Trial Outcomes & Findings for Use of Repetitive Transcranial Magnetic Stimulation to Augment Hypnotic Analgesia (NCT NCT02969707)

Results Overview

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).

Recruitment status

COMPLETED

Study phase

NA

Target enrollment

101 participants

Primary outcome timeframe

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

Results posted on

2024-12-20

Participant Flow

1,058 individuals completed the online interest survey; 157 completed in-person screening, and 101 were randomized to a study arm.

Participant milestones

Participant milestones
Measure	Active rTMS The active group received active repetitive Transcranial Magnetic Stimulation Active repetitive Transcranial Magnetic Stimulation: The investigators performed 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 dorsolateral prefrontal cortex (DLPFC) was determined by Localite Neuronavigation and targeted at the posterior middle frontal gyrus. The baseline structural scan obtained during the scan 1 was utilized for this localization process. rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).	Sham rTMS The sham repetitive Transcranial Magnetic Stimulation group had the stimulation blocked. Sham repetitive Transcranial Magnetic Stimulation: This was identical to active rTMS except the stimulation was blocked. Both active and sham repetitive Transcranial Magnetic Stimulation received simulation from a specially designed coil which is capable of delivering either active rTMS or sham rTMS in a manner, which is randomized by the system itself and therefore blinded to the treater. Sham rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).
Overall Study STARTED	49	52
Overall Study Received Intervention	40	40
Overall Study Completed Pain Evaluation Study Day	41	44
Overall Study Completed Mechanistic Evaluation Study Day	40	40
Overall Study COMPLETED	40	40
Overall Study NOT COMPLETED	9	12

Reasons for withdrawal

Reasons for withdrawal
Measure	Active rTMS The active group received active repetitive Transcranial Magnetic Stimulation Active repetitive Transcranial Magnetic Stimulation: The investigators performed 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 dorsolateral prefrontal cortex (DLPFC) was determined by Localite Neuronavigation and targeted at the posterior middle frontal gyrus. The baseline structural scan obtained during the scan 1 was utilized for this localization process. rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).	Sham rTMS The sham repetitive Transcranial Magnetic Stimulation group had the stimulation blocked. Sham repetitive Transcranial Magnetic Stimulation: This was identical to active rTMS except the stimulation was blocked. Both active and sham repetitive Transcranial Magnetic Stimulation received simulation from a specially designed coil which is capable of delivering either active rTMS or sham rTMS in a manner, which is randomized by the system itself and therefore blinded to the treater. Sham rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).
Overall Study Withdrawal by Subject	6	5
Overall Study Severe anxiety	0	1
Overall Study Positive toxicology screen	0	2
Overall Study Claustrophobia	2	2
Overall Study Non-compliance	1	2

Baseline Characteristics

Use of Repetitive Transcranial Magnetic Stimulation to Augment Hypnotic Analgesia

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Active rTMS n=49 Participants The active group received active repetitive Transcranial Magnetic Stimulation Active repetitive Transcranial Magnetic Stimulation: The investigators performed 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 was determined by Localite Neuronavigation and targeted at the posterior middle frontal gyrus. The baseline structural scan obtained during the scan 1 was utilized for this localization process. rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).	Sham rTMS n=52 Participants The sham repetitive Transcranial Magnetic Stimulation group had the stimulation blocked. Sham repetitive Transcranial Magnetic Stimulation: This was identical to active rTMS except the stimulation was blocked. Both active and sham repetitive Transcranial Magnetic Stimulation received simulation from a specially designed coil which is capable of delivering either active rTMS or sham rTMS in a manner, which is randomized by the system itself and therefore blinded to the treater. Sham rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).	Total n=101 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	47 Participants n=5 Participants	50 Participants n=7 Participants	97 Participants n=5 Participants
Age, Categorical >=65 years	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Age, Continuous	48.9 years STANDARD_DEVIATION 12.8 • n=5 Participants	50 years STANDARD_DEVIATION 11.6 • n=7 Participants	49.47 years STANDARD_DEVIATION 12.15 • n=5 Participants
Sex: Female, Male Female	48 Participants n=5 Participants	48 Participants n=7 Participants	96 Participants n=5 Participants
Sex: Female, Male Male	1 Participants n=5 Participants	4 Participants n=7 Participants	5 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Asian	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	35 Participants n=5 Participants	40 Participants n=7 Participants	75 Participants n=5 Participants
Race (NIH/OMB) More than one race	5 Participants n=5 Participants	1 Participants n=7 Participants	6 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	5 Participants n=5 Participants	9 Participants n=7 Participants	14 Participants n=5 Participants
Region of Enrollment United States	49 participants n=5 Participants	52 participants n=7 Participants	101 participants n=5 Participants

PRIMARY outcome

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

Population: Participants with resting-state scans for both pre and post-TMS conditions that passed QC and motion-based scan inclusion criteria; outlier data were excluded.

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).

Outcome measures

Outcome measures
Measure	Active rTMS n=26 Participants The active group received active repetitive Transcranial Magnetic Stimulation Active repetitive Transcranial Magnetic Stimulation: The investigators performed 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 was determined by Localite Neuronavigation and targeted at the posterior middle frontal gyrus. The baseline structural scan obtained during the scan 1 was utilized for this localization process. rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).utilized for this localization process. rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark).	Sham rTMS n=30 Participants The sham repetitive Transcranial Magnetic Stimulation group had the stimulation blocked. Sham repetitive Transcranial Magnetic Stimulation: This was identical to active rTMS except the stimulation was blocked. Both active and sham repetitive Transcranial Magnetic Stimulation received simulation from a specially designed coil which is capable of delivering either active rTMS or sham rTMS in a manner, which is randomized by the system itself and therefore blinded to the treater. Sham rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).
The Change in Functional Connectivity (FC) Between the Left Dorsolateral Prefrontal Cortex (L-DLPFC) and the Dorsal Anterior Cingulate Cortex (dACC) Change in sum of positive z-transformed CC.	61.98 Z-transformed CC Standard Error 21.63	4.16 Z-transformed CC Standard Error 16.43
The Change in Functional Connectivity (FC) Between the Left Dorsolateral Prefrontal Cortex (L-DLPFC) and the Dorsal Anterior Cingulate Cortex (dACC) Change in sum of negative z-transformed CC.	-21.41 Z-transformed CC Standard Error 16.8	-13.22 Z-transformed CC Standard Error 16.8
The Change in Functional Connectivity (FC) Between the Left Dorsolateral Prefrontal Cortex (L-DLPFC) and the Dorsal Anterior Cingulate Cortex (dACC) Change in sum of all z-transformed CC.	40.56 Z-transformed CC Standard Error 32.34	-9.06 Z-transformed CC Standard Error 28.25

SECONDARY outcome

Timeframe: Baseline and 2 hours

Population: During the study, data were not collected using interleaved TMS-BOLD, as originally planned.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and Immediately post rTMS (up to 30 min)

Population: Participants with available data are included in the analysis

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).

Outcome measures

Outcome measures
Measure	Active rTMS n=40 Participants The active group received active repetitive Transcranial Magnetic Stimulation Active repetitive Transcranial Magnetic Stimulation: The investigators performed 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 was determined by Localite Neuronavigation and targeted at the posterior middle frontal gyrus. The baseline structural scan obtained during the scan 1 was utilized for this localization process. rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).utilized for this localization process. rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark).	Sham rTMS n=40 Participants The sham repetitive Transcranial Magnetic Stimulation group had the stimulation blocked. Sham repetitive Transcranial Magnetic Stimulation: This was identical to active rTMS except the stimulation was blocked. Both active and sham repetitive Transcranial Magnetic Stimulation received simulation from a specially designed coil which is capable of delivering either active rTMS or sham rTMS in a manner, which is randomized by the system itself and therefore blinded to the treater. Sham rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).
Change in Hypnotic Induction Profile Score	.63 score on a scale Standard Deviation 1.18	.31 score on a scale Standard Deviation 1.67

SECONDARY outcome

Timeframe: Baseline and immediately post rTMS (up to 2 hrs)

Population: Participants who completed the protocol and completed HIS ratings are included in the analysis.

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).

Outcome measures

Outcome measures
Measure	Active rTMS n=40 Participants The active group received active repetitive Transcranial Magnetic Stimulation Active repetitive Transcranial Magnetic Stimulation: The investigators performed 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 was determined by Localite Neuronavigation and targeted at the posterior middle frontal gyrus. The baseline structural scan obtained during the scan 1 was utilized for this localization process. rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).utilized for this localization process. rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark).	Sham rTMS n=39 Participants The sham repetitive Transcranial Magnetic Stimulation group had the stimulation blocked. Sham repetitive Transcranial Magnetic Stimulation: This was identical to active rTMS except the stimulation was blocked. Both active and sham repetitive Transcranial Magnetic Stimulation received simulation from a specially designed coil which is capable of delivering either active rTMS or sham rTMS in a manner, which is randomized by the system itself and therefore blinded to the treater. Sham rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).
Change in The Hypnosis Intensity Scale	.475 score on a scale Standard Deviation 2.242	-.128 score on a scale Standard Deviation 1.490

SECONDARY outcome

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

Population: Population consisted of patients with fibromyalgia who underwent either active or sham cTBS either in combination with hypnosis or without it. Participants were excluded from the original sample for 1) fMRI imaging problems, 2) missing data. For the analyses below additional outliers were excluded on a test by test basis.

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).

Outcome measures

Outcome measures
Measure	Active rTMS n=25 Participants The active group received active repetitive Transcranial Magnetic Stimulation Active repetitive Transcranial Magnetic Stimulation: The investigators performed 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 was determined by Localite Neuronavigation and targeted at the posterior middle frontal gyrus. The baseline structural scan obtained during the scan 1 was utilized for this localization process. rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).utilized for this localization process. rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark).	Sham rTMS n=24 Participants The sham repetitive Transcranial Magnetic Stimulation group had the stimulation blocked. Sham repetitive Transcranial Magnetic Stimulation: This was identical to active rTMS except the stimulation was blocked. Both active and sham repetitive Transcranial Magnetic Stimulation received simulation from a specially designed coil which is capable of delivering either active rTMS or sham rTMS in a manner, which is randomized by the system itself and therefore blinded to the treater. Sham rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).
The Change in Functional Connectivity (FC) Within The Neural Network Underlying Conflict Regulation. Change in sum of all z-transformed CC in L-DLPFC.	0.01 Z-transformed CC Standard Deviation 0.14	-0.003 Z-transformed CC Standard Deviation 0.13
The Change in Functional Connectivity (FC) Within The Neural Network Underlying Conflict Regulation. Change in sum of positive z-transformed CC in L-DLPFC.	33.76 Z-transformed CC Standard Deviation 136.5	6.39 Z-transformed CC Standard Deviation 99.82
The Change in Functional Connectivity (FC) Within The Neural Network Underlying Conflict Regulation. Change in sum of negative z-transformed CC in L-DLPFC.	-20.36 Z-transformed CC Standard Deviation 88.88	-10.11 Z-transformed CC Standard Deviation 96.55
The Change in Functional Connectivity (FC) Within The Neural Network Underlying Conflict Regulation. Change in sum of all z-transformed CC in DMN.	0.004 Z-transformed CC Standard Deviation 0.05	-0.01 Z-transformed CC Standard Deviation 0.05
The Change in Functional Connectivity (FC) Within The Neural Network Underlying Conflict Regulation. Change in sum of positive z-transformed CC in DMN.	-31.20 Z-transformed CC Standard Deviation 137.73	21.12 Z-transformed CC Standard Deviation 153.54
The Change in Functional Connectivity (FC) Within The Neural Network Underlying Conflict Regulation. Change in sum of negative z-transformed CC in DMN.	51.35 Z-transformed CC Standard Deviation 243.68	-67.65 Z-transformed CC Standard Deviation 219.05

SECONDARY outcome

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

Population: Population consisted of patients with fibromyalgia who underwent either active or sham cTBS either in combination with hypnosis or without it. Participants were excluded from the original sample for 1) poor Stroop task performance, 2) fMRI imaging problems, 3) missing data. For the analyses below additional outliers were excluded on a test by test basis.

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.

Outcome measures

Outcome measures
Measure	Active rTMS n=23 Participants The active group received active repetitive Transcranial Magnetic Stimulation Active repetitive Transcranial Magnetic Stimulation: The investigators performed 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 was determined by Localite Neuronavigation and targeted at the posterior middle frontal gyrus. The baseline structural scan obtained during the scan 1 was utilized for this localization process. rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).utilized for this localization process. rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark).	Sham rTMS n=24 Participants The sham repetitive Transcranial Magnetic Stimulation group had the stimulation blocked. Sham repetitive Transcranial Magnetic Stimulation: This was identical to active rTMS except the stimulation was blocked. Both active and sham repetitive Transcranial Magnetic Stimulation received simulation from a specially designed coil which is capable of delivering either active rTMS or sham rTMS in a manner, which is randomized by the system itself and therefore blinded to the treater. Sham rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).
The Change in Stroop Performance Mean difference in change in Stroop effect (s) without hypnosis (TMS - no TMS) condition.	0.01 Seconds Standard Deviation 0.1	-0.02 Seconds Standard Deviation 0.082
The Change in Stroop Performance Mean difference in change in Stroop effect (s) with hypnosis (TMS - no TMS) condition.	-0.04 Seconds Standard Deviation 0.12	-0.009 Seconds Standard Deviation .10

SECONDARY outcome

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

Population: Subjects who had pre and post TMS resting-state fMRI scans that passed QC and motion-based inclusion criteria

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).

Outcome measures

Outcome measures
Measure	Active rTMS n=27 Participants The active group received active repetitive Transcranial Magnetic Stimulation Active repetitive Transcranial Magnetic Stimulation: The investigators performed 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 was determined by Localite Neuronavigation and targeted at the posterior middle frontal gyrus. The baseline structural scan obtained during the scan 1 was utilized for this localization process. rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).utilized for this localization process. rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark).	Sham rTMS n=30 Participants The sham repetitive Transcranial Magnetic Stimulation group had the stimulation blocked. Sham repetitive Transcranial Magnetic Stimulation: This was identical to active rTMS except the stimulation was blocked. Both active and sham repetitive Transcranial Magnetic Stimulation received simulation from a specially designed coil which is capable of delivering either active rTMS or sham rTMS in a manner, which is randomized by the system itself and therefore blinded to the treater. Sham rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).
Stroop Task	-0.026 Z-transformed CC Standard Error 0.0265	0.155 Z-transformed CC Standard Error 0.0297

SECONDARY outcome

Timeframe: Baseline and at 15-20 min post-TMS (up to 1 hr)

Population: Population consisted of patients with fibromyalgia who underwent either active or sham cTBS either in combination with hypnosis or without it. Participants were excluded from the original sample for 1) poor Stroop task performance, 2) fMRI imaging problems, 3) missing data. Subjects who had pre and post TMS resting-state fMRI scans that passed QC and motion-based inclusion criteria were included.

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.

Outcome measures

Outcome measures
Measure	Active rTMS n=27 Participants The active group received active repetitive Transcranial Magnetic Stimulation Active repetitive Transcranial Magnetic Stimulation: The investigators performed 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 was determined by Localite Neuronavigation and targeted at the posterior middle frontal gyrus. The baseline structural scan obtained during the scan 1 was utilized for this localization process. rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).utilized for this localization process. rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark).	Sham rTMS n=30 Participants The sham repetitive Transcranial Magnetic Stimulation group had the stimulation blocked. Sham repetitive Transcranial Magnetic Stimulation: This was identical to active rTMS except the stimulation was blocked. Both active and sham repetitive Transcranial Magnetic Stimulation received simulation from a specially designed coil which is capable of delivering either active rTMS or sham rTMS in a manner, which is randomized by the system itself and therefore blinded to the treater. Sham rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).
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.	0.18 Correlation Coefficient	-0.58 Correlation Coefficient

SECONDARY outcome

Timeframe: Baseline and at 15-20 min post-TMS (up to 1 hr)

Population: Population consisted of patients with fibromyalgia who underwent either active or sham cTBS either in combination with hypnosis or without it. Participants were excluded from the original sample for 1) poor Stroop task performance, 2) fMRI imaging problems, 3) missing data. Subjects who had pre and post TMS resting-state fMRI scans that passed QC and motion-based inclusion criteria were included.

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.

Outcome measures

Outcome measures
Measure	Active rTMS n=27 Participants The active group received active repetitive Transcranial Magnetic Stimulation Active repetitive Transcranial Magnetic Stimulation: The investigators performed 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 was determined by Localite Neuronavigation and targeted at the posterior middle frontal gyrus. The baseline structural scan obtained during the scan 1 was utilized for this localization process. rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).utilized for this localization process. rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark).	Sham rTMS n=30 Participants The sham repetitive Transcranial Magnetic Stimulation group had the stimulation blocked. Sham repetitive Transcranial Magnetic Stimulation: This was identical to active rTMS except the stimulation was blocked. Both active and sham repetitive Transcranial Magnetic Stimulation received simulation from a specially designed coil which is capable of delivering either active rTMS or sham rTMS in a manner, which is randomized by the system itself and therefore blinded to the treater. Sham rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).
Linear Relationship Between the Change in FC of the VAN to the DMN and the Change in Stroop Performance (Correlation Coefficient) With Hypnosis Intervention.	0.16 Correlation Coefficient	0.16 Correlation Coefficient

SECONDARY outcome

Timeframe: Baseline and at 15-20 min post-TMS (up to 1 hr)

Population: Population consisted of patients with fibromyalgia who underwent either active or sham cTBS either in combination with hypnosis or without it. Participants were excluded from the original sample for 1) poor Stroop task performance, 2) fMRI imaging problems, 3) missing data. Subjects who had pre and post TMS resting-state fMRI scans that passed QC and motion-based inclusion criteria were included.

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.

Outcome measures

Outcome measures
Measure	Active rTMS n=27 Participants The active group received active repetitive Transcranial Magnetic Stimulation Active repetitive Transcranial Magnetic Stimulation: The investigators performed 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 was determined by Localite Neuronavigation and targeted at the posterior middle frontal gyrus. The baseline structural scan obtained during the scan 1 was utilized for this localization process. rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).utilized for this localization process. rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark).	Sham rTMS n=30 Participants The sham repetitive Transcranial Magnetic Stimulation group had the stimulation blocked. Sham repetitive Transcranial Magnetic Stimulation: This was identical to active rTMS except the stimulation was blocked. Both active and sham repetitive Transcranial Magnetic Stimulation received simulation from a specially designed coil which is capable of delivering either active rTMS or sham rTMS in a manner, which is randomized by the system itself and therefore blinded to the treater. Sham rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).
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.	0.24 Correlation Coefficient	-0.44 Correlation Coefficient

SECONDARY outcome

Timeframe: Baseline and at 15-20 min post-TMS (up to 1 hr)

Population: Population consisted of patients with fibromyalgia who underwent either active or sham cTBS either in combination with hypnosis or without it. Participants were excluded from the original sample for 1) poor Stroop task performance, 2) fMRI imaging problems, 3) missing data. Subjects who had pre and post TMS resting-state fMRI scans that passed QC and motion-based inclusion criteria were included.

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.

Outcome measures

Outcome measures
Measure	Active rTMS n=27 Participants The active group received active repetitive Transcranial Magnetic Stimulation Active repetitive Transcranial Magnetic Stimulation: The investigators performed 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 was determined by Localite Neuronavigation and targeted at the posterior middle frontal gyrus. The baseline structural scan obtained during the scan 1 was utilized for this localization process. rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).utilized for this localization process. rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark).	Sham rTMS n=30 Participants The sham repetitive Transcranial Magnetic Stimulation group had the stimulation blocked. Sham repetitive Transcranial Magnetic Stimulation: This was identical to active rTMS except the stimulation was blocked. Both active and sham repetitive Transcranial Magnetic Stimulation received simulation from a specially designed coil which is capable of delivering either active rTMS or sham rTMS in a manner, which is randomized by the system itself and therefore blinded to the treater. Sham rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).
Linear Relationship Between the Change in FC of the VAN to the DMN and the Change in Stroop Interference (Correlation Coefficient) With Hypnosis Intervention.	0.07 Correlation Coefficient	0.28 Correlation Coefficient

SECONDARY outcome

Timeframe: Baseline and immediately post-rTMS (up to 30 minutes)

Population: Participants with available data are included in the analysis

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).

Outcome measures

Outcome measures
Measure	Active rTMS n=38 Participants The active group received active repetitive Transcranial Magnetic Stimulation Active repetitive Transcranial Magnetic Stimulation: The investigators performed 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 was determined by Localite Neuronavigation and targeted at the posterior middle frontal gyrus. The baseline structural scan obtained during the scan 1 was utilized for this localization process. rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).utilized for this localization process. rTMS will be delivered using a MagPro TMS system (MagVenture, Denmark).	Sham rTMS n=42 Participants The sham repetitive Transcranial Magnetic Stimulation group had the stimulation blocked. Sham repetitive Transcranial Magnetic Stimulation: This was identical to active rTMS except the stimulation was blocked. Both active and sham repetitive Transcranial Magnetic Stimulation received simulation from a specially designed coil which is capable of delivering either active rTMS or sham rTMS in a manner, which is randomized by the system itself and therefore blinded to the treater. Sham rTMS was delivered using a MagPro TMS system (MagVenture, Denmark).
Change in the Numeric Pain Rating Scale Non-hypnosis condition	-0.13 mean change of scores on a scale Standard Error 0.20	0.19 mean change of scores on a scale Standard Error 0.19
Change in the Numeric Pain Rating Scale Hypnosis condition	-0.09 mean change of scores on a scale Standard Error 0.20	-0.05 mean change of scores on a scale Standard Error 0.19

SECONDARY outcome

Timeframe: Baseline and immediately post-rTMS (up to 30 min)

Population: Participants who completed the protocol and completed all items of the SOARS are included in the analysis.

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).