Use of repetitive transcranial magnetic stimulation in pain relief

Repetitive transcranial magnetic stimulation (rTMS) of the cerebral cortex is a noninvasive strategy that could have the potential to relieve severe chronic pain, at least partially and transiently. The most studied target of stimulation is the precentral (motor) cortex, but other targets, such as the dorsolateral prefrontal cortex or the parietal cortex, could be of interest. Analgesic effects have been produced by rTMS in patients with neuropathic pain, fibromyalgia or visceral pain. Therapeutic applications of rTMS in pain syndromes are limited by the short duration of the induced effects, but prolonged pain relief can be obtained by performing rTMS sessions every day for several weeks. In patients who respond to rTMS but relapse, surgical implantation of epidural cortical electrodes and a pulse generator can be proposed to make clinical effects more permanent. The rate of improvement produced by rTMS may be predictive for the outcome of the implanted procedure. The place of rTMS as a therapeutic tool in the management of chronic pain remains to be determined.     

Non pharmacological treatment for neuropathic pain: Invasive and non-invasive cortical stimulation

The use of medications in chronic neuropathic pain may be limited with regard to efficacy and tolerance. Therefore, non-pharmacological approaches, using electrical stimulation of the cortex has been proposed as an alternative. First, in the early nineties, surgically-implanted epidural motor cortex stimulation (EMCS) was proven to be effective to relieve refractory neuropathic pain. Later, non-invasive stimulation techniques were found to produce similar analgesic effects, at least by means of repetitive transcranial magnetic stimulation (rTMS) targeting the primary motor cortex (M1). Following “high-frequency” rTMS (e.g., stimulation frequency ranging from 5 to 20 Hz) delivered to the precentral gyrus (e.g., M1 region), it is possible to obtain an analgesic effect via the modulation of several remote brain regions involved in nociceptive information processing or control. This pain reduction can last for weeks beyond the time of the stimulation, especially if repeated sessions are performed, probably related to processes of long-term synaptic plasticity. Transcranial direct current stimulation (tDCS), another form of transcranial stimulation, using low-intensity electrical currents, generally delivered by a pair of large electrodes, has also shown some efficacy to improve patients with chronic pain syndromes. The mechanism of action of tDCS differs from that of EMCS and rTMS, but the cortical target is the same, which is M1. Although the level of evidence of therapeutic efficacy in the context of neuropathic pain is lower for tDCS than for rTMS, interesting perspectives are opened by using at-home tDCS protocols for long-term management. Now, there is a scientific basis for recommending both EMCS and rTMS of M1 to treat refractory chronic neuropathic pain, but their application in clinical practice remains limited due to practical and regulatory issues.     

Motor Cortex Stimulation for Pain: A Narrative Review of Indications,Techniques, and Outcomes

BackgroundMotor cortex stimulation (MCS) was introduced in 1985 and has been tested extensively for different types of peripheral and central neuropathic pain syndromes (eg, central poststroke pain, phantom limb pain, trigeminal neuropathic pain, migraines, etc). The motor cortex can be stimulated through different routes, including subdural, epidural, and transcranial.ObjectivesIn this review, we discuss the current uses, surgical techniques, localization techniques, stimulation parameters, and clinical outcomes of patients who underwent chronic MCS for treatment-resistant pain syndromes.Materials and MethodsA broad literature search was conducted through PubMed to include all articles focusing on MCS for pain relief (keywords: subdural, epidural, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, motor cortex stimulation, pain).Literature ReviewEpidural MCS was the most widely used technique and had varying response rates across studies. Long-term efficacy was limited, and pain relief tended to decrease over time. Subdural MCS using similar stimulation parameters demonstrated similar efficacy to epidural stimulation and less invasive methods, such as repetitive transcranial magnetic stimulation (rTMS), which have been shown to provide adequate pain relief. rTMS and certain medications (ketamine and morphine) have been shown to predict the long-term response to epidural MCS. Complications tend to be rare, the most reported being seizures during subdural or epidural stimulation or hardware infection.ConclusionsScientific evidence supports the use of MCS for treatment of refractory neuropathic pain syndromes. Further studies are warranted to elucidate the specific indications and stimulation protocols that are most amenable to the different types of MCS.     

Motor cortex rTMS reduces acute pain provoked by laser stimulation in patients with chronic neuropathic pain

ObjectiveTo assess the modulation of acute provoked pain by repetitive transcranial magnetic stimulation (rTMS) of the motor cortex in patients with chronic neuropathic pain.MethodsIn 32 patients with chronic neuropathic pain affecting one upper limb, laser-evoked potentials (LEPs) (N2 and P2 components) were recorded in response to laser stimulation of the painful or painless hand, before and after active or sham rTMS applied at 10 Hz over the motor cortex corresponding to the painful hand. Laser-induced pain was scored on a visual analogue scale.ResultsBoth active and sham rTMS reduced N2–P2 amplitude of the LEPs in response to painful or painless hand stimulation, likely due to the decline of attention during the sessions. However, active rTMS, but not sham rTMS, specifically reduced N2 amplitude and N2/P2 amplitude ratio of the painful hand LEPs. Painful hand LEP attenuation correlated with the magnitude of pain relief produced by active rTMS.ConclusionMotor cortex rTMS delivered at high frequency (10 Hz) was able to reduce LEP amplitude in parallel with laser-induced pain scores in patients with chronic neuropathic pain. The preferential change in the N2 component suggested a modulation of the sensori-discriminative aspect of laser-induced pain.SignificancePrevious studies have shown that rTMS delivered to various cortical targets by different protocols could modulate experimental pain, primarily in healthy subjects. The present results demonstrate the ability of motor cortex rTMS to interfere with the processing of acute provoked pain, even if there is an underlying chronic neuropathic pain.     

Neurogenic pain relief by repetitive transcranial magnetic cortical stimulation depends on the origin and the site of pain

OBJECTIVE: Drug resistant neurogenic pain can be relieved by repetitive transcranial magnetic stimulation (rTMS) of the motor cortex. This study was designed to assess the influence of pain origin, pain site, and sensory loss on rTMS efficacy. PATIENTS AND METHODS: Sixty right handed patients were included, suffering from intractable pain secondary to one of the following types of lesion: thalamic stroke, brainstem stroke, spinal cord lesion, brachial plexus lesion, or trigeminal nerve lesion. The pain predominated unilaterally in the face, the upper limb, or the lower limb. The thermal sensory thresholds were measured within the painful zone and were found to be highly or moderately elevated. Finally, the pain level was scored on a visual analogue scale before and after a 20 minute session of "real" or "sham" 10 Hz rTMS over the side of the motor cortex corresponding to the hand on the painful side, even if the pain was not experienced in the hand itself. RESULTS: and discussion: The percentage pain reduction was significantly greater following real than sham rTMS (-22.9% v -7.8%, p = 0.0002), confirming that motor cortex rTMS was able to induce antalgic effects. These effects were significantly influenced by the origin and the site of pain. For pain origin, results were worse in patients with brainstem stroke, whatever the site of pain. This was consistent with a descending modulation within the brainstem, triggered by the motor corticothalamic output. For pain site, better results were obtained for facial pain, although stimulation was targeted on the hand cortical area. Thus, in contrast to implanted stimulation, the target for rTMS procedure in pain control may not be the area corresponding to the painful zone but an adjacent one. Across representation plasticity of cortical areas resulting from deafferentation could explain this discrepancy. Finally, the degree of sensory loss did not interfere with pain origin or pain site regarding rTMS effects. CONCLUSION: Motor cortex rTMS was found to result in a significant but transient relief of chronic pain, influenced by pain origin and pain site. These parameters should be taken into account in any further study of rTMS application in chronic pain control.     

Repetitive transcranial magnetic stimulation (rTMS): insights into the treatment of Parkinson's disease by cortical stimulation.

Repetitive transcranial magnetic stimulation (rTMS) is a potent tool that can be used to modify activity of targeted cortical areas. Significant clinical effects have been obtained in patients with Parkinson's disease (PD) by stimulating different cortical regions with rTMS at inhibitory (low) or excitatory (high) frequency. These effects were thought to result from plastic changes in motor cortical networks. Actually cortical dysfunction has been documented in PD by neuroimaging and neurophysiologic studies showing either hypo- or hyper-activation of various brain areas. In addition, cortical excitability studies using transcranial magnetic stimulation disclosed significant alterations in intracortical facilitatory or inhibitory processes according to the resting state or to phases of movement preparation or execution. These observations clearly support the therapeutic potential of cortical neuromodulation in PD. Motor cortex stimulation could impact on any station within the cortico-basal ganglia-thalamo-cortical loops that are involved in motor control, providing alleviation of parkinsonian symptoms. Depending on the target, cortical stimulation might improve motor performance or other symptoms associated with PD, like depression. Clinical application of rTMS to treat PD patients is limited by the short duration of the effects beyond the time of stimulation, even if long-lasting improvements have been observed after repeated rTMS sessions. In any case, the place of cortical stimulation in the therapeutic management of PD patients remains to be determined, as an alternative or a complementary technique to deep brain stimulation. The rTMS technique could be used to better define the targets and the parameters of stimulation subsequently applied in chronic epidural stimulation.     

Transcranial Magnetic Stimulation in Neurology: What We Have Learned From Randomized Controlled Studies

Background. Initially developed to excite peripheral nerves, magnetic stimulation was quickly recognized as a valuable tool to noninvasively activate the cerebral cortex. The subsequent discovery that repetitive transcranial magnetic stimulation (rTMS) could have long‐lasting effects on cortical excitability spawned a broad interest in the use of this technique as a new therapeutic method in a variety of neuropsychiatric disorders. Although the current outcomes from initial trials include some conflicting results, initial evidence supports that rTMS might have a therapeutic value in different neurologic conditions. Methods. We reviewed the results of clinical trials of rTMS on four different disorders: stroke, Parkinson's disease, chronic refractory pain, and epilepsy. We reviewed randomized, controlled studies only in order to obtain the strongest evidence for the clinical effects of rTMS. Results. An extensive literature review revealed 32 articles that met our criteria. From these studies, we found evidence for the therapeutic efficacy of rTMS, particularly in the relief of chronic pain and motor neurorehabilitation in single hemisphere stroke patients. Repetitive TMS also seems to have a therapeutic effect on motor function in Parkinson's disease, but the evidence is somewhat confounded by the uncontrolled variability of multiple factors. Lastly, only two randomized, sham‐controlled studies have been performed for epilepsy; although evidence indicates rTMS may reduce seizure frequency in patients with neocortical foci, more research is needed to confirm these initial findings. Conclusions. There is mounting evidence for the efficacy of rTMS in the short‐term treatment of certain neurologic conditions. More long‐term research is needed in order to properly evaluate the effects of this method in a clinical setting.     

重复经颅磁刺激治疗慢性神经病理性疼痛

目的探讨重复经颅磁刺激（rTMS）对慢性神经病理性疼痛的疗效和安全性。方法回顾性分析4例慢性神经病理性疼痛病人的资料,其中丘脑痛3例,臂丛神经撕脱伤后疼痛1例,均经正规药物治疗效果欠佳,给予运动皮质10Hz的rTMS（1000次刺激）治疗,每个疗程5d,共3个疗程。分别于治疗前、每个疗程后以及全部疗程结束后1个月、6个月和1年采用视觉模拟疼痛评分（VAS）、汉密尔顿抑郁评分（HAMD）和汉密尔顿焦虑评分（HAMA）来评估疗效。结果全部疗程结束后,疗效满意3例,疗效差l例。疗效满意病人中,随访1年后复发2例。副作用为治疗期间头面部轻度疼痛1例。结论rTMS对部分慢性神经病理性疼痛安全有效．尤其是面部和肢体疼痛的病人。但其疗效不持久,可作为运动皮质电刺激的测试方法。     

Interventional neurophysiology for pain control: duration of pain relief following repetitive transcranial magnetic stimulation of the motor cortex.

The chronic electrical stimulation of a motor cortical area corresponding to a painful region of the body, by means of surgically-implanted epidural electrodes is a validated therapeutical strategy to control medication-resistant neurogenic pain. Repetitive transcranial magnetic stimulation (rTMS) permits to stimulate non-invasively and precisely the motor cortex. We applied a 20-min session of rTMS of the motor cortex at 10 Hz using a 'real' or a 'sham' coil in a series of 14 patients with intractable pain due to thalamic stroke or trigeminal neuropathy. We studied the effects of rTMS on pain level assessed on a 0-10 visual analogue scale from day 1 to day 12 following the rTMS session. A significant pain decrease was observed up to 8 days after the 'real' rTMS session. This study shows that a transient pain relief can be induced in patients suffering from chronic neurogenic pain during about the week that follows a 20-min session of 10 Hz-rTMS applied over the motor cortex.     

Pain relief induced by repetitive transcranial magnetic stimulation of precentral cortex

Chronic electrical stimulation of the precentral (motor) cortex using surgically implanted electrodes is performed to treat medication-resistant neurogenic pain. The goal of this placebo-controlled study was to obtain such antalgic effects by means of a non-invasive cortical stimulation using repetitive transcranial magnetic stimulation (rTMS). Eighteen patients with intractable neurogenic pain of various origins were included and underwent a 20 min session of either 10 Hz, 0.5 Hz or* sham rTMS over the motor cortex in a random order. A significant decrease in the mean pain level of the series was obtained only after 10 Hz rTMS. This study shows that a transient pain relief can be induced by 10 Hz rTMS of the motor cortex in some patients suffering from chronic neurogenic pain.     

The effects of motor cortex rTMS on corticospinal descending activity

Repetitive transcranial magnetic stimulation (rTMS) of the human motor cortex can produce long-lasting changes in the excitability of the motor cortex to single pulse transcranial magnetic stimulation (TMS). rTMS may increase or decrease motor cortical excitability depending critically on the characteristics of the stimulation protocol. However, it is still poorly defined which mechanisms and central motor circuits contribute to these rTMS induced long-lasting excitability changes. We have had the opportunity to perform a series of direct recordings of the corticospinal volley evoked by single pulse TMS from the epidural space of conscious patients with chronically implanted spinal electrodes before and after several protocols of rTMS that increase or decrease brain excitability. These recordings provided insight into the physiological basis of the effects of rTMS and the specific motor cortical circuits involved.     

Chronic epidural motor cortical stimulation for movement disorders

Recent data suggest that epidural chronic motor cortical stimulation could improve movement disorders. Because the procedure is safe, it might be a valuable therapeutic option. Although the therapeutic effects of cortical stimulation still need to be assessed in controlled studies, we discuss its rationale and the possible physiological mechanisms involved. There are several factors that support the use of chronic cortical stimulation in patients with movement disorders, including the strategic position of the motor cortex, the improvement induced in some motor disorders by cortical lesions, the functional imaging findings documenting widespread cortical dysfunction in movement disorders, and the improvement induced in patients with Parkinson's disease and dystonia by repetitive transcranial magnetic stimulation. Among the possible mechanisms of action of chronic motor cortex stimulation, besides modifications in the motor cortex itself, the most probable is that of eliciting distant bilateral changes through efferents and afferents that bilaterally connect the motor cortex with other cortical and subcortical structures.     

Transcranial magnetic stimulation for pain control. Double-blind study of different frequencies against placebo, and correlation with motor cortex stimulation efficacy.

OBJECTIVE: To assess, using a double-blind procedure, the pain-relieving effects of rTMS against placebo, and their predictive value regarding the efficacy of implanted motor cortex stimulation (MCS). METHODS: Three randomised, double-blinded, 25 min sessions of focal rTMS (1 Hz, 20 Hz and sham) were performed in 12 patients, at 2 weeks intervals. Effects on pain were estimated from daily scores across 5 days before, and 6 days after each session. Analgesic effects were correlated with those of subsequent implanted motor cortex stimulation (MCS). RESULTS: Immediately after the stimulating session, pain scores were similarly decreased by all rTMS modalities. Conversely, during the following week, 1 Hz stimulation provided significantly less analgesia than 20 Hz and placebo, and was pro-algesic in some patients. Placebo and 20 Hz rTMS were effective on different patients, and only 20 Hz rTMS predicted the efficacy of subsequent MCS, with no false positives. CONCLUSIONS: While 1Hz rTMS should not be used with analgesic purposes, high-frequency rTMS may become useful to select candidates for MCS. Placebo effects are powerful and should be controlled for. Immediate results after a single rTMS session are misleading. SIGNIFICANCE: Defining rTMS parameters is a crucial step before proposing rTMS as predictive test of SCM efficacy in clinical practice.     

Repetitive transcranial magnetic stimulation for the treatment of chronic pain - a pilot study

Invasive electrical stimulation of the motor cortex has been reported to be of therapeutic value in pain control. We were interested whether noninvasive repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex might also act beneficially. Twelve patients with therapy-resistant chronic pain syndromes (mean age 51.3 +/- 12.6, 6 males) were included in a pilot study. They were treated with rTMS of the corresponding motor cortex area for 20 min (20 Hz, 20 x 2 s trains, intensity 80% of motor threshold) and sham stimulation (sequence-controlled cross-over design). Some of the patients (6/6) had an analgesic effect, but for the whole group, the difference between active and sham stimulation did not reach a level of significance (active rTMS: mean VAS reduction -4.0 +/- 15.6%; sham rTMS: -2.3 +/- 8.8%). Further studies using different rTMS stimulation parameters (duration and frequency of rTMS) or stimulation sites (e.g. anterior cingulate gyrus) are strongly encouraged.     

Motor cortex stimulation for Parkinson's disease and dystonia: lessons from transcranial magnetic stimulation? A review of the literature

INTRODUCTION: Over the last few years, deep brain stimulation techniques, with targets such as the subthalamic nucleus or the pallidum, have bee found to be beneficial in the treatment of Parkinson's disease and dystonia. Conversely, therapeutic strategies of cortical stimulation have not yet been validated in these diseases, although they are known to be associated with various cortical dysfunctions. Transcranial magnetic stimulation (TMS) is a valuable tool for non-invasive study of the role played by the motor cortex in the pathophysiology of movement disorders, in particular by assessing various cortical excitability determinants using single or paired pulse paradigms. In addition, repetitive TMS (rTMS) trains can be used to study the effects of transient activity changes of a targeted cortical area. BACKGROUND: Studies with TMS revealed significant motor cortex excitability changes, particularly regarding intracortical inhibitory pathways, both in Parkinson's disease and in dystonia, and these changes can be distinguished owing to the resting state or to the phases of movement preparation or execution. However, more specific correlation between electrophysiological features and clinical symptoms remains to be established. In addition, the stimulation of various cortical targets by rTMS protocols applied at low or high frequencies have induced some clear clinical effects. PERSPECTIVES: The TMS effects are and will remain applied in movement disorders to better understand the role played by the motor cortex, to assess various types of treatment and appraise the therapeutic potential of cortical stimulation. CONCLUSION: TMS provides evidence for motor cortex dysfunction in Parkinson's disease or dystonia. Moreover, rTMS results have opened new perspectives for therapeutic strategies of implanted cortical stimulation. By these both aspects, TMS techniques show their usefulness in the assessment of movement disorders.     

Repetitive transcranial magnetic stimulation to improve mood and motor function in Parkinson's disease

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that can produce lasting changes in excitability and activity in cortical regions underneath the stimulation coil (local effect), but also within functionally connected cortical or subcortical regions (remote effects). Since the clinical presentation of Parkinson's disease (PD) is related to abnormal neuronal activity within the basal ganglia and cortical regions, including the primary motor cortex, the premotor cortex and the prefrontal cortex, several studies have used rTMS to improve brain function in PD. Here, we review the studies that have investigated the possible therapeutic effects of rTMS on mood and motor function in PD patients. We highlight some methodological inconsistencies and problems, including the difficulty to define the most effective protocol for rTMS or to establish an appropriate placebo condition. We finally propose future directions of research that may help to improve the therapeutic efficacy of rTMS in PD.     

Motor cortical excitability in depressive patients after electroconvulsive therapy and repetitive transcranial magnetic stimulation

Electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex are brain stimulation techniques that are used as therapeutic interventions in major depression. However, the exact therapeutic mode of action needs further clarification. In this case report, we describe the impact of these stimulation techniques on motor cortical excitability, as revealed by transcranial magnetic stimulation-elicited motor-evoked potentials in 2 patients who received consecutively both rTMS and ECT. Both patients showed a decrease in motor cortical excitability after response to antidepressant brain stimulation, whereas parameters of motor cortical excitability remained unchanged after the first non-successful intervention. These results suggest that both ECT and rTMS may have an impact on parameters of motor cortical neuronal excitability. Furthermore, measurement of motor cortical excitability may be a useful tool for investigating and monitoring inhibitory brain effects of different antidepressant stimulation techniques.     

The effect of repetitive transcranial magnetic stimulation on dystonia: a clinical and pathophysiological approach

Dystonia is characterized by sustained muscle contraction, which frequently causes repetitive, twisting movements or abnormal posture. The precise pathophysiological mechanisms of dystonia are still unknown. Several studies did demonstrate that, although motor cortex hyperexcitability appears to be responsible for abnormal co-contraction and overflow to adjacent muscles, plasticity mechanisms and integrative sensorimotor processing are also likely to be involved in this condition. Current dystonia treatments are based on oral medication, injection of botulinum toxin and, in a low proportion of cases, bi-pallidal deep brain stimulation. However, treatment outcome is generally disappointing. A few researchers have reported the application of repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex or the premotor cortex, with the goal of decreasing motor cortex hyperexcitability. This article reviews all studies using this technique in dystonia and discusses rTMS therapeutic impact and its possible mechanisms of action in this indication. Currently, the premotor cortex seems to be the best target for rTMS in dystonia. Rather than merely reducing the hyperexcitability of the primary motor cortex, this technique's clinical benefit seems to result from modifications in plasticity and restoration of sensorimotor integration. The corollary technique for chronic rTMS is electrical cortical stimulation. Even though this new therapeutic tool may have therapeutic promise, more studies are required to confirm it. In particular, we need to broaden our knowledge of rTMS impact on the various forms of dystonia and to optimize target localization.     

Theta burst stimulation of the motor cortex reduces laser-evoked pain perception

Repetitive transcranial magnetic stimulation over the primary motor cortex (M1) was recently introduced to modulate pain perception. The aim of this double-blind cross-over study was to investigate the effect of a modified rTMS paradigm, called cTBS on experimentally induced laser-evoked pain applied over the left M1. cTBS inhibits the cortical excitability of the M1 for approximately 1 h. Subjective pain was measured using the verbal analogue scale prior to, immediately after and 30 min post-stimulation. cTBS, and not the sham stimulation resulted in a significant decrease in pain perception on both hands, accentuated on the right hand. Further studies are needed using motor cortex TBS in chronic pain to pave the way towards a therapeutic tool.     

Crossed inhibition of sensory cortex by 0.3 Hz transcranial magnetic stimulation of motor cortex.

Low-frequency repetitive transcranial magnetic stimulation (rTMS) of motor cortex causes persistent inhibitory effects in the targeted area. rTMS of motor cortex impairs sensory perception and results in a persistent change in cortical function at remote sites. The ability of rTMS to induce sustained changes in cortical function has led to studies testing its therapeutic efficacy in neurologic disorders, including epilepsy. Studies on the effect of low-frequency rTMS of motor cortex on the contralateral motor cortex have provided evidence for both inhibitory and excitatory changes. This study was designed to determine the effect of low-frequency rTMS of the right motor cortex on the contralateral sensory cortex. Before and after 0.3-Hz rTMS of right motor cortex, perception of ipsilateral threshold of cutaneous stimuli was assessed and somatosensory evoked potentials (SEPs) recorded after stimulation of the right thumb in eight normal subjects. In a control group of six subjects, sensory responses were assessed after rTMS anterior to the right motor cortex. After rTMS of motor cortex, detection of threshold sensory stimuli decreased by more than 50% compared with pre-rTMS (P < 0.05). The change in sensory perception lasted at least 30 minutes. No change was detected in the control group. Amplitude of the N20-P25 waveform of the SEP decreased from a mean of 0.84 muV before rTMS to 0.54 muV immediately after rTMS of motor cortex (P < 0.05). 0.3 Hz rTMS of motor cortex inhibits the contralateral sensory cortex.