up to 30 min)
measure: Metabolic Alterations in Fibromyalgia (FMS) Defined by Excitatory / Inhibitory Ratio
timeFrame: Baseline Scan (up to 15 min)
measure: Alterations in Pain Perception in Fibromyalgia
timeFrame: Baseline visit (up to 30 min)
measure: Linear Regression of Thermal Pain Threshold to Logarithm of E/I Ratio as it Relates to Water in Fibromyalgia (Coefficient of Determination)
timeFrame: Baseline visit (up to 45 min)
measure: Linear Regression of Thermal Pain Tolerance to Logarithm of E/I Ratio as it Relates to Water in Fibromyalgia (Coefficient of Determination)
timeFrame: Baseline visit (up to 45 min)
measure: Linear Regression of Thermal Pain Threshold to Logarithm of E/I Ratio as it Relates to Creatine in Fibromyalgia (Coefficient of Determination)
timeFrame: Baseline visit (up to 45 min)
measure: Linear Regression of Thermal Pain Tolerance to Logarithm of E/I Ratio as it Relates to Creatine in Fibromyalgia (Coefficient of Determination)
timeFrame: Baseline visit (up to 45 min)
measure: Metabolic Changes in L-DLPFC Pre- and Post-rTMS
timeFrame: Baseline Scan and at 15-20 min post-TMS (up to 30 min)
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Stanford University
state: California
Study officials:
affiliation: Stanford University
name: Nolan Williams, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.