Use of Repetitive Transcranial Magnetic Stimulation to Augment Hypnotic Analgesia

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).

Time frame: 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.

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).

Time frame: Baseline visit (up to 30 min)

Population: Participants with baseline MegaPress scan data

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).

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

Population: Participants with available data 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).

Time frame: 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 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).

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

Population: Participants who completed the protocol and completed HIS ratings 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).

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

Population: Participants with available data are included in the analysis

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.

Time frame: Baseline visit (up to 45 min)

Population: Participants with baseline MegaPress scan data

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.

Time frame: Baseline visit (up to 45 min)

Population: Participants with baseline MegaPress scan data

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.

Time frame: Baseline visit (up to 45 min)

Population: Participants with baseline MegaPress scan data

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.

Time frame: Baseline visit (up to 45 min)

Population: Participants with baseline MegaPress scan data

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

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.

Time frame: Baseline Scan (up to 15 min)

Population: Participants with baseline MegaPress scan data

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.

Time frame: Baseline Scan and at 15-20 min post-TMS (up to 30 min)

Population: Participants with available data

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).

Time frame: 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

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).

Time frame: 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.

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.

Time frame: 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.

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.

Time frame: Baseline and 2 hours

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