Characterizing the opioidergic mechanisms of repetitive transcranial magnetic stimulation-induced analgesia: a randomized controlled trial.

ABSTRACT: Repetitive transcranial magnetic stimulation (rTMS) is a promising technology to reduce chronic pain. Investigating the mechanisms of rTMS analgesia holds the potential to improve treatment efficacy. Using a double-blind and placebo-controlled design at both stimulation and pharmacologic ends, this study investigated the opioidergic mechanisms of rTMS analgesia by abolishing and recovering analgesia in 2 separate stages across brain regions and TMS doses. A group of 45 healthy participants were equally randomized to the primary motor cortex (M1), the dorsolateral prefrontal cortex (DLPFC), and the Sham group. In each session, participants received an intravenous infusion of naloxone or saline before the first rTMS session. Participants then received a second dose of rTMS session after the drugs were metabolized at 90 minutes. M1-rTMS-induced analgesia was abolished by naloxone compared with saline and was recovered by the second rTMS run when naloxone was metabolized. In the DLPFC, double but not the first TMS session induced significant pain reduction in the saline condition, resulting in less pain compared with the naloxone condition. In addition, TMS over the M1 or DLPFC selectively increased plasma concentrations of ß-endorphin or encephalin, respectively. Overall, we present causal evidence that opioidergic mechanisms are involved in both M1-induced and DLPFC-rTMS-induced analgesia; however, these are shaped by rTMS dosage and the release of different endogenous opioids.

How to Interpret Effect Sizes for Biopsychosocial Outcomes and Implications for Current Research.

Biopsychosocial factors are associated with pain, but they can be difficult to compare. One way of comparing them is to use standardized mean differences. Previously, these effects sizes have been termed as small, medium, or large, if they are bigger than or equal to, respectively, .2, .5, or .8. These cut-offs are arbitrary and recent evidence showed that they need to be reconsidered. We argue it is necessary to determine cut-offs for each biopsychosocial factor. To achieve this, we propose 3 potential approaches: 1) examining, for each factor, how the effect size differs depending upon disease severity; 2) using an existing minimum clinically important difference to anchor the large effect size; and 3) define cut-offs by comparing data from people with and without pain. This is important for pain research, as exploring these methodologies has potential to improve comparability of biopsychosocial factors and lead to more directed treatments. We note assumptions and limitations of these methods that should also be considered. PERSPECTIVE: Standardized mean differences can estimate effect sizes between groups and could theoretically allow for comparison of biopsychosocial factors. However, common thresholds to define effect sizes are arbitrary and likely differ based on outcome. We propose methods that could overcome this and be used to derive biopsychosocial outcome-specific effect sizes.

Comparisons of Accelerated Continuous and Intermittent Theta Burst Stimulation for Treatment-Resistant Depression and Suicidal Ideation.

BACKGROUND: Suicidal ideation is a substantial clinical challenge in treatment-resistant depression (TRD). Recent work demonstrated promising antidepressant effects in TRD patients with no or mild suicidal ideation using a specific protocol termed intermittent theta burst stimulation (iTBS). Here, we examined the clinical effects of accelerated schedules of iTBS and continuous TBS (cTBS) in patients with moderate to severe suicidal ideation. METHODS: Patients with TRD and moderate to severe suicidal ideation (n = 44) were randomly assigned to receive accelerated iTBS or cTBS treatment. Treatments were delivered in 10 daily TBS sessions (1800 pulses/session) for 5 consecutive days (total of 90,000 pulses). Neuronavigation was employed to target accelerated iTBS and cTBS to the left and right dorsolateral prefrontal cortex (DLPFC), respectively. Clinical outcomes were evaluated in a 4-week follow-up period. RESULTS: Accelerated cTBS was superior to iTBS in the management of suicidal ideation (pweek 1 = .027) and anxiety symptoms (pweek 1 = .01). Accelerated iTBS and cTBS were comparable in antidepressant effects (p < .001; accelerated cTBS: mean change at weeks 1, 3, 5 = 49.55%, 54.99%, 53.11%; accelerated iTBS: mean change at weeks 1, 3, 5 = 44.52%, 48.04%, 51.74%). No serious adverse events occurred during the trial. One patient withdrew due to hypomania. The most common adverse event was discomfort at the treatment site (22.73% in both groups). CONCLUSIONS: These findings provide the first evidence that accelerated schedules of left DLPFC iTBS and right DLPFC cTBS are comparably effective in managing antidepressant symptoms and indicate that right DLPFC cTBS is potentially superior in reducing suicidal ideation and anxiety symptoms.

Towards data-driven biopsychosocial classification of non-specific chronic low back pain: a pilot study.

The classification of non-specific chronic low back pain (CLBP) according to multidimensional data could guide clinical management; yet recent systematic reviews show this has not been attempted. This was a prospective cross-sectional study of participants with CLBP (n = 21) and age-, sex- and height-matched pain-free controls (n = 21). Nervous system, lumbar spinal tissue and psychosocial factors were collected. Dimensionality reduction was followed by fuzzy c-means clustering to determine sub-groups. Machine learning models (Support Vector Machine, k-Nearest Neighbour, Naïve Bayes and Random Forest) were used to determine the accuracy of classification to sub-groups. The primary analysis showed that four factors (cognitive function, depressive symptoms, general self-efficacy and anxiety symptoms) and two clusters (normal versus impaired psychosocial profiles) optimally classified participants. The error rates in classification models ranged from 4.2 to 14.2% when only CLBP patients were considered and increased to 24.2 to 37.5% when pain-free controls were added. This data-driven pilot study classified participants with CLBP into sub-groups, primarily based on psychosocial factors. This contributes to the literature as it was the first study to evaluate data-driven machine learning CLBP classification based on nervous system, lumbar spinal tissue and psychosocial factors. Future studies with larger sample sizes should validate these findings.

Analgesic efficacy of theta-burst stimulation for postoperative pain.

OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) may be a relevant method to assist postoperative pain. However, studies to date have only used conventional 10 Hz rTMS and targeted the DLPFC for postoperative pain. A more recent form of rTMS, termed intermittent Theta Burst Stimulation (iTBS), enables to increase cortical excitability in a short period of time. This preliminary double-blind, randomised, sham controlled study was designed to evaluate the efficacy of iTBS in postoperative care across two distinct stimulation targets. METHODS: A group of 45 patients post laparoscopic surgery were randomised to receive a single session of iTBS over either the dorsolateral prefrontal cortex (DLPFC), primary motor cortex (M1), or Sham stimulation (1:1:1 ratio). Outcome measurements were number of pump attempts, total anaesthetic volume used, and self-rated pain experience, assessed at 1 hour, 6 hours, 24 hours, and 48 hours post stimulation. All randomised patients were analysed (n = 15 in each group). RESULTS: Compared to Sham stimulation, DLPFC-iTBS reduced pump attempts at 6 (DLPFC = 0.73 ± 0.88, Sham = 2.36 ± 1.65, P = 0.031), 24 (DLPFC = 1.40 ± 1.24, Sham = 5.03 ± 3.87, P = 0.008), and 48 (DLPFC = 1.47 ± 1.41, Sham = 5.87 ± 4.34, P = 0.014) hours post-surgery, whereby M1 stimulation had no effect. No group effect was observed on total anaesthetics, which was mainly provided through the continuous administration of opioids at a set speed for each group. There was also no group or interaction effect on pain ratings. Pump attempts were positively associated with pain ratings in the DLPFC (r = 0.59, P = 0.02) and M1 (r = 0.56, P = 0.03) stimulation. CONCLUSIONS: Our findings show that iTBS to the DLPFC reduces pump attempts for additional anaesthetics following a laparoscopic surgery. However, reduced pump attempts by DLPFC stimulation did not translate into a significantly smaller volume of total anaesthetic, due to the continuous administration of opioids at a set speed for each group. SIGNIFICANCE: Our findings therefore provide preliminary evidence for iTBS targeting the DLPFC to be used to improve postoperative pain management.

The Interaction Between Psychosocial Factors and Exercise-Induced Hypoalgesia in Pain-Free Nurses.

Purpose: This cross-sectional study aimed to investigate whether psychosocial factors were predictive for exercise-induced hypoalgesia (EIH) in pain-free adults. Methods: A sample of 38 pain-free nurses with a mean (SD) age of 26 (6) years were included in this study. Participants completed psychosocial questionnaires prior to physical tests. Pressure pain threshold (PPT) was assessed bilaterally at the calves (local), lower back (semi-local) and forearm (remote) before and immediately after a maximal graded cycling exercise test. Separate linear mixed effects models were used to determine change in PPT before and after cycling exercise (EIH). Multiple linear regression for all psychosocial variables and best subset regression was used to identify predictors of EIH at all locations. Results: The relative mean increase in PPT at the forearm, lumbar, calf, and globally (all sites pooled) was 6.0% (p<0.001), 10.1% (p<0.001), 13.9% (p<0.001), and 10.2% (p=0.013), respectively. Separate best subset multiple linear regression models at the forearm (predictors; Multidimensional Scale of Perceived Social Support (MSPSS) total), lumbar (predictors; MSPSS total, Pain Catastrophizing Scale (PCS) total, Depression Anxiety Stress Scale (DASS) depression), calf (predictors; MSPSS friends, PCS total), and global (predictors; MSPSS friends, PCS total) accounted for 7.5% (p=0.053), 13% (p=0.052), 24% (p=0.003), and 17% (p=0.015) of the variance, respectively. Conclusion: These findings confirm that cycling exercise produced EIH in young nurses and provided preliminary evidence to support the interaction between perceived social support, pain catastrophizing and EIH. Further investigation is required to better understand psychological and social factors that mediate EIH on a larger sample of adults at high risk of developing chronic musculoskeletal pain.

Chronic back pain sub-grouped via psychosocial, brain and physical factors using machine learning.

Chronic back pain (CBP) is heterogenous and identifying sub-groups could improve clinical decision making. Machine learning can build upon prior sub-grouping approaches by using a data-driven approach to overcome clinician subjectivity, however, only binary classification of pain versus no-pain has been attempted to date. In our cross-sectional study, age- and sex-matched participants with CBP (n = 4156) and pain-free controls (n = 14,927) from the UkBioBank were included. We included variables of body mass index, depression, loneliness/social isolation, grip strength, brain grey matter volumes and functional connectivity. We used fuzzy c-means clustering to derive CBP sub-groups and Support Vector Machine (SVM), Naïve Bayes, k-Nearest Neighbour (kNN) and Random Forest classifiers to determine classification accuracy. We showed that two variables (loneliness/social isolation and depression) and five clusters were optimal for creating sub-groups of CBP individuals. Classification accuracy was greater than 95% for when CBP sub-groups were assessed only, while misclassification in CBP sub-groups increased to 35-53% across classifiers when pain-free controls were added. We showed that individuals with CBP could sub-grouped and accurately classified. Future research should optimise variables by including specific spinal, psychosocial and nervous system measures associated with CBP to create more robust sub-groups that are discernible from pain-free controls.

Brain structure, psychosocial, and physical health in acute and chronic back pain: a UK Biobank study.

ABSTRACT: Brain structure, psychosocial, and physical factors underpin back pain conditions; however, less is known about how these factors differ based on pain duration and location. We examined, cross-sectionally, 11,106 individuals from the UK Biobank who (1) were pain-free (n = 5616), (2) had acute back pain (n = 1746), (3) had chronic localised back pain (CBP; n = 1872), or (4) had chronic back pain and additional chronic pain sites (CWP; n = 1872). We found differences in structural brain measures in the chronic pain groups alone. Both CBP and CWP groups had lower primary somatosensory cortex {CBP mean difference (MD) (95% confidence interval [CI]): -250 (-393, -107) mm3, P < 0.001; CWP: -170 (-313, -27)mm3, P = 0.011} and higher caudate gray matter volumes (CBP: 127 [38,216]mm3, P = 0.001; CWP: 122 [33,210]mm3, P = 0.002) compared with pain-free controls. The CBP group also had a lower primary motor cortex volume (-215 [-382, -50]mm3, P = 0.005), whereas the CWP group had a lower amygdala gray matter volume (-27 [-52, -3]mm3, P = 0.021) compared with pain-free controls. Differences in gray matter volumes in some regions may be moderated by sex and body mass index. Psychosocial factors and body mass index differed between all groups and affected those with widespread pain the most (all, P < 0.001), whereas grip strength was only compromised in individuals with widespread pain (-1.0 [-1.4, -0.5] kg, P < 0.001) compared with pain-free controls. Longitudinal research is necessary to confirm these interactions to determine the process of pain development in relation to assessed variables and covariates. However, our results suggest that categorised pain duration and the number of pain sites warrant consideration when assessing markers of brain structure, psychosocial, and physical health.

Relative contributions of the nervous system, spinal tissue and psychosocial health to non-specific low back pain: Multivariate meta-analysis.

BACKGROUND AND OBJECTIVES: Nervous system, psychosocial and spinal tissue biomarkers are associated with non-specific low back pain (nsLBP), though relative contributions are unclear. DATABASES AND DATA TREATMENT: MEDLINE, EMBASE, CINAHL, PsycINFO and SPORTDiscus were searched up to 25 March 2020. Related reviews and reference lists were also screened. Observational studies examining structural and functional nervous system biomarkers (e.g. quantitative sensory tests, structural and functional brain measures), psychosocial factors (e.g. mental health, catastrophizing) and structural spinal imaging biomarkers (e.g. intervertebral disc degeneration, paraspinal muscle size) between nsLBP and pain-free controls were included. For multivariate meta-analysis, two of three domains were required in each study. Random-effects pairwise and multivariate meta-analyses were performed. GRADE approach assessed evidence certainty. Newcastle-Ottawa scale assessed risk of bias. Main outcomes were the effect size difference of domains between nsLBP and pain-free controls. RESULTS: Of 4519 unique records identified, 33 studies (LBP = 1552, referents = 1322) were meta-analysed. Psychosocial state (Hedges' g [95%CI]: 0.90 [0.69-1.10], p < 0.001) in nsLBP showed larger effect sizes than nervous system (0.31 [0.13-0.49], p < 0.001; difference: 0.61 [0.36-0.86], p < 0.001) and spine imaging biomarkers (0.55 [0.37-0.73], p < 0.001; difference: 0.36 [0.04-0.67], p = 0.027). The relationship between domains changes depending on if pain duration is acute or chronic. CONCLUSIONS: Psychosocial effect sizes in nsLBP are greater than those for spinal imaging and nervous system biomarkers. Limitations include cross-sectional design of studies included and inference of causality. Future research should investigate the clinical relevance of these effect size differences in relation to pain intensity and disability. STUDY REGISTRATION: PROSPERO-CRD42020159188. SIGNIFICANCE: Spinal structural lesions (e.g. intervertebral disc degeneration), psychosocial (e.g. depression) and nervous system factors (detected by e.g. quantitative sensory tests, structural and functional measures) contribute to non-specific low back pain. However, psychosocial factors may be more compromised than nervous system and spinal imaging biomarkers. This relationship depends on if the pain is acute or chronic. These findings underscore that the 'non-specific' label in back pain should be reconsidered, and more specific multidimensional categories evaluated to guide patient management.

Lessons from an initiative to address gender bias.

How a letter addressing the lack of women invited to speak at a conference in brain stimulation encouraged researchers to take action.

Examining resting-state functional connectivity in key hubs of the default mode network in chronic low back pain.

OBJECTIVES: Changes in brain connectivity have been observed within the default mode network (DMN) in chronic low back pain (CLBP), however the extent of these disruptions and how they may be related to CLBP requires further examination. While studies using seed-based analysis have found disrupted functional connectivity in the medial prefrontal cortex (mPFC), a major hub of the DMN, limited studies have investigated other equally important hubs, such as the posterior cingulate cortex (PCC) in CLBP. METHODS: This preliminary study comprised 12 individuals with CLBP and 12 healthy controls who completed a resting-state functional magnetic resonance imaging (fMRI) scan. The mPFC and PCC were used as seeds to assess functional connectivity. RESULTS: Both groups displayed similar patterns of DMN connectivity, however group comparisons showed that CLBP group had reduced connectivity between the PCC and angular gyrus compared to healthy controls. An exploratory analysis examined whether the alterations observed in mPFC and PCC connectivity were related to pain catastrophizing in CLBP, but no significant associations were observed. CONCLUSIONS: These results may suggest alterations in the PCC are apparent in CLBP, however, the impact and functional role of these disruptions require further investigation.

High-frequency rTMS over the dorsolateral prefrontal cortex on chronic and provoked pain: A systematic review and meta-analysis.

BACKGROUND: High-frequency rTMS over the dorsolateral prefrontal cortex (DLPFC) has demonstrated mixed effects on chronic and provoked pain. OBJECTIVES/METHODS: In this study, a meta-analysis was conducted to characterise the potential analgesic effects of high-frequency rTMS over the DLPFC on both chronic and provoked pain. RESULTS: A total of 626 studies were identified in a systematic search. Twenty-six eligible studies were included for the quantitative review, among which 17 modulated chronic pain and the remaining investigated the influence on provoked pain. The left side DLPFC was uniformly targeted in the chronic pain studies. While our data identified no overall effect of TMS across chronic pain conditions, there was a significant short-term analgesia in neuropathic pain conditions only (SMD = -0.87). In terms of long-lasting analgesia, there was an overall pain reduction in the midterm (SMD = -0.53, 24.6 days average) and long term (SMD = -0.63, 3 months average) post DLPFC stimulation, although these effects were not observed within specific chronic pain conditions. Surprisingly, the number of sessions was demonstrated to have no impact on rTMS analgesia. In the analysis of provoked pain, our data also indicated a significant analgesic effect following HF-rTMS over the DLPFC (SMD = -0.73). Importantly, we identified a publication bias in the studies of provoked pain but not for chronic pain conditions. CONCLUSIONS: Overall, our findings support that HF-DLPFC stimulation is able to induce an analgesic effect in chronic pain and in response to provoked pain. These results highlight the potential of DLPFC-rTMS in the management of certain chronic pain conditions and future directions are discussed to enhance the potential long-term analgesic effects.

EEG correlates of attentional control in anxiety disorders: A systematic review of error-related negativity and correct-response negativity findings.

BACKGROUND: Anxiety disorders are highly prevalent and cause substantial personal, social and economic burden. Altered attentional control has been shown to be present across anxiety disorders and is associated with specific changes in brain activity which can be recorded by electroencephalogram (EEG). These include changes in the EEG markers of error-related negativity (ERN) and correct-response negativity (CRN), both believed to reflect response monitoring and attentional control pathophysiology in anxiety. The aim of this review was to systematically assess the research on ERN and CRN in attentional control in individuals with clinical anxiety and healthy controls, across emotional and non-emotional attentional control. METHODS: A comprehensive literature search was conducted for studies published prior to October 22nd, 2020. Details of the protocol for this systematic review were registered on PROSPERO (CRD42019144885). RESULTS: 66 studies had their data extracted. All 66 studies measured ERN, with 85% finding significantly increased ERN amplitudes associated with clinical anxiety. Only 44 of the extracted studies analysed CRN and only ~20% of these found significant changes in CRN amplitude associated with individuals with clinical anxiety. LIMITATIONS: There were several anxiety disorders that had either limited literature (i.e. specific phobia, separation anxiety disorder or agoraphobia) or nil literature (i.e. selective mutism) available. No extracted studies included samples of older adults (i.e. aged 60+ years), and only six extracted studies included measures of emotional attentional control. CONCLUSIONS: Findings indicate the promising utility of ERN of attentional control as a robust, transdiagnostic trait marker of clinical anxiety.

Neural activity during cognitive reappraisal in chronic low back pain: a preliminary study.

OBJECTIVES: Chronic pain patients often report higher levels of negative emotions, suggesting reduced ability to regulate emotions effectively, however, little is known of the underlying neural cognitive mechanisms. Therefore, the aim of this study was to explore brain activity and connectivity during cognitive reappraisal in chronic low back pain (CLBP). METHODS: This study recruited 24 female participants; 12 with CLBP and 12 healthy controls. Participants completed an emotion regulation task that involved cognitive reappraisal of negative images during functional magnetic resonance imaging. The negative affect following each image and perceived success of the task were reported. Region of interest and seed-to-voxel analyses were conducted using key regions involved in cognitive reappraisal (i.e., amygdalae and dorsomedial prefrontal cortex) as seed regions. RESULTS: During the task, there were no group differences in the behavioural measures and blood oxygen level-dependent (BOLD) brain activation in the seed regions. Functional connectivity analysis showed reduced coupling between the amygdalae and dorsolateral prefrontal cortex, orbitofrontal cortex and inferior parietal cortex in the CLBP group compared to controls. Connectivity between the amygdala and inferior parietal cortex positively correlated with the percent of reduced negative affect during reappraisal in the CLBP group. CONCLUSIONS: These preliminary findings demonstrate that individuals with CLBP exhibit similar emotion regulation abilities to healthy controls at the behavioural and BOLD level. However, altered functional connectivity observed in the CLBP group may reduce effective cognitive reappraisal. These results provide evidence for the potential clinical impact of network changes in CLBP.

Investigating high- and low-frequency neuro-cardiac-guided TMS for probing the frontal vagal pathway.

BACKGROUND: Investigating approaches for determining a functionally meaningful dorsolateral prefrontal cortex (DLPFC) stimulation site is imperative for optimising repetitive transcranial magnetic stimulation (rTMS) response rates for treatment-resistant depression. One proposed approach is neuro-cardiac-guided rTMS (NCG-TMS) in which high frequency rTMS is applied to the DLPFC to determine the site of greatest heart rate deceleration. This site is thought to index a frontal-vagal autonomic pathway that intersects a key pathway believed to underlie rTMS response. OBJECTIVE: We aimed to independently replicate previous findings of high-frequency NCG-TMS and extend it to evaluate the use of low-frequency rTMS for NCG-TMS. METHODS: Twenty healthy participants (13 female; aged 38.6 ± 13.9) underwent NCG-TMS on frontal, fronto-central (active) and central (control) sites. For high-frequency NCG-TMS, three 5 s trains of 10 Hz were provided at each left hemisphere site. For low-frequency NCG-TMS, 60 s trains of 1 Hz were applied to left and right hemispheres and heart rate and heart rate variability outcome measures were analysed. RESULTS: For high-frequency NCG-TMS, heart rate deceleration was observed at the left frontal compared with the central site. For low-frequency NCG-TMS, accelerated heart rate was found at the right frontal compared with central sites. No other site differences were observed. CONCLUSION: Opposite patterns of heart rate activity were found for high- and low-frequency NCG-TMS. The high-frequency NCG-TMS data replicate previous findings and support further investigations on the clinical utility of NCG-TMS for optimising rTMS site localisation. Further work assessing the value of low-frequency NCG-TMS for rTMS site localisation is warranted.

The dorsomedial prefrontal cortex as a flexible hub mediating behavioral as well as local and distributed neural effects of social support context on pain: A Theta Burst Stimulation and TMS-EEG study.

Increasing evidence points to an analgesic influence of social support context, in which the dorsomedial prefrontal cortex (dmPFC) may play a key role. Transcranial Magnetic Stimulation (TMS) has the capacity to causally modulate brain activity. This study was designed to investigate the potential role of dmPFC in orchestrating the behavioral and neural effects of social context during pain. Twenty-three healthy participants underwent a three-session cross-over, single-blinded, sham-controlled protocol in which they received Theta Burst Stimulation (TBS) (facilitatory intermittent TBS, suppressive continuous TBS, or Sham) delivered to the dmPFC. In each session, participants underwent cold pain while viewing an image of a romantic partner or a stranger. Effects of TBS to the dmPFC were assessed using a measure of pain perception, neural activity and network connectivity using electroencephalography (EEG) and TMS-EEG. In the stranger condition, pain experience increased following iTBS. This was associated with increased connectivity between central regions and fronto-parietal regions. In contrast, in the romantic partner condition, iTBS increased connectivity only between frontal and occipital regions and did not modulate pain experience. In line with recent studies, neither cTBS nor Sham stimulation elicited neural or behavioral changes. Together these findings suggest that the dmPFC has the capacity to causally modulate pain-related information integration and network configuration in a context-dependent manner.

Low-frequency rTMS is better tolerated than high-frequency rTMS in healthy people: Empirical evidence from a single session study.

Low-frequency and high-frequency repetitive transcranial magnetic stimulation (rTMS) are similarly efficacious for treatment-resistant depression. Low-frequency is posited to be better tolerated than high-frequency rTMS, however, this is not supported by empirical evidence to date. This study aimed to quantify and compare the tolerability of low-versus high-frequency rTMS. Twenty healthy participants (mean age 38.6 ±â€¯13.9 years) underwent low- and high-frequency rTMS administered on left frontal, fronto-central and central sites at 100% resting motor threshold. For the low-frequency protocol, 60 s of 1 Hz stimulation was applied at each site and for the high-frequency protocol, 3 × 5 s trains of 10 Hz stimulation with a 30 s inter-train interval were applied at each site. Tolerance for each stimulation type was assessed immediately after stimulation through participant ratings of overall intensity of scalp sensations, pain, muscle twitching, discomfort and any other sensation. Low-frequency rTMS was significantly less intense than high-frequency rTMS in overall intensity, pain, muscle twitching (all p < .01) and discomfort (p < .001). Limitations of this study include the healthy participant sample and administration of a single session of rTMS. While further work is needed in clinical samples using typical rTMS treatment protocols, these data provide the first evidence that low-frequency is better tolerated than high-frequency. These findings may inform clinical practice of rTMS treatment for depression (and other illnesses) by supporting the application of low-frequency protocols.