Cancer is a major public health issue, with an estimated 20 million new cases and 9.7 million cancer-related deaths worldwide in 2022. Approximately 44.5% of patients experience cancer pain, significantly impacting their quality of life and causing physical and psychological burdens. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive neuromodulation technique, shows potential in managing cancer pain. This review summarizes current research on rTMS for cancer pain, focusing on pain directly caused by tumors, pain from cancer treatments, postoperative pain, and cancer-related symptoms. Additionally, rTMS shows promise in improving cancer-related fatigue, anxiety, depression, and cognitive dysfunction, which can indirectly reduce cancer pain. The analgesic mechanisms of rTMS include inhibiting nociceptive signal transmission in the spinal cord, modulating hemodynamic changes in brain regions, and promoting endogenous opioid release. High-frequency stimulation of the primary motor cortex (M1) has shown significant analgesic effects, improving patients' emotional and cognitive functions and overall quality of life. rTMS has a favorable safety profile, with most studies reporting no severe adverse events. In conclusion, rTMS holds substantial potential for cancer pain management, offering a non-invasive and multifaceted therapeutic approach. Continued research and clinical application are expected to establish rTMS as an essential component of comprehensive cancer pain treatment strategies, significantly enhancing the overall well-being of patients with cancer.

Electric-field orientation is crucial for optimizing neuronal excitation in transcranial magnetic stimulation (TMS). Yet, the stimulus orientation effects on short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) are poorly understood due to technical challenges in manipulating the TMS-induced stimulus orientation within milliseconds. We aimed to assess the orientation sensitivity of SICI and ICF paradigms and identify optimal orientations for motor evoked potential (MEP) facilitation and suppression.

We applied paired-pulse multi-channel TMS to 12 healthy subjects with conditioning and test stimuli in the same, opposite, and perpendicular orientations to each other at four interstimulus intervals (ISI) to generate refractoriness, SICI, and ICF.

MEP modulation was affected by the conditioning- and test-stimulus orientation, being strongest when both pulses were in the same direction. MEP modulation with 2.5-ms and 6.0-ms ISIs were more sensitive to orientation changes than 0.5- and 8.0-ms ISIs.

SICI and ICF orientation sensitivity exhibit a complex dependence on the conditioning stimulus orientation, which might be explained by anatomical and morphological arrangements of inhibitory and excitatory neuronal populations.

Distinct mechanisms mediating SICI and ICF are sensitive to stimulus orientation at specific ISIs, describing a structural-functional relationship that maximizes each effect at the cortical level.

Pain-related motor adaptations may be enacted predictively at the mere threat of pain, before pain occurrence. Yet, in humans, the neurophysiological mechanisms underlying motor adaptations in anticipation of pain remain poorly understood. We tracked the evolution of changes in corticospinal excitability (CSE) as healthy adults learned to anticipate the occurrence of lateralized, muscle-specific pain to the upper limb. Using a Pavlovian threat conditioning task, different visual stimuli predicted pain to the right or left forearm (experiment 1) or hand (experiment 2). During stimuli presentation before pain occurrence, single-pulse transcranial magnetic stimulation was applied over the left primary motor cortex to probe CSE and elicit motor evoked potentials from target right forearm and hand muscles. The correlation between participants' trait anxiety and CSE was also assessed. Results showed that threat of pain triggered corticospinal inhibition specifically in the limb where pain was expected. In addition, corticospinal inhibition was modulated relative to the threatened muscle, with threat of pain to the forearm inhibiting the forearm and hand muscles, whereas threat of pain to the hand inhibited the hand muscle only. Finally, stronger corticospinal inhibition correlated with greater trait anxiety. These results advance the mechanistic understanding of pain processes showing that pain-related motor adaptations are enacted at the mere threat of pain, as sets of anticipatory, topographically organized motor changes that are associated with the expected pain and are shaped by individual anxiety levels. Including such anticipatory motor changes into models of pain may lead to new treatments for pain-related disorders.

The treatment of neuropathic pain (NeP) often leads to partial or incomplete pain relief, with up to 40 % of patients being pharmaco-resistant. In this chapter the efficacy of neuromodulation techniques in treating NeP is reviewed. It presents a detailed evaluation of the mechanisms of action and evidence supporting the clinical use of the most common approaches like transcutaneous electrical nerve stimulation (TENS), transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), deep brain stimulation (DBS), invasive motor cortex stimulation (iMCS), spinal cord stimulation (SCS), dorsal root ganglion stimulation (DRG-S), and peripheral nerve stimulation (PNS). Current literature suggests that motor cortex rTMS is effective for peripheral and central NeP, and TENS for peripheral NeP. Evidence for tDCS is inconclusive. DBS is reserved for research settings due to heterogeneous results, while iMSC has shown efficacy in a small randomized trial in neuropathic pain due to stroke and brachial plexus avulsion. SCS has moderate evidence for painful diabetic neuropathy and failed back surgery syndrome, but trials were not controlled with sham. DRG-S and PNS have shown positive results for complex regional pain syndrome and post-surgical neuropathic pain, respectively. Adverse effects vary, with non-invasive techniques showing local discomfort, dizziness and headache, and DBS and SCS hardware-related issues. To date, non-invasive techniques have been more extensively studied and some are included in international guidelines, while the evidence level for invasive techniques are less robust, potentially suggesting their use in a case-by-case indication considering patient´s preferences, costs and expected benefits.

Repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) at high frequency (HF) is an effective treatment of neuropathic pain. The classical HF-rTMS protocol (CHF-rTMS) includes a daily session for one week as an induction phase of treatment followed by more spaced sessions. Another type of protocol without an induction phase and based solely on spaced sessions of HF-rTMS (SHF-rTMS) has also been shown to produce neuropathic pain relief. However, CHF-rTMS and SHF-rTMS of M1 have never been compared regarding their analgesic potential. Another type of rTMS paradigm, called accelerated intermittent theta burst stimulation (ACC-iTBS), has recently been proposed for the treatment of depression, the other clinical condition for which HF-rTMS is proposed as an effective therapeutic strategy. ACC-iTBS combines a high number of pulses delivered in short sessions grouped into a few days of stimulation. This type of protocol has never been applied to M1 for the treatment of pain.

The objective of this single-centre randomized study is to compare the efficacy of three different rTMS protocols for the treatment of chronic neuropathic pain: CHF-rTMS, SHF-rTMS, and ACC-iTBS. The CHF-rTMS will consists of 10 stimulation sessions, including 5 daily sessions of 10Hz-rTMS (3,000 pulses per session) over one week, then one session per week for 5 weeks, for a total of 30,000 pulses delivered in 10 stimulation days. The SHF-rTMS protocol will only include 4 sessions of 20Hz-rTMS (1,600 pulses per session), one every 15 days, for a total of 6,400 pulses delivered in 4 stimulation days. The ACC-iTBS protocol will comprise 5 sessions of iTBS (600 pulses per session) completed in half a day for 2 consecutive days, repeated 5 weeks later, for a total of 30,000 pulses delivered in 4 stimulation days. Thus, CHF-rTMS and ACC-iTBS protocols will share a higher total number of TMS pulses (30,000 pulses) compared to SHF-rTMS protocol (6,400 pulses), while CHF-rTMS protocol will include a higher number of stimulation days (10 days) compared to ACC-iTBS and SHF-rTMS protocols (4 days). In all protocols, the M1 target will be defined in the same way and stimulated at the same intensity using a navigated rTMS (nTMS) procedure. The evaluation will be based on clinical outcomes with various scales and questionnaires assessed every week, from two weeks before the 7-week period of therapeutic stimulation until 4 weeks after. Additionally, three sets of neurophysiological outcomes (resting-state electroencephalography (EEG), nTMS-EEG recordings, and short intracortical inhibition measurement with threshold tracking method) will be assessed the week before and after the 7-week period of therapeutic stimulation.

This study will make it possible to compare the analgesic efficacy of the CHF-rTMS and SHF-rTMS protocols and to appraise that of the ACC-iTBS protocol for the first time. This study will also make it possible to determine the respective influence of the total number of pulses and days of stimulation delivered to M1 on the extent of pain relief. Thus, if their analgesic efficacy is not inferior to that of CHF-rTMS, SHF-rTMS and especially the new ACC-iTBS protocol could be an optimal compromise of a more easy-to-perform rTMS protocol for the treatment of patients with chronic neuropathic pain.

To first investigate the effectiveness of modified constraint-ınduced movement therapy (mCIMT) in low-functioning patients with stroke (PwS). Second, we aimed to investigate the efficiency of intermittent theta-burst stimulation (iTBS), applied on intermittent days, in addition to the mCIMT in PwS.

A randomized, sham-controlled, single-blinded study.

Outpatient clinic.

Fifteen PwS (age [mean±SD]: 66.3±9.2 years; 53% female) who were in the first 1 to 12 months after the incident were included in the study.

PwS were divided into 3 groups: (1) mCIMT alone; (2) mCIMT + sham iTBS; (3) mCIMT + iTBS. Each group received 15 sessions of mCIMT (1 hour/session, 3 sessions/week). iTBS was applied with 600 pulses on impaired M1 before mCIMT.

Upper extremity (UE) impairment was assessed with the Fugl-Meyer Test (FMT-UE), whereas the motor function was evaluated with the Wolf-Motor Function Test (WMFT). Motor Activity Log-28 (MAL-28) was used to evaluate the amount of use and how well (How Well Scale) the impaired UE movements.

With-in-group analysis revealed that all groups had statistically significant improvements based on the FMT-UE and MAL-28 (p<.05). However, the performance time and arm strength variables of WMFT were only increased in the mCIMT + iTBS group (p<.05). The only between-group difference was observed in the intracortical facilitation in favor of the mCIMT + iTBS group (p<.05). The effect size of iTBS was f=0.18.

Our findings suggest that mCIMT with and without the application of iTBS has increased the UE motor function in low-functioning PwS. iTBS applied on intermittent days may have additional benefits as an adjunct therapy for facilitating cortical excitability, increasing the speed and strength of the impaired UE as well as decreasing disability.

The dorsolateral prefrontal cortex (DLPFC) is implicated in pain modulation, suggesting its potential as a therapeutic target for pain relief. However, studies on transcranial electrical stimulation (tES) over the DLPFC yielded diverse results, likely due to differences in stimulation protocols or pain assessment methods. This study aims to evaluate the analgesic effects of DLPFC-tES using a meta-analytical approach.

A meta-analysis of 29 studies involving 785 participants was conducted. The effects of genuine and sham DLPFC-tES on pain perception were examined in healthy individuals and patients with clinical pain. Subgroup analyses explored the impact of stimulation parameters and pain modalities.

DLPFC-tES did not significantly affect pain outcomes in healthy populations but showed promise in reducing pain-intensity ratings in patients with clinical pain (Hedges' g = -0.78, 95% CI = [-1.33, -0.24], p = 0.005). Electrode placement significantly influenced the analgesic effect, with better results observed when the anode was at F3 and the cathode at F4.

DLPFC-tES holds potential as a cost-effective pain management option, particularly for clinical populations. Optimizing electrode placement, especially with an symmetrical configuration, may enhance therapeutic efficacy. These findings underscore the promise of DLPFC-tES for alleviating perceived pain intensity in clinical settings, emphasizing the importance of electrode placement optimization.

Chronic pain is highly burdening and multifactorial in etiology. The endogenous-pain-healing system restores body tissue to a non-painful state after an injury leading to pain, and its disruption could represent a relevant mechanism, especially for nursing interventions.

To review the literature and summarize the results that support this hypothesis.

We hypothesized that the mechanism behind this system mainly depends on the endogenous pain modulatory system (EPMS), which is responsible for inhibiting pain after tissue healing is complete and facilitating it when tissue damage is still present. Different biomarkers can quantify EPMS functioning. We reviewed the literature and included relevant information regarding this hypothesis.

First, conditioned pain modulation (CPM) measures pain inhibition and is a possible predictor for pain chronification. Second, motor cortex excitability measures the cortical control of the EPMS, which can be assessed through transcranial magnetic stimulation (using intracortical inhibition) or electroencephalography. Modifiable factors disrupt its functioning, such as sleep deprivation, medication overuse, and mental health status, but could be protective, such as exercise, certain medications, mind-body techniques, and non-invasive neuromodulation therapies. The acquisition of neurophysiological knowledge of how the chronicity of pain occurs and the EPMS involvement in this process may allow for better management of these patients.

We raised the hypothesis that the impairment of the EPMS (altered cortical excitability and descendent pain modulation pathways) seems to be related to the disruption of the pain healing process and its chronicity. Further longitudinal studies evaluating the relationship between these biomarkers and chronic pain development are necessary.

Impaired motor function is a major cause of disability in multiple sclerosis (MS), involving various neuroplasticity processes typically assessed by neuroimaging. This study aimed to determine whether navigated transcranial magnetic stimulation (nTMS) could also provide biomarkers of motor cortex plasticity in patients with MS (pwMS).

nTMS motor mapping was performed for hand and leg muscles bilaterally. nTMS variables included the amplitude and latency of motor evoked potentials (MEPs), corticospinal excitability measures, and the size of cortical motor maps (CMMs). Clinical assessment included disability (Expanded Disability Status Scale, EDSS), strength (MRC scale, pinch and grip), and dexterity (9-hole Pegboard Test).

nTMS motor mapping was performed in 68 pwMS. PwMS with high disability (EDSS ≥ 3) had enlarged CMMs with less dense distribution of MEPs and various MEP parameter changes compared to pwMS with low disability (EDSS < 3). Patients with progressive MS had also various MEP parameter changes compared to pwMS with relapsing remitting form. MRC score correlated positively with MEP amplitude and negatively with MEP latency, pinch strength correlated negatively with CMM volume and dexterity with MEP latency.

This is the first study to perform 4-limb cortical motor mapping in pwMS using a dedicated nTMS procedure. By quantifying the cortical surface representation of a given muscle and the variability of MEP within this representation, nTMS can provide new biomarkers of motor function impairment in pwMS. Our study opens perspectives for the use of nTMS as an objective method for assessing pwMS disability in clinical practice.

Central post-stroke pain (CPSP) significantly interferes with the quality of life and psychological well-being of stroke patients. Non-invasive brain stimulation (NIBS) has attracted significant attention as an emerging method for treating patients with CPSP.

To compare the clinical efficacy of noninvasive brain stimulation on pain, and psychological status of patients with central post-stroke pain using meta-analysis.

A computerized search of multiple databases was performed for identification of randomized controlled trials involving NIBS-led treatment of CPSP patients. Two researchers worked independently on literature screening, data extraction, and quality assessment. Research was conducted from inception of the database until October 2023. RevMan 5.0 and Stata 15.0 software were used to conduct statistical analysis.

Sixteen papers with 807 patients were finally included. The results showed that NIBS reduced patients' pain intensity [SMD = -0.39, 95% CI (-0.54, -0.24), p < 0.01] and was more effective in short-term CPSP patients. However, the included studies did not show a significant impact on psychological status, particularly depression. Subgroup analysis suggested that the M1 stimulation point was more effective than other stimulation points [SMD = -0.45, 95% CI (-0.65, -0.25), p < 0.001]. Other stimulation modalities also demonstrated favorable outcomes when compared to rTMS [SMD = -0.67, 95% CI (-1.09, -0.25), p < 0.01].

NIBS has a positive impact on pain relief in patients with CPSP, but does not enhance patients' psychological well-being in terms of anxiety or depression. Furthermore, large-sample, high-quality, and multi-center RCTs are needed to explore the benefits of different stimulation durations and parameters in patients with CPSP. The current study has been registered with Prospero under the registration number CRD42023468419.

The treatments based on motor control and motor learning principles have gained popularity in the last 20 years, as well as non-invasive brain stimulations that enhance neuroplastic changes after stroke. However, the effect of intermittent theta burst stimulation (iTBS) in addition to evidence-based, intensive neurorehabilitation approaches such as modified constraint-induced movement therapy (mCIMT) is yet to be investigated.

We aim to establish a protocol for a randomized controlled study investigating the efficiency of mCIMT primed with iTBS after stroke.

In this randomized controlled, single-blind study, patients with stroke (N = 17) will be divided into 3 groups: (a) mCIMT + real iTBS, (b) mCIMT + sham iTBS, and (c) mCIMT alone. 600-pulse iTBS will be delivered to the primary motor cortex on the ipsilesional hemisphere, and then, patients will receive mCIMT for 1 h/session, 3 sessions/week for 5 weeks. Upper extremity recovery will be assessed with Fugl-Meyer Test-Upper Extremity and Wolf Motor Function Test. Electrophysiological assessments, such as Motor-Evoked Potentials, Resting Motor Threshold, Short-Intracortical Inhibition, and Intracortical Facilitation, will also be included.

In this study, a protocol of an ongoing intervention study investigating the effectiveness of iTBS on ipsilesional M1 prior to the mCIMT in patients with stroke is proposed. This will be the first study to research priming mCIMT with iTBS and it may have the potential to reveal the true effect of the iTBS when it is added to the high-quality neurorehabilitation approaches.

Trial registration number: NCT05308667.

We directly compared the analgesic effects of "superficial" and 'deep" repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex in patients with central neuropathic pain. Fifty-nine consecutive patients were randomly assigned to active or sham "superficial" (using a figure-of-8 [F8]-coil) or "deep" (using a Hesed [H]-coil) stimulation according to a double-blind crossover design. Each treatment period consisted of 5 daily stimulation sessions and 2 follow-up visits at 1 and 3 weeks after the last stimulation session. The primary outcome was the comparison of the mean change in average pain intensity over the course of the treatment (group × time interaction). Secondary outcomes included neuropathic symptoms (NPSI), pain interference, patient global impression of change (PGIC), anxiety, depression, and catastrophizing. In total, 51 patients participated in at least one session of both treatments. There was a significant interaction between "treatment" and "time" (F = 2.7; P = 0.0024), indicating that both figure-8 (F8-coil) and H-coil active stimulation induced significantly higher analgesic effects than sham stimulation. The analgesic effects of both types of coils had a similar magnitude but were only moderately correlated ( r = 0.39, P = 0.02). The effects of F8-coil stimulation appeared earlier, whereas the effects of H-coil stimulation were delayed, but tended to last longer (up to 3 weeks) as regards to several secondary outcomes (PGIC and total NPSI score). In conclusion, "deep" and "superficial" rTMS induced analgesic effects of similar magnitude in patients with central pain, which may involve different mechanisms of action.

In clinical routine, navigated transcranial magnetic stimulation (nTMS) is usually applied down to 25 mm. Yet, besides clinical experience and mathematical models, the penetration depth remains unclear. This study aims to investigate the maximum cortical stimulation depth of nTMS in patients with meningioma above the primary motor cortex, causing a displacement of the primary motor cortex away from the skull.

nTMS stimulation data was reviewed regarding the maximum depth of stimulations eliciting motor-evoked potentials (MEPs). Additionally, electric field values and stimulation intensity were analyzed.

Out of a consecutive cohort of 17 meningioma cases, 3 cases of meningioma located in motor-eloquent regions of the upper extremity and 3 cases of the lower extremity were analyzed after fulfilling all inclusion criteria. Regarding the upper extremity motor representations, the MEP could be elicited at a stimulation depth of up to 44 mm, with an electric field of 69 V/m. These results were found in 1 case with the maximum potential distance to the cortex being higher than the maximum stimulation depth eliciting MEPs. For the lower extremities, a maximum depth of 40 mm was recorded (electric field 64 V/m).

None available CONCLUSIONS: The effect of nTMS is not limited to superficial cortical stimulation alone. Depending on electric-field intensity and focality, nTMS stimulation can be applied at a depth of 44 mm. In all cases, electric field strength was comparable and no superficial cortex with comparable electric field strength was observed to elicit MEPs.

Mild traumatic brain injury patients commonly complain headache and central pain, and the pain accompanies depressive mood change. This case study reports the therapeutic effect of repetitive transcranial magnetic stimulation (rTMS) in mild traumatic brain injury patient with headache and depression through objective serial changes of diffusion tensor imaging (DTI).

The 51-year-old man complained of headache and depression despite conventional treatment for 13 months. We applied 15 times rTMS on the left dorsolateral prefrontal cortex. We checked the pain and depression through numeric rating scale (NRS) and Beck depression inventory (BDI) when admission, discharged, and 1 month after discharge. DTI was performed 3 times; before, during-day of rTMS 6th stimulation, and after-day of rTMS 15th stimulation. Then the reconstructed White matter related to pain and depression was obtained.

NRS and BDI showed significant improvement and it was maintained 1 year after discharge. DTI-based metrics of the White matters related to pain and depression gradually increased before - during - after rTMS.

Studies focused on examining changes in pain, depression and DTI-based metrics of White matter are rare. This case is significant in that not only pain and depression improved after the rTMS, but also serial changes in White matter were observed in DTI.

Neuropathic pain is caused by a lesion or disease of the somatosensory system and is one of the most incapacitating pain types, representing a significant non-met medical need. Due to the increase in research in the field and since innovative therapeutic strategies are required, namely in intractable neuropathic pain, neurostimulation has been used. Within this approach, transcranial magnetic stimulation (TMS) that uses a transient magnetic field to produce electrical currents over the cortex emerges as a popular method in the literature. Since this is an area in expansion and due to the putative role of TMS, we performed a bibliometric analysis in Scopus with the primary objective of identifying the scientific production related to the use of TMS to manage neuropathic pain. The research had no restrictions, and the analysis focused on the characteristics of the literature retrieved, scientific collaboration and main research topics from inception to 6 July 2023. A total of 474 articles were collected. A biggest co-occurrence between the terms "neuropathic pain" and "transcranial magnetic stimulation" was obtained. The journal "Clinical Neurophysiology" leads the Top 5 most productive sources. The United States is the most productive country, with 50% of US documents being "review articles", followed by France, with 56% of French documents being "original articles". Lefaucheur, JP and Saitoh, Y are the two most influential authors. The most frequent type of document was "original article". Most of the studies (34%) that identified the neuropathic pain type focused on traumatic neuropathic pain, although a large proportion (38%) did not report the neuropathic pain type. This study allows us to provide a general overview of the field of TMS application for neuropathic pain and is useful for establishing future directions of research in this field.

(1) Background: Degenerative cervical myelopathy is one of the main causes of disability in the elderly. The treatment of choice in patients with clear symptomatology and radiological correlation is surgical decompression. The application of navigated transcranial magnetic stimulation (nTMS) techniques has the potential to provide additional insights into the cortical and corticospinal behavior of the myelopathic cord and to better characterize the possible extent of clinical recovery. The objective of our study was to use nTMS to evaluate the effect of surgical decompression on neurophysiological properties at the cortical and corticospinal level and to better characterize the extent of possible clinical recovery. (2) Methods: We conducted a longitudinal study in which we assessed and compared nTMS neurophysiological indexes and clinical parameters (modified Japanese Orthopedic Association score and nine-hole pegboard test) before surgery, at 6 months, and at 12 months' follow-up in a population of 15 patients. (3) Results: We found a significant reduction in resting motor threshold (RMT; average 7%), cortical silent period (CSP; average 15%), and motor area (average 25%) at both 6 months and 12 months. A statistically significant linear correlation emerged between recruitment curve (RC) values obtained at follow-up appointments and at baseline (r = 0.95 at 6 months, r = 0.98 at 12 months). A concomitant improvement in the mJOA score and in the nine-hole pegboard task was observed after surgery. (4) Conclusions: Our results suggest that surgical decompression of the myelopathic spinal cord improves the neurophysiological balance at the cortical and corticospinal level, resulting in clinically significant recovery. Such findings contribute to the existing evidence characterizing the brain and the spinal cord as a dynamic system capable of functional and reversible plasticity and provide useful clinical insights to be used for patient counseling.

The aim of this systematic review is to analyze the efficacy of noninvasive brain stimulation (NBS) in the treatment of central post-stroke pain (CPSP).

We included randomized controlled trials testing the efficacy of transcranial magnetic stimulation (TMS) or transcranial direct current stimulation versus placebo or other usual therapy in patients with CPSP. Articles in English, Portuguese, Spanish, Italian, and French were included. A bibliographic search was independently conducted on June 1, 2022, by two authors, using the databases MEDLINE (PubMed), Embase (Elsevier), Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, and Web of Science Core Collection. The risk of bias was assessed using the second version of the Cochrane risk of bias (RoB 2) tool and the certainty of the evidence was evaluated through Grading of Recommendations Assessment, Development and Evaluation.

A total of 2,674 records were identified after removing duplicates, of which 5 eligible studies were included, involving a total of 119 patients. All five studies evaluated repetitive TMS, four of which stimulated the primary motor cortex (M1) and one stimulated the premotor/dorsolateral prefrontal cortex. Only the former one reported a significant pain reduction in the short term, while the latter one was interrupted due to a consistent lack of analgesic effect.

NBS in the M1 area seems to be effective in reducing short-term pain; however, more high-quality homogeneous studies, with long-term follow-up, are required to determine the efficacy of this treatment in CSPS.

Noninvasive brain stimulation (NIBS) techniques have demonstrated their potential for chronic pain management, yet their efficacy exhibits variability across studies. Refining stimulation targets and exploring additional targets offer a possible solution to this challenge. This study aimed to identify potential brain surface targets for NIBS in treating chronic pain disorders by integrating literature review, neuroimaging meta-analysis, and functional connectivity analysis on 90 chronic low back pain patients. Our results showed that the primary motor cortex (M1) (C3/C4, 10-20 EEG system) and prefrontal cortex (F3/F4/Fz) were the most used brain stimulation targets for chronic pain treatment according to the literature review. The bilateral precentral gyrus (M1), supplementary motor area, Rolandic operculum, and temporoparietal junction, were all identified as common potential NIBS targets through both a meta-analysis sourced from Neurosynth and functional connectivity analysis. This study presents a comprehensive summary of the current literature and refines the existing NIBS targets through a combination of imaging meta-analysis and functional connectivity analysis for chronic pain conditions. The derived coordinates (with integration of the international electroencephalography (EEG) 10/20 electrode placement system) within the above brain regions may further facilitate the localization of these targets for NIBS application. Our findings may have the potential to expand NIBS target selection beyond current clinical trials and improve chronic pain treatment.

Central neuropathic pain arises from a lesion or disease of the central somatosensory nervous system such as brain injury, spinal cord injury, stroke, multiple sclerosis or related neuroinflammatory conditions. The incidence of central neuropathic pain differs based on its underlying cause. Individuals with spinal cord injury are at the highest risk; however, central post-stroke pain is the most prevalent form of central neuropathic pain worldwide. The mechanisms that underlie central neuropathic pain are not fully understood, but the pathophysiology likely involves intricate interactions and maladaptive plasticity within spinal circuits and brain circuits associated with nociception and antinociception coupled with neuronal hyperexcitability. Modulation of neuronal activity, neuron-glia and neuro-immune interactions and targeting pain-related alterations in brain connectivity, represent potential therapeutic approaches. Current evidence-based pharmacological treatments include antidepressants and gabapentinoids as first-line options. Non-pharmacological pain management options include self-management strategies, exercise and neuromodulation. A comprehensive pain history and clinical examination form the foundation of central neuropathic pain classification, identification of potential risk factors and stratification of patients for clinical trials. Advanced neurophysiological and neuroimaging techniques hold promise to improve the understanding of mechanisms that underlie central neuropathic pain and as predictive biomarkers of treatment outcome.

Neuropathic pain (NeuP), the result of a lesion or disease of the somatosensory nervous system, is tricky to cure clinically. Mounting researches reveal that neuromodulation can safely and effectively ameliorate NeuP. The number of publications associated with neuromodulation and NeuP increases with time. However, bibliometric analysis on the field is rare. The present study aims to analyze trends and topics in neuromodulation and NeuP research by using a bibliometric method.

This study systematically collected the relevant publications on the Science Citation Index Expanded of Web of Science from January 1994 to January 17, 2023. CiteSpace software was used to draw and analyze corresponding visualization maps.

A total of 1404 publications were ultimately obtained under our specified inclusion criteria. The analysis showed that the focus of research on neuromodulation and NeuP had been developing steadily in recent years, with papers published in 58 countries/regions and 411 academic journals. The Journal of Neuromodulation and the author J.P. Lefaucheur published the most papers. The papers published in Harvard University and the United States contributed significantly. The cited keywords show that motor cortex stimulation, spinal cord stimulation, electrical stimulation, transcranial magnetic stimulation, and mechanism are the research hotspots in the field.

The bibliometric analysis showed that the number of publications on neuromodulation and NeuP are increasing rapidly, especially in the past 5 years. "Motor cortex stimulation," "electrical stimulation," "spinal cord stimulation," "transcranial magnetic stimulation" and "mechanism" catch the most attention among researchers in this field.

Cognitive impairment secondary to traumatic brain injury (TBI) is difficult to treat and usually results in severe disability.

A 48-year-old man presented with chronic refractory headaches and persistent disabling cognitive impairment after TBI. He was first treated with occipital nerve stimulation (ONS) implanted bilaterally to relieve headaches (8 years after the head trauma). Two years later, he was treated with a 6-week protocol combining repetitive transcranial magnetic stimulation (rTMS) delivered to multiple cortical sites (prefrontal cortex, language areas, and areas involved in visuo-spatial functions) and computerized cognitive training (CogT) (targeting memory, language, and visuo-spatial functions) to improve cognitive performance.

Executive and cognitive functions (attention, ability to perform calculations, and verbal fluency) improved in association with pain relief after ONS (33-42% improvement) and then improved even more after the rTMS-CogT protocol with an additional improvement of 36-40% on apathy, depression, and anxiety, leading to a significant reduction in caregiver burden. The functional improvement persisted and even increased at 6 months after the end of the rTMS-CogT procedure (10 years after the onset of TBI and 2 years after ONS implantation).

This is the first observation describing sustained improvement in post-TBI refractory headache, depression, and cognitive impairment by the association of bilaterally implanted ONS and a combined procedure of multisite rTMS and CogT to target various brain functions.

Repetitive transcranial magnetic stimulation (rTMS) applied to the motor cortex provides supplementary relief for some individuals with chronic pain who are refractory to pharmacological treatment. As rTMS slowly enters treatment guidelines for pain relief, its starts to be confronted with challenges long known to pharmacological approaches: efficacy at the group-level does not grant pain relief for a particular patient. In this review, we present and discuss a series of ongoing attempts to overcome this therapeutic challenge in a personalized medicine framework.

Relevant scientific publications published in main databases such as PubMed and EMBASE from inception until March 2023 were systematically assessed, as well as a wide number of studies dedicated to the exploration of the mechanistic grounds of rTMS analgesic effects in humans, primates and rodents.

The main strategies reported to personalize cortical neuromodulation are: (i) the use of rTMS to predict individual response to implanted motor cortex stimulation; (ii) modifications of motor cortex stimulation patterns; (iii) stimulation of extra-motor targets; (iv) assessment of individual cortical networks and rhythms to personalize treatment; (v) deep sensory phenotyping; (vi) personalization of location, precision and intensity of motor rTMS. All approaches except (i) have so far low or moderate levels of evidence.

Although current evidence for most strategies under study remains at best moderate, the multiple mechanisms set up by cortical stimulation are an advantage over single-target 'clean' drugs, as they can influence multiple pathophysiologic paths and offer multiple possibilities of individualization.

Non-invasive neuromodulation is on the verge of personalised medicine. Strategies ranging from integration of detailed clinical phenotyping into treatment design to advanced patient neurophysiological characterisation are being actively explored and creating a framework for actual individualisation of care.

Neuromodulation techniques are being increasingly used to alleviate pain and enhance quality of life. Non-invasive cortical stimulation was originally intended to predict the efficacy of invasive (neurosurgical) techniques, but has now gained a place as an analgesic procedure in its own right.

Repetitive transcranial magnetic stimulation (rTMS): Evidence from 14 randomised, placebo-controlled trials (~750 patients) supports a significant analgesic effect of high-frequency motor cortex rTMS in neuropathic pain. Dorsolateral frontal stimulation has not proven efficacious so far. The posterior operculo-insular cortex is an attractive target but evidence remains insufficient. Short-term efficacy can be achieved with NNT (numbers needed to treat) ~2-3, but long-lasting efficacy remains a challenge.Like rTMS, transcranial direct-current stimulation (tDCS) induces activity changes in distributed brain networks and can influence various aspects of pain. Lower cost relative to rTMS, few safety issues and availability of home-based protocols are practical advantages. The limited quality of many published reports lowers the level of evidence, which will remain uncertain until more prospective controlled studies are available.

Both rTMS and tDCS act preferentially upon abnormal hyperexcitable states of pain, rather than acute or experimental pain. For both techniques, M1 appears to be the best target for chronic pain relief, and repeated sessions over relatively long periods of time may be required to obtain clinically significant benefits. Patients responsive to tDCS may differ from those improved by rTMS.

A new paradigm for Transcranial Magnetic Stimulation (TMS), referred to as prolonged continuous theta burst stimulation (pcTBS), has recently received attention in the literature because of its advantages over high frequency repetitive TMS (HF-rTMS). Clinical advantages include less time per intervention session and the effects appear to be more robust and reproducible than HF-rTMS to modulate cortical excitability. HF-rTMS targeted at the primary motor cortex (M1) has demonstrated analgesic effects in patients with neuropathic pain but their mechanisms of action are unclear and pcTBS has been studied in healthy subjects only. This study examined the neural mechanisms that have been proposed to play a role in explaining the effects of pcTBS targeted at the M1 and DLPFC brain regions in neuropathic pain (NP) patients with Type 2 diabetes.

Forty-two patients with painful diabetic neuropathy were randomized to receive a single session of pcTBS targeted at the left M1 or left DLPFC. pcTBS stimulation consisted of 1,200 pulses delivered in 1 min and 44 s with a 35-45 min gap between sham and active pcTBS stimulation. Both the activity of the descending pain system which was examined using conditioned pain modulation and the activity of the ascending pain system which was assessed using temporal summation of pain were recorded using a handheld pressure algometer by measuring pressure pain thresholds. The amplitude of the motor evoked potential (MEP) was used to measure motor corticospinal excitability and GABA activity was assessed using short (SICI) and long intracortical inhibition (LICI). All these measurements were performed at baseline and post-pcTBS stimulation.

Following a single session of pcTBS targeted at M1 and DLPFC, there was no change in BPI-DN scores and on the activity of the descending (measured using conditioned pain modulation) and ascending pain systems (measured using temporal summation of pain) compared to baseline but there was a significant improvement of >13% in perception of acute pain intensity, increased motor corticospinal excitability (measured using MEP amplitude) and intracortical inhibition (measured using SICI and LICI).

In patients with NP, a single session of pcTBS targeted at the M1 and DLPFC modulated the neurophysiological mechanisms related to motor corticospinal excitability and neurochemical mechanisms linked to GABA activity, but it did not modulate the activity of the ascending and descending endogenous modulatory systems. In addition, although BPI-DN scores did not change, there was a 13% improvement in self-reported perception of acute pain intensity.

The main aim of this study was to assess the effects of repetitive-transcranial magnetic stimulation (rTMS) in patients with fibromyalgia (FMS).

We systematically searched PubMed, PEDro, EMBASE, and CINAHL. Methodological quality was analyzed using the AMSTAR and ROBIS scales, and the strength of evidence was established according to the guidelines advisory committee grading criteria. A total of 11 systematic reviews were included. The assessed variables were pain intensity, depressive symptoms, anxiety, and general health.

Regarding pain intensity, it seems that high-frequency rTMS significantly reduces pain intensity at a 1-month follow-up when the primary motor cortex (M1) is stimulated. However, we cannot robustly conclude the same for low-frequency protocols. When we look at the combination of high and low-frequency rTMS, there seems to be a significant effect on pain intensity up to 1-week post-intervention, but after that point of follow-up, the results are controversial. Regarding depressive symptoms and anxiety, results showed that the effects of rTMS are almost non-existent. Finally, in regard to general health, results showed that rTMS caused significant post-intervention effects in a robust way. However, the results of the follow-ups are contradictory.

The results obtained showed that high-frequency rTMS applied on the M1 showed some effect on the variable of pain intensity with a limited quality of evidence. Overall, rTMS was shown to be effective in improving general health with moderate quality of evidence. Finally, rTMS was not shown to be effective in managing depressive symptoms and anxiety with a limited to moderate quality of evidence. PROSPERO number: This review was previously registered in PROSPERO (CRD42023391032).

Repeated spaced TMS protocols, also termed accelerated TMS protocols, are of increasing therapeutic interest. The long-term potentiation (LTP)-like effects of repeated spaced intermittent theta-burst transcranial magnetic stimulation (iTBS) are presumed to be N-Methyl-D-Aspartate receptor (NMDA-R) dependent; however, this has not been tested. We tested whether the LTP-like effects of repeated spaced iTBS are influenced by low-dose D-Cycloserine (100 mg), an NMDA-R partial-agonist. We conducted a randomized, double-blind, placebo-controlled crossover trial in 20 healthy adults from August 2021-Feb 2022. Participants received repeated spaced iTBS, consisting of two iTBS sessions 60 minutes apart, to the primary motor cortex. The peak-to-peak amplitude of the motor evoked potentials (MEP) at 120% resting motor threshold (RMT) was measured after each iTBS. The TMS stimulus-response (TMS-SR; 100-150% RMT) was measured at baseline, +30 min, and +60 min after each iTBS. We found evidence for a significant Drug*iTBS effect in MEP amplitude, revealing that D-Cycloserine enhanced MEP amplitudes relative to the placebo. When examining TMS-SR, pairing iTBS with D-Cycloserine increased the TMS-SR slope relative to placebo after both iTBS tetani, and this was due to an increase in the upper bound of the TMS-SR. This indicates that LTP-like and metaplastic effects of repeated-spaced iTBS involve NMDA-R, as revealed by two measures of corticospinal excitability, and that low-dose D-Cycloserine facilitates the physiological effects of repeated spaced iTBS. However, extension of these findings to clinical populations and therapeutic protocols targeting non-motor regions of cortex requires empirical validation.

The aim of the present study was to compare the analgesic effect of motor cortex stimulation using high-frequency repetitive transcranial magnetic stimulation or transcranial direct current stimulation and transcutaneous spinal direct current stimulation in patients with complex regional pain syndrome. Thirty-three patients with complex regional pain syndrome were randomized to one of the three treatment groups (repetitive transcranial magnetic stimulation, n = 11; transcranial direct current stimulation, n = 10; transcutaneous spinal direct current stimulation, n = 12) and received a series of 12 sessions of stimulation for 3 weeks (induction phase) and 11 sessions for 4 months (maintenance therapy). The primary end-point was the mean pain intensity assessed weekly with a visual numerical scale during the month prior to treatment (baseline), the 5-month stimulation period and 1 month after the treatment. The weekly visual numerical scale pain score was significantly reduced at all time points compared to baseline in the transcutaneous spinal direct current stimulation group, at the last two time points in the repetitive transcranial magnetic stimulation group (end of the 5-month stimulation period and 1 month later), but at no time point in the transcranial direct current stimulation group. A significant pain relief was observed at the end of induction phase using transcutaneous spinal direct current stimulation compared to repetitive transcranial magnetic stimulation (P = 0.008) and to transcranial direct current stimulation (P = 0.003). In this trial, transcutaneous spinal direct current stimulation was more efficient to relieve pain in patients with complex regional pain syndrome compared to motor cortex stimulation techniques (repetitive transcranial magnetic stimulation, transcranial direct current stimulation). This efficacy was found during the induction phase and was maintained thereafter. This study warrants further investigation to confirm the potentiality of transcutaneous spinal direct current stimulation as a therapeutic option in complex regional pain syndrome.

It is not known whether cortical plastic changes reported in low-back pain (LBP) are present in all etiologies of LBP. Here we report on the assessment of patients with three LBP conditions: non-specific-LBP (ns-LBP), failed back surgery syndrome (FBSS), and sciatica (Sc).

Patients underwent a standardized assessment of clinical pain, conditioned pain modulation (CPM), and measures of motor evoked potential (MEPs)-based motor corticospinal excitability (CE) by transcranial magnetic stimulation, including short interval intracortical inhibition (SICI), and intracortical facilitation (ICF). Comparisons were also made with normative data from sex- and age-matched healthy volunteers.

60 patients (42 women, 55.1±9.1 years old) with LBP were included (20 in each group). Pain intensity was higher in patients with neuropathic pain [FBSS (6.8±1.3), and Sc (6.4±1.4)] than in those with ns-LBP (4.7±1.0, P<0.001). The same was shown for pain interference (5.9±2.0, 5.9±1.8, 3.2±1.9, P<0.001), disability (16.4±3.3, 16.3±4.3, 10.4±4.3, P<0.001), and catastrophism (31.1±12.3, 33.0±10.4, 17.4±10.7, P<0.001) scores for FBSS, Sc, and ns-LBP groups, respectively. Patients with neuropathic pain (FBSS, Sc) had lower CPM (-14.8±1.9, -14.1±16.7, respectively) compared to ns-LBP (-25.4±16.6; P<0.02). 80.0% of the FBSS group had defective ICF compared to the other two groups (52.5% for ns-LBP, P=0.025 and 52.5% for Sc, P=0.046). MEPs (140%-rest motor threshold) were low in 50.0% of patients in the FBSS group compared to 20.0% of ns-LBP (P=0.018) and 15.0% of Sc (P=0.001) groups. Higher MEPs were correlated with mood scores (r=0.489), and with lower neuropathic pain symptom scores(r=-0.415) in FBSS.

Different types of LBP were associated with different clinical, CPM and CE profiles, which were not uniquely related to the presence of neuropathic pain. These results highlight the need to further characterize patients with LBP in psychophysics and cortical neurophysiology studies.

The review provides a comprehensive update (previous report: Chen R, Cros D, Curra A, Di Lazzaro V, Lefaucheur JP, Magistris MR, et al. The clinical diagnostic utility of transcranial magnetic stimulation: report of an IFCN committee. Clin Neurophysiol 2008;119(3):504-32) on clinical diagnostic utility of transcranial magnetic stimulation (TMS) in neurological diseases. Most TMS measures rely on stimulation of motor cortex and recording of motor evoked potentials. Paired-pulse TMS techniques, incorporating conventional amplitude-based and threshold tracking, have established clinical utility in neurodegenerative, movement, episodic (epilepsy, migraines), chronic pain and functional diseases. Cortical hyperexcitability has emerged as a diagnostic aid in amyotrophic lateral sclerosis. Single-pulse TMS measures are of utility in stroke, and myelopathy even in the absence of radiological changes. Short-latency afferent inhibition, related to central cholinergic transmission, is reduced in Alzheimer's disease. The triple stimulation technique (TST) may enhance diagnostic utility of conventional TMS measures to detect upper motor neuron involvement. The recording of motor evoked potentials can be used to perform functional mapping of the motor cortex or in preoperative assessment of eloquent brain regions before surgical resection of brain tumors. TMS exhibits utility in assessing lumbosacral/cervical nerve root function, especially in demyelinating neuropathies, and may be of utility in localizing the site of facial nerve palsies. TMS measures also have high sensitivity in detecting subclinical corticospinal lesions in multiple sclerosis. Abnormalities in central motor conduction time or TST correlate with motor impairment and disability in MS. Cerebellar stimulation may detect lesions in the cerebellum or cerebello-dentato-thalamo-motor cortical pathways. Combining TMS with electroencephalography, provides a novel method to measure parameters altered in neurological disorders, including cortical excitability, effective connectivity, and response complexity.

Central neuropathic pain (CNP) is associated with altered corticomotor excitability (CE), which can potentially provide insights into its mechanisms. The objective of this study is to describe the CE changes that are specifically related to CNP.

We evaluated CNP associated with brain injury after stroke or spinal cord injury (SCI) due to neuromyelitis optica through a battery of CE measurements and comprehensive pain, neurological, functional, and quality of life assessments. CNP was compared to two groups of patients with the same disease: i. with non-neuropathic pain and ii. without chronic pain, matched by sex and lesion location.

We included 163 patients (stroke=93; SCI=70: 74 had CNP, 43 had non-neuropathic pain, and 46 were pain-free). Stroke patients with CNP had lower motor evoked potential (MEP) in both affected and unaffected hemispheres compared to non- neuropathic pain and no-pain patients. Patients with CNP had lower amplitudes of MEPs (366 μV ±464 μV) than non-neuropathic (478 ±489) and no-pain (765 μV ± 880 μV) patients, p < 0.001. Short-interval intracortical inhibition (SICI) was defective (less inhibited) in patients with CNP (2.6±11.6) compared to no-pain (0.8±0.7), p = 0.021. MEPs negatively correlated with mechanical and cold-induced allodynia. Furthermore, classifying patients' results according to normative data revealed that at least 75% of patients had abnormalities in some CE parameters and confirmed MEP findings based on group analyses.

CNP is associated with decreased MEPs and SICI compared to non-neuropathic pain and no-pain patients. Corticomotor excitability changes may be helpful as neurophysiological markers of the development and persistence of pain after CNS injury, as they are likely to provide insights into global CE plasticity changes occurring after CNS lesions associated with CNP.

Stroke is a leading cause of mortality and disability worldwide, with most survivors reporting dysfunctions of motor, sensation, deglutition, cognition, emotion, and speech, etc. Repetitive transcranial magnetic stimulation (rTMS), one of noninvasive brain stimulation (NIBS) techniques, is able to modulate neural excitability of brain regions and has been utilized in neurological and psychiatric diseases. Moreover, a large number of studies have shown that the rTMS presents positive effects on function recovery of stroke patients. In this review, we would like to summarized the clinical benefits of rTMS for stroke rehabilitation, including improvements of motor impairment, dysphagia, depression, cognitive function, and central post-stroke pain. In addition, this review will also discuss the molecular and cellular mechanisms underlying rTMS-mediated stroke rehabilitation, especially immune regulatory mechanisms, such as regulation of immune cells and inflammatory cytokines. Moreover, the neuroimaging technique as an important tool in rTMS-mediated stroke rehabilitation has been discussed, to better understanding the mechanisms underlying the effects of rTMS. Finally, the current challenges and future prospects of rTMS-mediated stroke rehabilitation are also elucidated with the intention to accelerate its widespread clinical application.

Transcranial magnetic stimulation (TMS) has revealed differences in the motor cortex (M1) between people with and without low back pain (LBP). There is potential to reverse these changes using motor skill training, but it remains unclear whether changes can be induced in people with LBP or whether this differs between LBP presentations. This study (1) compared TMS measures of M1 (single and paired-pulse) and performance of a motor task (lumbopelvic tilting) between individuals with LBP of predominant nociceptive (n = 9) or nociplastic presentation (n = 9) and pain-free individuals (n = 16); (2) compared these measures pre- and post-training; and (3) explored correlations between TMS measures, motor performance, and clinical features. TMS measures did not differ between groups at baseline. The nociplastic group undershot the target in the motor task. Despite improved motor performance for all groups, only MEP amplitudes increased across the recruitment curve and only for the pain-free and nociplastic groups. TMS measures did not correlate with motor performance or clinical features. Some elements of motor task performance and changes in corticomotor excitability differed between LBP groups. Absence of changes in intra-cortical TMS measures suggests regions other than M1 are likely to be involved in skill learning of back muscles.

Postherpetic neuralgia (PHN) is a refractory neuropathic pain condition in which new treatment options are being developed. Repetitive transcranial magnetic stimulation (rTMS) may have the potential to reduce pain sensations in patients with postherpetic neuralgia.

This study investigated the efficacy on postherpetic neuralgia by stimulating two potential targets, the motor cortex (M1) and the dorsolateral prefrontal cortex (DLPFC).

This is a double-blind, randomised, sham-controlled study. Potential participants were recruited from Hangzhou First People's Hospital. Patients were randomly assigned to either the M1, DLPFC or Sham group. Patients received ten daily sessions of 10-Hz rTMS in 2 consecutive weeks. The primary outcome measure was visual analogue scale (VAS) assessed at baseline, first week of treatment (week 1), post-treatment (week 2), 1-week (week 4), 1-month (week 6) and 3-month (week 14) follow-up.

Of sixty patients enrolled, 51 received treatment and completed all outcome assessments. M1 stimulation resulted in a larger analgesia during and after treatment compared to the Sham (week 2 - week 14, p < 0.005), as well as to the DLPFC stimulation (week 1 - week 14, p < 0.05). In addition to pain, sleep disturbance was significantly improved and relieved by targeting either the M1 or the DLPFC (M1: week 4 - week 14, p < 0.01; DLPFC: week 4 - week 14, p < 0.01). Moreover, pain sensations following M1 stimulation uniquely predicted improvement in sleep quality.

M1 rTMS is superior to DLPFC stimulation in treating PHN with excellent pain response and long-term analgesia. Meanwhile, M1 and DLPFC stimulation were equally effective in improving sleep quality in PHN.

https://www.chictr.org.cn/, identifier ChiCTR2100051963.

Chronic pain is a debilitating condition with a growing prevalence both in the USA and globally. The complex nature of this condition necessitates a multimodal approach to pain management that extends beyond the established pharmaceutical interventions currently employed. A variety of devices comprising both invasive and noninvasive approaches are available to patients, serving as adjuvants to existing regimens. The benefits of these interventions are notable for their lack of addiction potential, potential for patient autonomy regarding self-administration, minimal to no drug interaction, and overall relative safety. However, there remains a need for further research and more robust clinical trials to assess the true efficacy of these interventions and elucidate if there is an underlying physiological mechanism to their benefit in treating chronic pain or if their effect is predominantly placebo in nature. Regardless, the field of device-based intervention and treatment remains an evolving field with much promise for the future chronic pain management.

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.

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).

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.

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.

Our findings therefore provide preliminary evidence for iTBS targeting the DLPFC to be used to improve postoperative pain management.

Pain is a common symptom in palliative care cancer patients and is often insufficiently relieved. In recent years, transcranial direct-current stimulation (tDCS) of the motor cortex has been shown to be effective to treat chronic pain, essentially neuropathic pain. We propose to test the efficacy of tDCS in patients experiencing cancer pain in the palliative care setting.

This article describes the protocol of a bicentre, randomized, parallel-arm, sham-controlled clinical trial evaluating tDCS in the treatment of palliative care patients with refractory cancer pain. Seventy patients between the ages of 18 and 80 years experiencing refractory pain with a pain score of 4/10 on a numerical rating scale (NRS) ranging from 0 to 10 will be enrolled in this trial. The main exclusion criteria are patients unable to fill in the various rating scales and life expectancy less than 3 weeks. Treatment consists of 5 consecutive tDCS sessions targeting the motor cortex (one daily session for 5 days) on the contralateral side to the pain. After randomization (1:1 ratio), 35 patients will receive active stimulation and 35 patients will receive sham stimulation. The primary endpoint is the NRS score and the primary objective is a significant improvement of this score between the baseline score recorded between D-3 and D-1 and the score recorded 4 days after stopping treatment (D8). The secondary objectives are to evaluate whether this improvement is maintained 16 days after stopping treatment (D21) and whether the following scores are improved on D14 and D21: Brief Pain Inventory, Edmonton Symptom Assessment System, Hospital Anxiety and Depression scale, State-Trait Anxiety Inventory and Medication Quantification Scale.

Positive results of this trial would indicate that tDCS can improve pain and quality of life of cancer patients in the palliative care setting. Reduction of analgesic consumption and improvement of activities of daily living should allow many patients to return home with a decreased workload for caregivers.

Post-stroke pain (PSP) is a common complication after stroke and affects patients' quality of life. Currently, drug therapy and non-invasive brain stimulation are common treatments for PSP. Given the poor efficacy of drug therapy and various side effects, non-invasive brain stimulation, such as repetitive transcranial magnetic stimulation (rTMS), has been accepted by many patients and attracted the attention of many researchers because of its non-invasive and painless nature. This article reviews the therapeutic effect of rTMS on PSP and discusses the possible mechanisms. In general, rTMS has a good therapeutic effect on PSP. Possible mechanisms of its analgesia include altering cortical excitability and synaptic plasticity, modulating the release of related neurotransmitters, and affecting the structural and functional connectivity of brain regions involved in pain processing and modulation. At present, studies on the mechanism of rTMS in the treatment of PSP are lacking, so we hope this review can provide a theoretical basis for future mechanism studies.

Treatment refractory or recurrent trigeminal neuralgia (TN) is a severe chronic pain illness. Single-session repetitive transcranial magnetic stimulation (rTMS) has been shown to elicit analgesic effects in several craniofacial pain syndromes, including TN. However, the safety and long-term effect of multi-session rTMS for TN have yet to be fully explored. In this study, we present a case of a patient with medical treatment-refractory TN after microvascular decompression. The patient volunteered to undergo 73 sessions of 10 Hz rTMS over 23 months. Neurovagination was used for precise localization and stimulation of the hand and face representation at the left motor cortex. The numeric pain intensity scores derived using the visual analog scale served as a daily index of treatment efficacy. The patient experienced a significant weekly reduction in pain scores, cumulating in 70.89% overall pain relief. The medication dosages were reduced and then discontinued toward the end of the intervention period. No severe adverse events were reported. From our results, we can conclude that the longitudinal multi-session application of rTMS over the hand and face area of M1 is a safe and effective method for producing long-lasting pain relief in TN. Using rTMS may thus prove helpful as an adjunct to conventional methods for treating pain in TN.

The purpose of this review was to systematically assess the effectiveness of 10-Hz repetitive transcranial magnetic stimulation (rTMS) in fibromyalgia.

We searched PubMed, Cochrane Library, Embase, Web of Science, and Ovid databases as of November 6, 2021.

The inclusion criteria for this review were randomized controlled trials of 10-Hz rTMS for fibromyalgia, exploring the effects of 10-Hz rTMS on pain, depression, and quality of life in patients with fibromyalgia.

Data extraction was performed independently by 2 evaluators according to predefined criteria, and the quality of the included literature was assessed using the Cochrane Bias Risk Assessment Tool. The measurement outcomes include visual analog scale, Hamilton Depression Rating Scale, and Fibromyalgia Impact Questionnaire, and so on.

A total of 488 articles were screened, and the final 7 selected high-quality articles with 217 patients met our inclusion criteria. Analysis of the results showed that high-frequency transcranial magnetic stimulation at 10 Hz was significantly associated with reduced pain compared with sham stimulation in controls (standardized mean difference [SMD]=-0.72; 95% confidence interval [CI], -1.12 to -0.33; P<.001; I²=46%) and was able to improve quality of life (SMD=-0.70; 95% CI, -1.00 to -0.40; P<.001; I²=15%) but not improve depression (SMD=-0.23; 95% CI, -0.50 to 0.05; P=.11; I²=33%). In addition, a subgroup analysis of pain conducted based on stimulation at the primary motor cortex and dorsolateral prefrontal cortex showed no significant difference (SMD=-0.72; 95% CI, -1.12 to -0.33; P=.10; I²=62%).

Overall, 10-Hz rTMS has a significant effect on analgesia and improved quality of life in patients with FMS but did not improve depression.

While high-frequency transcranial magnetic stimulation (HF-rTMS) is now included in the armamentarium to treat chronic neuropathic pain (NP), direct-current anodal stimulation (a-tDCS) to the same cortical targets may represent a valuable alternative in terms of feasibility and cost. Here we performed a head-to-head, randomized, single-blinded, cross-over comparison of HF-rTMS versus a-tDCS over the motor cortex in 56 patients with drug-resistant NP, who received 5 daily sessions of each procedure, with a washout of at least 4 weeks. Daily scores of pain, sleep, and fatigue were obtained during 5 consecutive weeks, and functional magnetic resonance imaging (fMRI) to a motor task was performed in a subgroup of 31 patients. The percentage of responders, defined by a reduction in pain scores of > 2 SDs from pre-stimulus levels, was similar to both techniques (42.0% vs. 42.3%), while the magnitude of "best pain relief" was significantly skewed towards rTMS. Mean pain ratings in responders decreased by 32.6% (rTMS) and 29.6% (tDCS), with half of them being sensitive to only one technique. Movement-related fMRI showed significant activations in motor and premotor areas, which did not change after 5 days of stimulation, and did not discriminate responders from non-responders. Both HF-rTMS and a-tDCS showed efficacy at 1 month in drug-resistant NP, with magnitude of relief slightly favoring rTMS. Since a significant proportion of patients responded to one procedure only, both modalities should be tested before declaring a patient as unresponsive.

TMS is being used to aid in the diagnosis of central nervous system (CNS) illnesses. It is useful in planning rehabilitation programs and setting appropriate goals for patients. We used a parabolic coil with biphasic pulse stimulation to find normal values for diagnostic TMS parameters.

1. To determine the normal motor threshold (MT), motor evoked potentials (MEP), central motor conduction time (CMCT), intracortical facilitation (ICF), short-interval intracortical inhibition (SICI), and silent period (SP) values. 2. To measure the MEP latencies of abductor pollicis brevis (APB) and extensor digitorum brevis (EDB) at various ages, heights, and arm and leg lengths.

Descriptive Study.

Department of Rehabilitation Medicine, Chiang Mai University, Thailand.

Forty-eight healthy participants volunteered for the study.

All participants received a single diagnostic TMS using a parabolic coil with biphasic pulse stimulation on the left primary motor cortex (M1). All parameters: MT, MEP, CMCT, ICF, SICI, and SP were recorded through surface EMGs at the right APB and EDB. Outcome parameters were reported by the mean and standard deviation (SD) or median and interquartile range (IQR), according to data distribution. MEP latencies of APB and EDB were also measured at various ages, heights, and arm and leg lengths.

APB-MEP latencies at 120% and 140% MT were 21.77 ± 1.47 and 21.17 ± 1.44 ms. APB-CMCT at 120% and 140% MT were 7.81 ± 1.32 and 7.19 ± 1.21 ms. APB-MEP amplitudes at 120% and 140% MT were 1.04 (0.80-1.68) and 2.24 (1.47-3.52) mV. EDB-MEP latencies at 120% and 140% MT were 37.14 ± 2.85 and 36.46 ± 2.53 ms. EDB-CMCT at 120% and 140% MT were 14.33 ± 2.50 and 13.63 ± 2.57 ms. EDB-MEP amplitudes at 120% and 140% MT were 0.60 (0.38-0.98) and 0.95 (0.69-1.55) mV. ICF amplitudes of APB and EDB were 2.26 (1.61-3.49) and 1.26 (0.88-1.98) mV. SICI amplitudes of APB and EDB were 0.21 (0.13-0.51) and 0.18 (0.09-0.29) mV. MEP latencies of APB at 120% and 140% MT were different between heights < 160 cm and ≥ 160 cm (p < 0.001 and p < 0.001) and different between arm lengths < 65 and ≥ 65 cm (p = 0.022 and p = 0.002).

We established diagnostic TMS measurements using a parabolic coil with a biphasic pulse configuration. EDB has a higher MT than APB. The 140/120 MEP ratio of APB and EDB is two-fold. The optimal MEP recording for APB is 120%, whereas EDB is 140% of MT. CMCT by the F-wave is more convenient and tolerable for patients. ICF provides a twofold increase in MEP amplitude. SICI provides a ¼-fold of MEP amplitude. SP from APB and EDB are 121.58 ± 21.50 and 181.01 ± 40.99 ms, respectively. Height and MEP latencies have a modest relationship, whereas height and arm length share a strong positive correlation.

Chronic pain is associated with abnormal cortical excitability and increased pain intensity. Research investigating the potential for transcranial direct current stimulation (tDCS) to modulate motor cortex excitability and reduce pain in individuals with chronic lower back pain (CLBP) yield mixed results. The present randomised, placebo-controlled study examined the impact of anodal-tDCS over left-dorsolateral prefrontal cortex (left-DLPFC) on motor cortex excitability and pain in those with CLBP. Nineteen participants with CLBP (Mage = 53.16 years, SDage = 14.80 years) received 20-min of sham or anodal tDCS, twice weekly, for 4 weeks. Short interval intracortical inhibition (SICI) and intracortical facilitation (ICF) were assessed using paired-pulse Transcranial Magnetic Stimulation prior to and immediately following the tDCS intervention. Linear Mixed Models revealed no significant effect of tDCS group or time, on SICI or ICF. The interactions between tDCS group and time on SICI and ICF only approached significance. Bayesian analyses revealed the anodal-tDCS group demonstrated higher ICF and SICI following the intervention compared to the sham-tDCS group. The anodal-tDCS group also demonstrated a reduction in pain intensity and self-reported disability compared to the sham-tDCS group. These findings provide preliminary support for anodal-tDCS over left-DLPFC to modulate cortical excitability and reduce pain in CLBP.

Chronic noncancer pain is a global public health challenge. It is imperative to identify biological markers ("biomarkers") to understand the mechanisms underlying chronic pain and to monitor pain over time and after interventions. Transcranial magnetic stimulation (TMS) is a promising method for this purpose.

To examine differences in TMS-based outcomes between persons with chronic pain and healthy controls (HCs) and/or before versus after pain-modulating interventions and relationships between pain measures and TMS outcomes; To summarize the neurophysiological mechanisms underlying chronic pain as identified by TMS.

We searched the PubMed database for literature from January 1, 1985, to June 9, 2020, with the keywords "pain" and "transcranial magnetic stimulation." Eligible items included original studies of adult human participants with pain lasting for ≥ 6 months. We completed a narrative synthesis of the study findings stratified by chronic pain etiology (primary pain, neuropathic pain, and secondary musculoskeletal pain).

The search yielded 1265 records. The final 12 articles included 244 patients with chronic pain (192 females, aged 35-65 years) and 169 HCs (89 females, aged 28-59 years). Abnormalities in TMS outcomes that reflect GABAergic and glutamatergic activities were associated with many of the disorders studied and were distinct for each pain etiology. Chronic primary pain is characterized by reduced intracortical inhibition and corticospinal excitability, chronic neuropathic pain shows evidence of increased excitation and disinhibition, and chronic secondary musculoskeletal pain involves low corticospinal excitability.

TMS could be a useful tool for delineating the neurophysiological underpinnings of chronic pain syndromes.