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.     

Descending volleys generated by efficacious epidural motor cortex stimulation in patients with chronic neuropathic pain

Epidural motor cortex stimulation (EMCS) is a therapeutic option for chronic, drug-resistant neuropathic pain, but its mechanisms of action remain poorly understood. In two patients with refractory hand pain successfully treated by EMCS, the presence of implanted epidural cervical electrodes for spinal cord stimulation permitted to study the descending volleys generated by EMCS in order to better appraise the neural circuits involved in EMCS effects. Direct and indirect volleys (D- and I-waves) were produced depending on electrode polarity and montage and stimulus intensity. At low-intensity, anodal monopolar EMCS generated D-waves, suggesting direct activation of corticospinal fibers, whereas cathodal EMCS generated I2-waves, suggesting transsynaptic activation of corticospinal tract. The bipolar electrode configuration used in chronic EMCS to produce maximal pain relief generated mostly I3-waves. This result suggests that EMCS induces analgesia by activating top–down controls originating from intracortical horizontal fibers or interneurons but not by stimulating directly the pyramidal tract. The descending volleys elicited by bipolar EMCS are close to those elicited by transcranial magnetic stimulation using a coil with posteroanterior orientation. Different pathways are activated by EMCS according to stimulus intensity and electrode montage and polarity. Special attention should be paid to these parameters when programming EMCS for pain treatment.     

Paired Acute Invasive/Non-invasive Stimulation (PAINS) study: A phase I/II randomized,sham-controlled crossover trial in chronic neuropathic pain

BackgroundDorsal root ganglion (DRG) stimulation, an invasive method of neuromodulation, and transcranial direct current stimulation (tDCS), a non-invasive method of altering cortical excitability, have both proven effective in relieving chronic pain.ObjectiveWe employed a randomized, sham-controlled crossover study design to investigate whether single-session tDCS would have an additive therapeutic effect alongside DRG stimulation (DRGS) in the treatment of chronic pain.MethodsSixteen neuropathic pain patients who were previously implanted with DRG stimulators were recruited. Baseline pain scores were established with DRGS-OFF. Pain scores were then recorded with DRGS-ON, after paired sham tDCS stimulation, and after paired active anodal tDCS (a-tDCS) stimulation. For active tDCS, patients were randomized to ‘MEG (magnetoencephalography) localized’ tDCS or contralateral motor cortex (M1) tDCS for 30 min. EEG recordings and evaluations of tDCS adverse effects were also collected.ResultsAll participants reported the interventions to be tolerable with no significant adverse effects during the session. Paired DRGS/active tDCS resulted in a significant reduction in pain scores compared to paired DRGS-ON/sham tDCS or DRGS alone. There was no difference in the additive effect of M1 vs. MEG-localized tDCS. Significant augmentation of beta activity was observed between DRGS-OFF and DRGS-ON conditions, as well as between paired DRGS-ON/sham tDCS and paired DRGS-ON/active tDCS.ConclusionOur results indicate that a single session of tDCS alongside DRGS is safe and can significantly reduce pain acutely in neuropathic pain patients. Paired invasive/non-invasive neuromodulation is a promising new treatment strategy for pain management and should be evaluated further to assess long-term benefits.     

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。     

Revisiting interhemispheric imbalance in chronic stroke: A tDCS study

Objective

Chronic stroke patients with moderate-severe motor impairment may have an increased reliance on contralesional vs ipsilesional motor areas to control the paretic arm. We hypothesised that increasing contralesional excitability with anodal transcranial direct current stimulation (a-tDCS) would benefit motor performance in patients with moderate-severe impairment.

Stimulation cérébrale non invasive dans le traitement du trouble déficit de l’attention avec ou sans hyperactivité : une revue de la littérature

Objectives

The aim of this review is to summarize the available data in the literature about the therapeutic applications of transcranial magnetic stimulation and transcranial direct current stimulation in attention-deficit hyperactivity disorder (ADHD).

Does anodal transcranial direct current stimulation modulate sensory perception and pain? A meta-analysis study

ObjectiveThe primary aim of this systematic review was to evaluate the effects of anodal transcranial direct current stimulation (a-tDCS) on sensory (STh) and pain thresholds (PTh) in healthy individuals and pain levels (PL) in patients with chronic pain.MethodsElectronic databases were searched for a-tDCS studies. Methodological quality was examined using the PEDro and Downs and Black (D&B) assessment tools.Resultsa-tDCS of the primary motor cortex (M1) increases both STh (P < 0.005, with the effect size of 22.19%) and PTh (P < 0.001, effect size of 19.28%). In addition, STh was increased by a-tDCS of the primary sensory cortex (S1) (P < 0.05 with an effect size of 4.34). Likewise, PL decreased significantly in the patient group following application of a-tDCS to both the M1 and dorsolateral prefrontal cortex (DLPFC). The average decrease in visual analogue score was 14.9% and 19.3% after applying a-tDCS on the M1 and DLPFC. Moreover, meta-analysis showed that in all subgroups (except a-tDCS of S1) active a-tDCS and sham stimulation produced significant differences.ConclusionsThis review provides evidence for the effectiveness of a-tDCS in increasing STh/PTh in healthy group and decreasing PL in patients. However, due to small sample sizes in the included studies, our results should be interpreted cautiously. Given the level of blinding did not considered in inclusion criteria, the result of current study should be interpreted with caution.SignificanceSite of stimulation should have a differential effect over pain relief.     

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.     

Dual-hemisphere transcranial direct current stimulation improves performance in a tactile spatial discrimination task

ObjectiveThe aim of this study was to test the hypothesis that dual-hemisphere transcranial direct current stimulation (tDCS) over the primary somatosensory cortex (S1) could improve performance in a tactile spatial discriminative task, compared with uni-hemisphere or sham tDCS.MethodsNine healthy adults participated in this double-blind, sham-controlled, and cross-over design study. The performance in a grating orientation task (GOT) in the right index finger was evaluated before, during, immediately after and 30 min after the dual-hemisphere, uni-hemisphere (1 mA, 20 min), or sham tDCS (1 mA, 30 s) over S1. In the dual-hemisphere and sham conditions, anodal tDCS was applied over the left S1, and cathodal tDCS was applied over the right S1. In the uni-hemisphere condition, anodal tDCS was applied over the left S1, and cathodal tDCS was applied over the contralateral supraorbital front.ResultsThe percentage of correct responses on the GOT during dual-hemisphere tDCS was significantly higher than that in the uni-hemisphere or sham tDCS conditions when the grating width was set to 0.75 mm (all p < 0.05).ConclusionsDual-hemisphere tDCS over S1 improved performance in a tactile spatial discrimination task in healthy volunteers.SignificanceDual-hemisphere tDCS may be a useful strategy to improve sensory function in patients with sensory dysfunctions.     

The effect of transcranial direct current stimulation on motor sequence learning and upper limb function after stroke

Objective

To assess the impact of electrode arrangement on the efficacy of tDCS in stroke survivors and determine whether changes in transcallosal inhibition (TCI) underlie improvements.

Low-frequency repetitive transcranial magnetic stimulation for dyskinesia and motor performance in Parkinson’s disease

Dyskinesias are one of the most frequent and disabling complications of the long-term treatment of Parkinson’s disease (PD). Although the cause is not completely understood, it appears that an imbalance between excitatory and inhibitory inputs from the basal ganglia to the motor cortex leads to overactivation of motor and premotor areas. Overactivation of the supplementary motor area (SMA) has been observed in neuroimaging studies in dyskinetic PD patients. We investigated the effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) of the SMA on levodopa-induced dyskinesias (LID) and motor performance in PD. We tested whether longer duration (10 days) and higher number of total pulses (1800 pulses) would enhance the beneficial effect. Seventeen dyskinetic PD patients were randomly assigned to real rTMS or sham (placebo) rTMS, and 1 Hz rTMS or sham rTMS was applied over the SMA for 10 consecutive days. Patients were assessed at baseline and 1 day after the last rTMS with a levodopa challenge test, and video recordings were taken. Dyskinesias and motor performance were rated off-line by two blinded raters using video recordings. After 10 days of treatment with rTMS, we observed that 1 Hz rTMS delivered over the SMA had decreased LID lasting for 24 hours without a change in motor performance, whereas sham rTMS induced no significant change in dyskinesia scores. These results support a possible therapeutic effect of low-frequency rTMS in LID. However, in order to suggest rTMS as an effective treatment, long-term observations and further investigations with a larger patient population are essential.     

Posterior-superior insular deep transcranial magnetic stimulation alleviates peripheral neuropathic pain — A pilot double-blind,randomized cross-over study

ObjectivesPeripheral neuropathic pain (pNeP) is prevalent, and current treatments, including drugs and motor cortex repetitive transcranial magnetic stimulation (rTMS) leave a substantial proportion of patients with suboptimal pain relief.MethodsWe explored the intensity and short-term duration of the analgesic effects produced in pNeP patients by 5 days of neuronavigated deep rTMS targeting the posterior superior insula (PSI) with a double-cone coil in a sham-controlled randomized cross-over trial.ResultsThirty-one pNeP patients received induction series of five active or sham consecutive sessions of daily deep-rTMS to the PSI in a randomized sequence, with a washout period of at least 21 days between series. The primary outcome [number of responders (>50% pain intensity reduction from baseline in a numerical rating scale ranging from 0 to 10)] was significantly higher after real (58.1%) compared to sham (19.4%) stimulation (p = 0.002). The number needed to treat was 2.6, and the effect size was 0.97 [95% CI (0.6; 1.3)]. One week after the 5th stimulation day, pain scores were no longer different between groups, and no difference in neuropathic pain characteristics and interference with daily living were present. No major side effects occurred, and milder adverse events (i.e., short-lived headaches after stimulation) were reported in both groups. Blinding was effective, and analgesic effects were not affected by sequence of the stimulation series (active-first or sham-first), age, sex or pain duration of participants.DiscussionPSI deep-rTMS was safe in refractory pNeP and was able to provide significant pain intensity reduction after a five-day induction series of treatments. Post-hoc assessment of neuronavigation targeting confirmed deep-rTMS was delivered within the boundaries of the PSI in all participants.ConclusionPSI deep-rTMS provided significant pain relief during 5-day induction sessions compared to sham stimulation.     

Efectos de la estimulación transcraneal por corriente directa y de la estimulación magnética transcraneal en pacientes con fibromialgia. Revisión sistemática

IntroductionFibromyalgia syndrome (FM) is a chronic pathology characterized by widespread pain commonly associated with psychological distress affecting quality of life. In recent years, transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS) have been investigated to treat chronic pain. The aim of the current review is to determine the effects of tDCS and TMS on the main symptoms of patients with FM.DevelopmentA systematic review based on PRISMA guidelines was carried out. The search strategy was performed in Medline, Scopus, PEDro and Cochrane Library. Randomized controlled trials based on the effects of tDCS and TMS on pain, pressure pain threshold, fatigue, anxiety and depression, catastrophizing and quality of life in patients with FM were analysed. Fourteen studies were included.ConclusionsThe application of tDCS to the motor cortex is the only intervention shown to decrease pain in the short and medium-term in patients with FM. The application of both interventions showed improvements in pressure pain threshold, catastrophizing and quality of life when applied to the motor cortex, and in fatigue when applied to the dorsolateral prefrontal cortex. The effects of these interventions on anxiety and depression are unclear.     

Transcranial direct current stimulation during treadmill training in children with cerebral palsy: A randomized controlled double-blind clinical trial

Impaired gait constitutes an important functional limitation in children with cerebral palsy (CP). Treadmill training has achieved encouraging results regarding improvements in the gait pattern of this population. Moreover, transcranial direct current stimulation (tDCS) is believed to potentiate the results achieved during the motor rehabilitation process. The aim of the present study was to determine the effect of the administration of tDCS during treadmill training on the gait pattern of children with spastic diparetic CP. A double-blind randomized controlled trial was carried out involving 24 children with CP allocated to either an experimental group (active anodal tDCS [1 mA] over the primary motor cortex of the dominant hemisphere) or control group (placebo tDCS) during ten 20-min sessions of treadmill training. The experimental group exhibited improvements in temporal functional mobility, gait variables (spatiotemporal and kinematics variables). The results were maintained one month after the end of the intervention. There was a significant change in corticospinal excitability as compared to control group. In the present study, the administration of tDCS during treadmill training potentiated the effects of motor training in children with spastic diparetic CP.     

Modulation of motor cortex excitability by paired peripheral and transcranial magnetic stimulation

Objective

Repetitive application of peripheral electrical stimuli paired with transcranial magnetic stimulation (rTMS) of M1 cortex at low frequency, known as paired associative stimulation (PAS), is an effective method to induce motor cortex plasticity in humans. Here we investigated the effects of repetitive peripheral magnetic stimulation (rPMS) combined with low frequency rTMS (‘magnetic-PAS’) on intracortical and corticospinal excitability and whether those changes were widespread or circumscribed to the cortical area controlling the stimulated muscle.

The use of repetitive transcranial magnetic stimulation (rTMS) in chronic neuropathic pain.

Chronic motor cortex stimulation using implanted epidural stimulation was proposed to treat chronic, drug-resistant neuropathic pain. Various studies showed that repetitive transcranial magnetic stimulation (rTMS) applied over the motor cortex could also relieve neuropathic pain, at least partially and transiently. Controlled rTMS studies with other cortical targets, such as the dorsolateral prefrontal cortex, are in waiting. The mechanisms of action of rTMS on chronic pain are mostly unknown. The changes induced by rTMS in neural activities may occur at the stimulated cortical site as well as in remote structures along functional anatomical connections. Compared to chronic implanted procedure, the main limitation of rTMS application is the short duration of clinical effects. Repeated daily rTMS sessions have proved some efficacy to induce long-lasting pain relief that could have therapeutic potential. However, rTMS-induced analgesia varies with the site and parameters of stimulation, in particular the stimulus rate. The efficacious rTMS parameters could differ from those used in chronic epidural stimulation. Differences in the pattern of the current fields respectively induced in the brain by these two techniques might explain this finding. Actually, stimulation parameters remain to be optimised and clinical efficacy to be confirmed by multicentre randomised trials, before considering rTMS as therapeutic tool for patients with chronic pain in neurological practice.     

Non-invasive brain stimulation (rTMS and tDCS) in patients with aphasia: Mode of action at the cellular level

A high proportion of patients who have suffered a stroke also suffer from aphasia. Approximately half of those affected will remain in this state despite intensive language therapy. Non-invasive brain stimulation allows us to directly and focally stimulate areas of the brain. Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), methods used in the treatment of aphasia, are based on an imbalance of mutual interhemispheric inhibition. In open and sham-controlled studies, a low-frequency, 1 Hz stimulation of the non-lesioned hemisphere (the homologue of Broca's area) for a week or more significantly improved spontaneous speech and anomia in patients with non-fluent aphasia. These positive outcomes from rTMS stimulation developed slowly, often over months following treatment, and persisted. Effects of intermittent theta burst stimulation (iTBS) developed faster than the low-frequency stimulation, and high-activity enhancement was detected in the left hemisphere after the stimulation of Broca's region. Both types of tDCS stimulation resulted in improved comprehension and reduced anomia, their primary modes of action are distinct, however, both share a common site of action with regard to the balance that occurs between inhibitory and excitatory neurotransmitters (synaptic and non-synaptic). Both types of non-invasive stimulation prepare the lesioned brain for better outcome.     

Testing the limits: Investigating the effect of tDCS dose on working memory enhancement in healthy controls

Transcranial Direct Current Stimulation (tDCS) is a non-invasive form of brain stimulation which has been shown to induce changes in brain activity and subsequent functioning. In particular, there is a rapidly growing evidence base showing that anodal tDCS applied to the left prefrontal cortex (PFC) is able to enhance aspects of cognitive functioning, in particular working memory (WM). This has led to both excitement and concerns regarding the possibility of ‘electrodoping’ in order to greatly improve one's cognitive performance. We investigated the behavioural and neurophysiological effects of increasing the current (or ‘dose’) of tDCS on the degree of WM improvement in healthy controls. Single sessions of 1 mA, 2 mA and sham anodal tDCS to the left PFC were undertaken over a period of three weeks. Participants underwent a WM task at three time points post-stimulation (0, 20 and 40 min) with concurrent electrophysiological (EEG) recordings. Our results showed that while active tDCS can enhance behavioural performance, with neurophysiological findings indicating improve efficiency of cognitive processing; we showed that 1 mA produced the most significant effects. These findings are somewhat unexpected as tDCS dose effects in cognitive enhancement have been shown previously in patient populations. Our results provide valuable information regarding the potential limits of tDCS induced cognitive enhancement in healthy controls, as well as providing additional insights into the possible mechanisms of action of tDCS.     

Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS)

A group of European experts was commissioned to establish guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS) from evidence published up until March 2014, regarding pain, movement disorders, stroke, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, consciousness disorders, tinnitus, depression, anxiety disorders, obsessive-compulsive disorder, schizophrenia, craving/addiction, and conversion. Despite unavoidable inhomogeneities, there is a sufficient body of evidence to accept with level A (definite efficacy) the analgesic effect of high-frequency (HF) rTMS of the primary motor cortex (M1) contralateral to the pain and the antidepressant effect of HF-rTMS of the left dorsolateral prefrontal cortex (DLPFC). A Level B recommendation (probable efficacy) is proposed for the antidepressant effect of low-frequency (LF) rTMS of the right DLPFC, HF-rTMS of the left DLPFC for the negative symptoms of schizophrenia, and LF-rTMS of contralesional M1 in chronic motor stroke. The effects of rTMS in a number of indications reach level C (possible efficacy), including LF-rTMS of the left temporoparietal cortex in tinnitus and auditory hallucinations. It remains to determine how to optimize rTMS protocols and techniques to give them relevance in routine clinical practice. In addition, professionals carrying out rTMS protocols should undergo rigorous training to ensure the quality of the technical realization, guarantee the proper care of patients, and maximize the chances of success. Under these conditions, the therapeutic use of rTMS should be able to develop in the coming years.     

Reduced plastic brain responses to repetitive transcranial magnetic stimulation in severe obstructive sleep apnea syndrome

ObjectivesAbnormalities in cortical excitability have been proposed to underlie the pathophysiology of various neurocognitive manifestations of obstructive sleep apnea syndrome (OSAS). Transcranial magnetic stimulation (TMS) provides a noninvasive method for study and modulation of cortical excitability in the human brain, and repetitive TMS (rTMS) has been proven useful for neurophysiologic investigation in various neurologic conditions. We aimed to investigate cortical excitability in patients with OSAS during wakefulness and to determine if rTMS would change the abnormal excitability patterns.MethodsMeasures of motor cortical and corticospinal excitability (resting motor threshold [RMT], motor-evoked potential [MEP] amplitude, and cortical silent period [CSP]) were taken before and after a session of 10-Hz rTMS applied to the motor cortex in 13 individuals with untreated severe OSAS (apnea–hypopnea index [AHI] > 30) and 12 age- and sex-matched healthy controls (HC).ResultsOSAS subjects had a significantly higher RMT (P < .003) and a longer CSP duration (P < .002) compared to HC. No difference was observed between MEP values of OSAS subjects and HC (P > .05). In response to rTMS, the HC group had a significant increase in CSP and MEP values from baseline, which were absent in OSAS subjects.ConclusionsIndividuals with OSAS demonstrated increased motor cortex inhibition, which did not respond to 10-Hz rTMS. As rTMS-induced changes in MEP and CSP involve a separate neurotransmitter system (N-methyl-d-aspartate [NMDA] and gamma-aminobutyric acid [GABA], respectively), these findings suggest a widespread alteration in cortical neurophysiology in severe OSAS subjects that requires clarification with further exploration.